Indole-based melatonin analogues: Synthetic approaches and biological activity

Journal Pre-proof Indole-based melatonin analogues: Synthetic approaches and biological activity Su-Yan Wang, Xin-Chi Shi, Pedro Laborda PII:

S0223-5234(19)30999-7

DOI:

https://doi.org/10.1016/j.ejmech.2019.111847

Reference:

EJMECH 111847

To appear in:

European Journal of Medicinal Chemistry

Received Date: 29 August 2019 Revised Date:

1 November 2019

Accepted Date: 1 November 2019

Please cite this article as: S.-Y. Wang, X.-C. Shi, P. Laborda, Indole-based melatonin analogues: Synthetic approaches and biological activity, European Journal of Medicinal Chemistry (2019), doi: https://doi.org/10.1016/j.ejmech.2019.111847. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Masson SAS.

Graphical Abstract

Indole-based

melatonin

analogues:

Synthetic

approaches

and

biological activity Su-Yan Wang, Xin-Chi Shi, Pedro Laborda* School of Life Sciences, Nantong University, Nantong 226019, People’s Republic of China. *Corresponding author: Prof. Pedro Laborda; email: [email protected]

This review covers the synthetic approaches to indole-based melatonin analogues and their diverse pharmacological properties. Structure-activity relationships are discussed to provide an insight for further rational designs of new melatoninergic drugs.

1

Indole-based

melatonin

2

biological activity

analogues:

Synthetic

approaches

and

3 4

Su-Yan Wang, Xin-Chi Shi, Pedro Laborda*

5

School of Life Sciences, Nantong University, Nantong 226019, People’s Republic of

6

China.

7

*Corresponding author: Prof. Pedro Laborda; email: [email protected]

8 9

Abstract

10

Melatonin is a natural hormone primarily released by the pineal gland that regulates

11

the sleep-wake cycles. The diverse biological applications of melatonin, together with

12

the need to develop new melatoninergic ligands, have stimulated the preparation of a

13

wide range of melatonin derivatives. Here, all the synthetic approaches to indole-based

14

melatonin analogues as well as their biological applications are reviewed. The

15

modifications which have been performed on the melatonin´s indole ring and the effects

16

of these modifications on the biological activities have been analysed, detailing the

17

binding affinity of the derivatives for melatonin receptors.

18 19

Key-words: Melatonin analogues; melatoninergic ligands; melatonin receptors;

20

chemical synthesis; derivatization.

21

1

22

1. Introduction

23

Melatonin (N-acetyl-5-methoxytryptamine, 1) is ubiquitous throughout the plant and

24

animal kingdoms and is the hormone of the pineal gland in mammals, including humans

25

[1,2]. Melatonin is biosynthetized from tryptophan via a simple 4-step pathway [3-5].

26

Tryptophan 5-hydroxylase-catalyzed hydroxylation at position 5 of the indole ring and

27

subsequent decarboxylation allows the formation of serotonin. Then, serotonin is N-

28

acetylated and transformed into melatonin via methylation of the hydroxy group.

29

Previous studies have shown that melatonin has a variety of physiological effects, such

30

as retinal [6], anti-inflammatory [7], antibacterial [8,9], antioxidant [10,11], antitumor

31

[12], pain modulatory [13], cardiovascular [14], strokeprotective [15], neuroprotective

32

[16] and liver injury protective properties [17], treating chronic kidney disease [18], or

33

affecting offspring metabolism [19]. In humans, it has been demonstrated that melatonin

34

has a variety of clinical applications as a supplement to combat the delayed sleep phase

35

syndrome, jet lag and seasonal disorders, and it has been regulated as a hypnotic agent

36

for the treatment of insomnia [20,21]. The functions of melatonin are activated after

37

melatonin binds to G-protein-coupled receptors (GPCR), which activate a few

38

signalling pathways as a cascade effect [22]. Until date, 2 different types of melatonin

39

receptors have been described in mammals: MT1 and MT2. Both receptors are located in

40

many regions of the body in the central nervous system and peripheral tissues [23]. X-

41

ray studies have recently revealed that MT1 binding site is extremely compact, and

42

ligands interact with MT1 mainly by strong aromatic stacking with Phe179 [24].

43

Comparison of the structures of MT2 and MT1 indicated that, despite conservation of

44

the orthosteric ligand-binding site residues, there are notable conformational variations

45

between both melatonin receptor subtypes [25]. Melatonin can also bind to a co-

46

substrate binding site (MT3 binding site), which was showed to be quinone reductase-2

2

47

[26]. MT3 can be found not only in mammals but also in non-mammals [27]. Previous

48

studies have demonstrated that MT3 does not carry the same relevance to processes

49

related to sleep promotion as MT1 and MT2 receptors [22,28,29]. Further, there is a high

50

controversy about MT3 role since other compounds, such as resveratrol and chloroquine,

51

can also bind and modulate the functions of MT3 [30].

52

Some melatoninergic ligands showed non-selective binding affinity for MT1 and MT2,

53

whereas other ligands have demonstrated selective affinity at only one melatonin

54

receptor [31-33]. Selective melatoninergic ligands are necessary to clarify the respective

55

roles of MT1 and MT2 in biological processes. Recent advances in the field indicated

56

that the MT2 receptor appears to be the most promising target for the development of

57

new antidepressants, as selective ligands of this receptor modulate antidepressant-like

58

effects [32]. MT2 receptors have also been reported to be responsible for the non-rapid

59

eye movement (NREM) sleep maintenance, which can be activated by MT2-selective

60

agonists [34]. Preliminary studies indicated that selective MT1 receptor agonists may be

61

effective drugs for the treatment of Huntington’s disease, and breast and prostate

62

cancers [32]. It has been postulated that MT1 or MT2 melatonin receptor-selective drugs

63

may improve efficacy as compared to non-selective ligands by potentiating or

64

facilitating responses mediated by the target receptor [32]. This situation has stimulated

65

the screening, development and commercialization of non-natural melatoninergic

66

ligands during last decades. Melatoninergic ligands can be classified into melatonin

67

receptor agonists and antagonists. Some melatonin derivatives have shown binding

68

affinity not only for melatonin receptors but also for serotonin receptors, 5-HT, which

69

are involved in depressive disorders [35].

70

Melatonin consists of an indole core bearing an N-acetyl-2-aminoethyl chain at C3

71

and a methoxy group linked to C5 (Scheme 1). The derivatization of melatonin in order

3

72

to create new melatoninergic ligands has involved important structural modifications

73

[31,36]. Here, we are reviewing all synthetic approaches to indole-based melatonin

74

analogues, indicating all modifications on the structure of melatonin and how these

75

modifications have influenced the biological activity. This review is divided into 4

76

different sections: synthesis of melatonin, modifications on the melatonin structure,

77

nitrogenated indoles and polycyclic derivatives.

78 79

2. Synthesis of melatonin

80

Since melatonin (1) was discovered by Lerner et al. in 1958 [37], a number of

81

synthetic approaches have been attempted for the production of this hormone. All

82

synthetic routes can be divided into 4 different retrosynthetic analyses (Scheme 1)

83

[38,39]. A number of research groups have reported the construction of the indole ring

84

by Fischer-indole reaction using p-methoxyphenylhydrazine (2) as the starting material

85

(Scheme 1, a), whereas other synthetic approaches are based on the formation of the

86

bond between C3 and C3a by radical addition (Scheme 1, b). A synthetic approach that

87

involved the formation and aromatization of the indole core from monoprotected 1,4-

88

cyclohexanedione was described by Revial et al. (Scheme 1, c) [40]. Mentioned starting

89

material was aminated with benzyl amine, and the resulting imine was reacted with

90

maleic anhydride to form the indole ring. An alternative synthetic route to melatonin

91

consists of the use of C3 or C5 substituted indole structures as the starting material

92

(Scheme 1, d).

93

4

94 95

Scheme 1. Retrosynthetic analysis of the different synthetic approaches to melatonin.

96 97

The first synthesis of 1 was published by Szmuszkovicz et al. in 1960 (Scheme 2A)

98

[41]. This synthetic approach consisted in the Fischer-indole reaction between 2 and 4-

99

aminobutanal diethylacetal (3) using ZnCl2 at 170ºC to provide 5-methoxytryptamine in

100

31% yield. Then, 5-methoxytryptamine was acetylated in the presence of acetic

101

anhydride to give 1. Since then, a number of similar synthetic approaches based on

102

Fischer-indole reactions have been reported. The main objective of the new approaches

103

has focused on optimizing the yield, simplifying the Fischer-indole reaction conditions

104

or preparing 1 in one-step. In 1961, Keglevic et al. described the Fischer-indole reaction

105

between 2 and N-acetyl-4-aminobutanal diethylacetal (4) in water-acetic acid 3:1 at

106

80ºC to obtain directly 1 in 26% yield (Scheme 2B) [42]. Later, the same synthetic

107

approach was reported by Hwang and Lee but using a mixture of acetic

108

acid/ethanol/water as the solvent at 40ºC [43]. Verspui et al. reported the production of

109

1 by Fischer-indole reaction between 2 and 4-acetamidobutanal 6 (Scheme 2C) [44]. 6 5

110

was afforded via acetylation of allyamine (5) to provide N-allylacetamide, which was

111

subsequently hydroformylated in the presence of H2-CO (1:1) and an Rh-based catalyst.

112

The reaction conditions for the production of 6 were screened using different solvent

113

and catalysts, obtaining the best results, 97.9% yield, after employing water and Rh-

114

tppts. The synthesis of melatonin was performed in one-pot from 5 and 2 to achieve

115

melatonin in 44% yield.

116

117 118

Scheme 2. Synthetic approaches based on Fischer-indole reaction reported by A

119

Szmuszkovicz et al. [41], B Keglevic et al. [42], C Verspui et al. [44], D Marais et al.

120

[45] and E Gore et al. [46]. All synthetic approaches shown in the scheme provided

121

melatonin (1) using p-methoxyphenylhydrazine (2) as the starting material.

122

6

123

A similar synthetic strategy to 1 based on Fischer-indole reactions via coupling of the

124

2,3-dihydropyrrole 7 and 2 was reported by Marais and Holzapfel (Scheme 2D) [45].

125

Pyrrole was oxidized via treatment with sodium persulfate in the presence silver nitrate

126

and basic medium to provide 2,3-dihydropyrrole, which was N-protected with acetyl

127

chloride to give 7. Then, the Fischer reaction was performed in a mixture of acetic

128

acid/ethanol/water, obtaining 1 in 75% yield. Gore et al. described the Fischer reaction

129

between 2 and 2,3-dihydrofuran (8) in the presence of tartaric acid (TA)-dimethyl urea

130

(DMU) to provide 5-methoxytryptophol (9), which was then transformed into 1 in 80%

131

overall yield (Scheme 2E) [46].

132

Abramovitch and Shapiro reported the synthesis of 5-methoxytryptamine (18) using

133

acrylonitrile (10) and diethyl malonate (11) as the starting materials (Scheme 3A) [47].

134

10 and 11 were coupled in the presence of sodium to provide cyano compound 12,

135

which was submitted to hydrogenolysis to prepare the corresponding amine. Subsequent

136

intramolecular cyclization was carried out to give 2-oxopiperidine-3-carboxylate (13)

137

[48]. Reaction between 14 and 13 allowed the formation of 15, which was then

138

transformed into the tricyclic system 16 in the presence of polyphosphoric acid (PPA).

139

Basic hydrolysis of 16 provided the acid 17, which was submitted to decarboxylation

140

with hydrochloric acid to provide 18. Later, Misztal and Boksa described the same

141

synthetic strategy and added the acetylation of 18 to achieve 1 [49]. This synthetic

142

strategy was recently patented by Xiong and Zhao with minor modifications [50].

143

Fraschini et al. patented the Fischer reaction between acyclic derivative 19 and 14 to

144

obtain 20, which was then transformed to 1 using standard reactions (Scheme 3B) [51].

145

In this case, 1 was obtained in 34% overall yield.

146

7

147 148

Scheme 3. Synthetic approaches to melatonin (1) based on Fischer-indole reaction

149

between α-ketoesters (13 and 19) and p-methoxyphenyl diazonium chloride (14). A

150

Synthetic approach to 1 reported by Misztal and Boksa [47,49]. B Synthetic approach to

151

1 patented by Fraschini et al. [51].

152 153

Regarding the synthetic approaches that involve the formation of the indole ring by

154

radical addition, Quiclet-Sire et al. described a synthetic route to 1 using the N-

155

protected aniline 21 as the starting material (Scheme 4A) [52]. After intermolecular

156

radical addition of xanthate (22) to 21, followed by radical ring closure to the aromatic

157

ring, the indole 24 was obtained. Two different synthetic routes allowed the production

158

of 1 from 24. The first one consisted in cleaving both the ester and mesyl (Ms) groups

8

159

of 24 with 95% sulphuric acid at room temperature (r.t.) to give 25. Then, Curtius

160

rearrangement mediated by diphenylphosphoryl azide, capture of the intermediate

161

isocyanate with a 95:5 mixture of acetic acid/acetic anhydride and treatment with

162

methanolic potassium carbonate allowed the formation of 1. The second route involved

163

the hydrolysis of the ester group of 24 with conc. hydrochloric acid, followed by

164

Curtius degradation under acetylating conditions to provide 26. Final removal of the Ms

165

group and concomitant aromatization with 95% sulfuric acid allowed the formation of 1.

166

Although the second route contained one step longer, it gave a slightly better overall

167

yield (first route: 32% overall yield; second route: 34% overall yield).

168

Similarly, the synthesis of 1 was efficiently achieved by Thomson et al. in high

169

overall yield via radical-based indole synthesis using 2-iodo-4-methoxyaniline (27) as

170

the starting material (Scheme 4B) [53]. Connection of 28, and subsequent cyclization

171

with tris(trimethylsylil)silane allowed the formation of the indole 30. After cleavage of

172

the protecting groups using standard conditions, the deprotected indole was acetylated

173

in the presence of acetic anhydride to obtain 1 (39% overall yield). Although the

174

synthetic routes based on radical synthesis contains several steps, melatonin was

175

obtained in moderated-high overall yields.

176

9

177 178

Scheme 4. Synthetic approaches to melatonin (1) based on formation of the indole

179

ring using radical addition. A Synthetic approach reported by Quiclet-Sire et al. [52]. B

180

Synthetic approach reported by Thomson et al. [53].

181 182

An alternative synthetic approach was reported by Revial et al. using the

183

monoprotected 1,4-cyclohexanedione 31 as the starting material (Scheme 5) [40]. After

184

formation of the benzyl imine 32 via treatment of 31 with benzylamine, 32 was reacted

185

with maleic anhydride (33) to afford the adduct 34. Esterification of 34 led directly to

10

186

35. Aromatization of 35 was achieved in the presence of phosphoryl chloride and

187

pyridine (Py). After amidation of 36 with ammonia to give 37, amide reduction using

188

lithium aluminium hydride, benzyl deprotection and acetylation led to 1. The described

189

synthetic approach involved the formation of N1-C2 and C3-C3a bonds, as well as the

190

aromatization of the indole ring. The 8-step route allowed the production of 1 in 18%

191

overall yield.

192

193 194 195

Scheme 5. Alternative synthetic approach to melatonin (1) reported by Revial et al. using the monoprotected 1,4-cyclohexanedione 31 as the starting material [40].

196 197

The synthetic routes to 1 from indole structures can be divided into 3 different groups

198

depending on the starting material: tryptamine (39), 5-hydroxyindole (43) and 3,5-

199

disubstituted indoles. In this field, Somei et al. reported the synthesis of 1 from 39

200

(Scheme 6) [54,55]. Acetylation of 39 provided N-acetyltryptamine (40), which was

11

201

reduced with triethylsilane in trifluoroacetic acid (TFA) to afford the 2,3-

202

dihydrotryptamine 41. Oxidation of 41 using 30% hydrogen peroxide and sodium

203

tungstate dihydrate as a catalyst provided 42. The aromatic electrophilic substitution of

204

42 to give 1 was conducted in the presence of different acids. Results indicated that the

205

optimum yield, 80%, was obtained when using 20% boron trifluoride in methanol at

206

reflux. This synthetic strategy allowed the preparation of 1 in 52% overall yield.

207

Other synthetic approaches are based on the introduction of the 2-aminoethyl chain at

208

C3. In this field, Flaugh et al. reported a synthetic strategy to 1 from 5-methoxyindole

209

(43) (Scheme 7A) [56]. This was alkylated at the 3 position via reaction with

210

nitroethene, which was generated in situ by thermolyyis of nitroethyl acetate. Reduction

211

of the nitroethylated indole 44 via hydrogenation over platinum(IV) oxide, followed by

212

acetylation of the resulting tryptamine with acetic anhydride/Py completed the synthesis

213

of 1. This methodology allowed the preparation of 1 in 47% overall yield.

214

215 216 217

Scheme 6. Synthetic approach to melatonin (1) based on the introduction of the 5methoxy group reported by Somei et al. [54,55].

218 219

Amat et al. reported a similar synthetic approach, which provided 1 in 12% overall

220

yield (Scheme 7B) [57]. After N-silylation of 43 with t-butyldimethylsilyl chloride, 46 12

221

was brominated at C3 with N-bromosuccinimide (NBS) to give 47. The lithio derivative

222

48 was obtained after treatment with t-butyllithium. Then, 48 was reacted with 1-(4-

223

methylbenzenesulfonyl)aziridine in the presence trifluoroboron etherate to give 49.

224

Desilylation of 49 with tetra-n-butylammonium fluoride gave the indole 50, which was

225

N-deprotected and acetylated to obtain 1. Ates-Alagoz et al. described the synthesis of 1

226

from 43 (Scheme 7C) [58]. In this case, 43 was formylated via Vilsmeir-Haack reaction

227

to give 51. Condensation of 51 with nitromethane and subsequent reduction with

228

lithium aluminium hydride allowed the production of the amine 53, which was

229

acetylated to give 1 in 39% overall yield. Recently, Righi et al. studied the direct C3

230

reductive alkylation of N-benzyl-5-methoxyindole (54) with 55 to produce 1 (Scheme

231

7D) [59]. The reaction was carried out in 2 steps. Firstly, 54 was treated with

232

triethylsilane and 55 in TFA. Then, ammonia and sodium were added into the reaction

233

mixture, allowing the production of 1 in 51% yield.

234

13

235 236

Scheme 7. Synthetic approaches to melatonin (1) based on introduction of the C3

237

chain. A Synthetic approach reported by Flaugh et al. based on the introduction of a 2-

238

nitroethyl chain at C3 [56]. B Synthetic approach reported by Amat et al. based on the

239

lithiation at position 3 [57]. C Synthetic approach reported by Ates-Alagoz et al. based

240

on the Vilsmeir-Haack formylation at C3 [58]. D Synthetic approach reported by Righi

241

et al. based on the direct introduction of the N-acetyl-2-aminoethyl chain [59]. 14

242 243

It must be remarked that several companies patented the production of 1 from coffee

244

wax 5-hydroxytryptamides (Scheme 8) [39,60]. Three different 5-hydroxytryptamides,

245

including arachidonamide (56a), behenamide (56b) and lignoceramide (56c), were

246

found in coffee beans in approximately 0.5 to 2.5 g per Kg. 56a, 56b and 56c were

247

detected in 33:57:10 ratio. The synthesis of 1 was carried out via N-deacylation of 56a-c

248

with potassium hydroxide, and subsequent N-acetylation of the resulting amine in the

249

presence of acetic anhydride to obtain N-acetyl-5-hydroxytryptamine (58). This was

250

methylated with dimethyl sulfate to give 1.

251

252 253 254

Scheme 8. Synthetic approach to melatonin (1) from the coffee 5-hydroxytryptamides 56a-c [39,60].

255 256

3. Modifications on the melatonin structure

257

The modifications that have been performed in the melatonin structure were divided

258

into 7 different sections according to the modified position of the indole ring.

259

Derivatives with modifications on the 7 positions, including N1, C2, C3, C4, C5, C6

260

and C7, were found in the literature (Scheme 1). The modifications on N1, C2, C4, C6

261

and C7 were achieved by introduction of new substituents in mentioned positions, 15

262

whereas modifications on C3 and C5 were obtained by modification of the N-acetyl-2-

263

aminoethyl chain and methoxy group, respectively.

264 265

3.1. Modifications on N1

266

N-Substituted melatonin analogues have shown diverse biological activities, including

267

melatoninergic, antioxidant and anti-cancer. Regarding the binding affinities of N-

268

substituted melatonin analogues for melatonin receptors, derivatives bearing small

269

chains have shown interesting agonist activities, whereas the derivatives with

270

voluminous N-substitutions exhibited antagonist or partial antagonist/partial agonist

271

properties. In most occasions, the derivatization at N1 has been accompanied with

272

modifications on the C3 chain, including the replacement of the acetyl group by other

273

acyl chains or the introduction of substituents in the 2-aminoethyl chain. The synthetic

274

approaches to melatonin derivatives with substitutions at N1 can be classified into 2

275

different approaches: synthetic approaches that involve the formation of the indole ring,

276

and derivatizations of melatonin or other 3,5-disubstituted indoles.

277

Regarding the synthetic approaches that involve the formation of the indole ring,

278

Tsotinis et al. reported the synthesis of the N-methoxy melatonin derivatives 66a and

279

66b from 5-methoxy-2-nitrotoluene (59) (Scheme 9A) [61]. The key step of the

280

synthesis consisted in the formylation of 62 under modified Vilsmeier-Haack conditions

281

to the aldehyde 63 [62]. 66b showed up to 5-fold agonist potency of that of melatonin in

282

the Xenopus laevis melanophores model (66a, pEC50 = 8.10 nM; 66b, pEC50 = 10.75

283

nM; melatonin, pEC50 = 10.7 nM). This enhancement in melatoninergic activity was

284

ascribed to the presence of the methoxyl at N1, which may act synergistically to the 5-

285

methoxyl group. Later, the same group described the synthesis of N-methoxy fluoro-

286

indole melatoninergics 67, 68 and 69 (Scheme 9B) [63]. These compounds were

16

287

synthetized following a similar synthetic approach than that described for the

288

production of the N-methoxy melatonin derivatives 66a,b [61]. Interestingly, the 4-

289

fluoro indole derivatives 68 and 69 showed antagonist properties in the Xenopus laevis

290

melanophore model. In contrast, 5-fluoro substituted derivative 67 mainly showed

291

agonist activity. The different agonist/antagonist activities were attributed to the

292

position of the fluorine atom.

293

294 295

Scheme 9. Synthesis of N-methoxy melatonin derivatives 66a,b, 67, 68 and 69

296

reported by Tsotinis et al. A Synthetic approach to 66a and 66b [61]. These showed up

297

to 5-fold agonist potency of that of melatonin in the Xenopus laevis melanophore model.

298

B Fluoro-indole derivatives 67, 68 and 69 [63]. 4-Fluoro indole derivatives 68 and 69

17

299

showed antagonist properties, whereas 5-fluoro indole derivative 67 showed agonist

300

activity.

301 302

Regarding the synthetic approaches that use melatonin (1) as the starting material,

303

series of dimeric melatonin analogues by connecting 2 melatonin molecules through N1

304

spacers of 15-24 atoms were synthetized by Journé et al. (Scheme 10) [64]. N-alkylation

305

of 1 with methyl bromoacetate or ethyl 5-bromovalerate yielded 70a and 70b,

306

respectively. After ester hydrolysis using lithium hydroxide, the resulting acids 71a,b

307

were subjected to amide coupling with diamino alkanes of different chain lengths NH2-

308

(CH2)m-NH2 (m = 6-12) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

309

hydrochloride (EDC·HCl) as the coupling reagent. The binding constants of the target

310

compounds 72a-k were determined for human MT1 and MT2 receptors in competition

311

radioligand binding assays using 2-[125I]iodomelatonin. It was found that most bivalent

312

ligands showed 2-4 times higher affinity for MT2 than for MT1, demonstrating that the

313

introduction of bulky substituents at N1 increases the binding for MT2. Further,

314

bioluminescence resonance energy transfer (BRET) experiments revealed that 72b and

315

72k are among the compounds inducing the maximal BRET at MT2-homodimers and

316

MT1/MT2 heterodimes. It was observed that, in general, compounds with longer spacers,

317

with the exception of 72b, showed stronger binding affinities in comparison to

318

compounds with shorter spacers. It must be noted that all dimers showed lower binding

319

affinities in comparison to melatonin.

320

The synthesis of a number of N-substituted melatonin derivatives, including N-acyl,

321

N-succinoyl and N-glutaroyl melatonin, was described by Thoai et al. (Scheme 11A)

322

[65]. The synthetic approach consisted in the direct treatment of 1 with acyl chloride,

323

succinic anhydride or glutaric anhydride in the presence of sodium hydride in

18

324

dimethylformamide (DMF). The ability of the synthetized compounds to release

325

melatonin by self-immolation was examined using a human plasma assay. Compounds

326

73a and 73b showed the highest rate, obtaining 75 and 84% released melatonin,

327

respectively, after 4 h incubation.

328

329 330 331

Scheme 10. Synthesis of the dimeric melatonin analogues 72a-k reported by Journé et al. [64]. These derivatives showed weak binding affinities for human MT1 and MT2.

332 333

Melatonin is easily nitrosated at N1 to give N-nitrosomelatonin (74) (Scheme 11B)

334

[66]. The typical synthetic approach consists of the treatment of 1 with dinitrogen

335

trioxide at 4ºC to provide N-nitrosomelatonin [67]. Incident light or the presence of

336

ascorbate are highly effective in breaking the N–NO bond of N-nitrosomelatonin in a

337

homolytic manner to yield NO and presumably the aminyl radical of melatonin [68]. It

338

has been speculated that N-nitrosomelatonin must act as melatonin antagonist of MT1

339

and MT2 receptors and must show carcinogenic potential. It was demonstrated that N-

19

340

nitrosomelatonin can enhance photic synchronization of mammalian circadian rhythms

341

[69].

342

On the other hand, the synthesis of several N-acyl melatonin analogues with

343

antioxidant properties was successfully achieved by Ates-Alagoz et al. via treatment of

344

melatonin (1) with sodium hydride in the presence of the corresponding acyl chloride or

345

anhydride (Scheme 11C) [58]. The synthetic strategy allowed the formation of

346

melatonin derivatives bearing ethyl, n-propyl, i-propyl, p-fluorobenzyl or p-

347

chlorobenzyl chains attached to N1. Derivatives with a propanoyl chain, instead of an

348

acetyl group, in the C3 lateral chain were also studied. Antioxidant screening revealed

349

that the synthetized compounds are lipid peroxidation inhibitors. Interestingly, the

350

derivatives with ethyl/i-propyl chains at N1, (75a) and (75b), showed higher inhibitory

351

activities in comparison to melatonin (lipid peroxidation inhibition at 100 µM: 75a,

352

60%; 75b, 71%; melatonin, 30%). Similarly, Lira-Rocha et al. reported the synthesis of

353

N1-substituted melatonin analogues bearing aromatic moieties [70]. These derivatives

354

showed low binding affinity for the melatonin receptors from chicken brain membranes

355

in competition with 2-[125I]iodomelatonin (with no differentiation of MT1 and MT2

356

receptor subtypes). Later, Lozada et al. reported the nucleophilic addition of perezone, a

357

cytotoxic compound, into 1 to give the derivative 76 (Scheme 11D) [71]. The synthetic

358

approach consisted of the direct attachment of perezone into N1 in the presence of

359

Zn(AcO)2. The new derivative showed interesting cytotoxic activities against the human

360

tumor cell lines PC-3, K-562, HCT-15 and SKLU-1, achieving the inhibitory

361

concentration (IC50) values at 13.9, 8.9, 9.8 and 16.9 µM, respectively. Further, 76

362

showed stronger antioxidant activity as lipid peroxidation inhibitor in comparison to

363

melatonin.

364

20

365 366

Scheme 11. Synthetic approaches to N-substituted melatonin derivatives via direct

367

introduction into melatonin. A Synthesis of 73a,b reported by Thoai et al. [65]. 73a,b

368

were able to release 75 and 84% melatonin, respectively, by self-immolation after 4 h

369

incubation. B Synthesis of N-nitrosomelatonin (74) [66]. It was demonstrated that 74

370

can enhance photic synchronization of mammalian circadian rhythms [69]. C Synthesis

371

of 75a,b reported by Ates-Alagoz et al. [58]. 75a,b showed higher inhibitory activities

372

as lipid peroxidation inhibitors in comparison to melatonin. D Synthesis of 76 reported

373

by Lozada et al. [71]. 76 showed cytotoxic activities against human tumor cell lines. E

21

374

Synthesis of derivative 78 reported Bedini et al. [72]. 78 exhibited strong toxic effects

375

in HeLa cancer cells.

376 377

In 2019, the synthesis and biological evaluation of the hydrogen peroxide responsive

378

arylboronate hybrid 78 was reported by Bedini et al. (Scheme 11E) [72]. 78 was

379

prepared by N-carbamoylation of 1 with 4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-

380

yl)benzyl 1H-imidazole-1-carboxylate (77), which in turn was obtained by treating 4-

381

(hydroxymethyl)phenylboronic acid pinacol ester with carbonyldiimidazole (DCl). 78

382

can be activated by endogenously generated hydrogen peroxide to release 1 and 4-

383

methylenecyclohexa-2,5-dienone. After activation, 78 exhibited strong toxic effects in

384

HeLa cancer cells, without causing significant toxicity to normal NCTC-2544 cells.

385

Cytotoxicity was accompanied by depletion of cellular glutathione (GSH), probably as a

386

consequence of 4-methylenecyclohexa-2,5-dienone release, and increased ROS levels.

387

Iwaki et al. reported the introduction of monosaccharides, including ᴅ-xylose (82a), ᴅ-

388

glucose (82b), ᴅ-galactose (82c) and ᴅ-arabinose (84b), into N1 (Scheme 12) [73]. In

389

order to achieve the linkage between the sugars and melatonin (1), the C2-C3 double

390

bond in 1 was selectively reduced with triethylsilane to give the indoline 79. Then, 79

391

was linked to the O-acetylated sugars through the anomeric carbon using 2,3-dichloro-

392

5,6-dicyano-1,4-benzoquinone (DDQ) as the catalyst. Final deacetylation with sodium

393

hydroxide allowed the formation of the target structures 82a-c and 84b. It was found

394

that the corresponding N-substituted melatonines, 82a-c and 84b, showed higher

395

solubility in water in comparison to melatonin.

396

22

397 398

Scheme 12. Synthesis of melatonin derivatives with N1-attached sugars reported by

399

Iwaki et al. [73]. Synthetized melatonin derivatives showed higher solubility in

400

comparison to melatonin.

401 402

The synthesis of the N-phenethyl indoles 89-92 was described by Tsotinis et al.

403

(Scheme 13A) [74]. The synthesis was carried out using 85a,b as the starting materials.

404

These were N-alkylated with the tosylate 86 to give the cyano compounds 87a and 87b.

405

After reduction of 87a,b with lithium aluminium hydride in diethylether/benzene to

406

provide the amines 88a,b, 89a,b were obtained via acylation of 88a,b. The same

407

synthetic strategy was also used for the preparation of analogues 90-92, which contain

408

methyl groups attached into the 2-aminoethyl chain. The affinity of the synthetized

409

derivatives towards melatonin receptors was evaluated using the Xenopus laevis

410

melanophore model. The derivatives 89a showed antagonist activity, whereas the

411

derivatives 89b mainly showed partial agonist/partial antagonist activity, indicating that 23

412

the absence of the 5-methoxy group is relevant for the preparation of antagonist

413

derivatives. The methyl substitution on the α-carbon of the acylamino side chain (90)

414

eliminated the ability to activate the melatonin receptor, whereas a single or double

415

methyl substitution on the β-carbon (91 and 92) of the side-chain does not drastically

416

impede the access of compounds to the agonist site on the receptor. 90-92 showed

417

mainly antagonist activities. In general, the antagonist activity of 90-92 was stronger in

418

comparison to 89a,b. Interestingly, 91 and 92 with an N-acetyl chain showed stronger

419

antagonist activity in comparison to luzindole. The activity of the derivatives with

420

partial agonist properties was much lower in comparison to melatonin.

421

Tarzia et al. reported the synthesis of N-substituted indoles based on the general

422

structure 95 (Scheme 13B) [75]. The indole 93 was N-substituted with

423

chloroacetonitrile in the presence of sodium hydride and chloroacetonitrile to give the 1-

424

(cyanomethyl)indole 94. Then, the cyano compound 94 was converted to the target

425

compound 95 by hydrogenation over Raney nickel (Ra-Ni) and concomitant N-

426

acylation with a suitable anhydride. Affinity studies for quail optic tecta melatonin

427

receptors in competition with 2-[125I]iodomelatonin (with no differentiation of MT1 and

428

MT2 receptor subtypes) revealed that the biological activity of these new derivatives is

429

modulated by the presence and the position of the methoxy substituent. In this sense,

430

derivatives with the methoxy at C6 showed full agonist activity, whereas derivatives

431

with a methoxy group at C5 or no methoxy group exhibited different agonist and

432

antagonist properties depending on the nature of the N-acyl group. Compounds bearing

433

small substituents at C2, such as Br, phenyl or CO2Me, a methoxy group at C6 and an

434

N-propanoyl chain showed higher agonist affinities in comparison to melatonin (C2-Br

435

derivative, Ki = 0.044 nM; C2-Ph derivative, Ki = 0.014 nM; C2-CO2Me, Ki = 0.23 nM;

436

melatonin, Ki = 0.61 nM).

24

437

438 439

Scheme 13. Synthetic approaches to N1-subtituted indoles with melatonergic

440

activities. A Synthetic strategy to the melatonin derivatives 89-92 reported by Tsotinis

441

et al. [74]. 89-92 showed mainly antagonist properties. 91 and 92, with an N-acetyl

442

chain at C3, showed stronger antagonist activity in comparison to luzindole. B Synthetic

443

strategy to the melatoninergic ligand 95 reported by Tarzia et al. [75]. Some derivatives

444

with small substituents at N1/C2 and a methoxy group at C6 showed stronger agonist

445

affinity in comparison to melatonin.

25

446 447

3.2. Modifications on C2

448

Melatonin analogues with modifications on C2 were classified according to the

449

structural features into 2,3-disubstituted indoles (Section 3.2.1) and 2-substituted

450

indoles (Section 3.2.2). At the same time, derivatives based on an 2,3-disubstituted

451

indole core have been classified into C2-halogenated and C2-oxo melatonin analogues

452

(Section 3.2.1.1), 2-substituted melatonin analogues (Section 3.2.1.2) and synthesis of

453

luzindole (Section 3.2.1.3).

454

2-Substituted melatonin analogues have found diverse applications, including as

455

melatonin receptor ligands or anti-cancer, antibacterial and antioxidant agents.

456

Concerning the melatoninergic activity of 2-substituted melatonin analogues, several

457

derivatives have shown stronger binding affinities in comparison to melatonin. In

458

general, derivatives with small substituents at C2 showed strong agonist activities,

459

whereas derivatives bearing hindered substituents were found to be antagonists or

460

partial agonist/partial antagonists [76]. Interestingly, some derivatives were found to be

461

selective for MT2. Some significant examples of 2-substituted melatonin ligands are 2-

462

iodomelatonin, 2-[125I]iodomelatonin, luzindole, 5-methoxyluzindole or 2-(indolin-yl)-

463

melatonin. 2-Iodomelatonin and luzindole were shown to be agonist and antagonist,

464

respectively, non-selective melatonin receptor ligands. In contrast with luzindole, 5-

465

methoxyluzindole is a MT2-selective partial agonist. On the other hand, 2-(indolin-yl)-

466

melatonin was found to be a MT2-selective antagonist. Interestingly, the double

467

modification achieved by the introduction of substituents at C2 and, at the same time,

468

the removal of the methoxy group at C5 allowed the formation of full antagonist

469

melatonin receptor ligands such as luzindole. The studies performed with 2-substituted

470

indoles, lacking of chain at C3, revealed that these compounds are commonly partial

26

471

agonist or antagonists with low binding affinities. The 2-substituted indole UCM 454

472

exhibited 100-fold higher affinity for hMT2 receptor than for hMT1 (see page 58) [77].

473 474

3.2.1. 2,3-Disubstituted indoles

475

A number of synthetic approaches for the synthesis of 2,3-disubstituted melatonin

476

analogues were described until date (Scheme 14). These synthetic approaches can be

477

divided into 5 different retrosynthetic pathways. In this sense, one of the most common

478

retrosynthetic strategies consists of the halogenation of melatonin at C2 (Scheme 14,

479

route a). In some cases, the obtained halogenated derivatives were further used for the

480

introduction of unsaturated scaffolds via palladium-mediated reactions. Another

481

retrosynthetic analysis is based on the derivatization of p-anisidine by introduction of

482

the C3 chain (Scheme 14, route b). A typical retrosynthetic analysis consists of the

483

derivatization of indole structures, such as 5-methoxyindole or 5-methoxyindole-2-

484

carboxylic acid, via introduction of the chain at C3 (Scheme 14, route c). Two different

485

retrosynthetic routes based on the formation of the indole ring, either by Houlihan

486

methodology [78] or Fischer indole reaction [41], were reported (Scheme 14, route d

487

and route e). It must be noted that routes a-c use indole structures as the starting

488

materials, whereas routes d and e are based on the formation of the indole ring.

489

27

490 491 492

Scheme 14. Retrosynthetic analysis of the synthetic approaches to 2-substituted melatonin analogues.

493 494

3.2.1.1. C2-Halogenated and C2-oxo melatonin analogues

495

Among radiolabelled melatonin analogues,

125

I-labelled 2-iodomelatonin (96) has

496

become the most widely used ligand for the identification and study of melatonin

497

binding sites and/or receptors in animal tissues [79-81]. In 1984, 96 was prepared by

498

direct iodization of melatonin (1) using Iodo-Gen as oxidyzing reagent, achieving the

499

target compound in 20-50% yield (Scheme 15A) [82]. Molinari et al. reported the

500

synthesis of a novel radio ligand, 2-[125I]MCA-NAT (97) (Scheme 15B) [83]. This was

501

prepared via introduction of [125I] into 5-methoxycarbonylamino-N-acetyltryptamine (5-

502

MCA-NAT) at C2. 5-MCA-NAT, 5-methoxycarbonylamino N-acetyltryptamine, is a

503

known selective melatonin MT2 receptor ligand. Consistently, 97 was demonstrated to

504

be a specific radioligand for the identification of MT2 binding sites in hamster brain

505

membranes. Several oxidying reagents, including chloramine-T, hydrogen peroxide and

506

in situ generated peracetic acid, were evaluated for the oxidative [123I]radioiodination of

507

1 [84]. The highest yield, 68%, was obtained when using in situ generated peracetic acid. 28

508

In 2006, the synthesis and biodistribution of 2-[123I]iodomelatonin in normal mice was

509

studied by Al-Jammaz et al. [85]. In this case, the radioionitation of melatonin was

510

performed by in situ generation of peracetic acid as the oxidyzing reagent in the

511

presence of Na[123I]. The radiochemical yield was greater than 80% after 20 min

512

reaction time. Biodistribution studies indicated that 2-[123I]iodomelatonin does not show

513

any selectivity towards MT1 and MT2 receptors. Chen et al. reported the synthesis of the

514

11

515

[11C]carbon dioxide (98) (Scheme 15C) [86]. Carbonylation of methyl magnesium

516

bromide with 98 allowed the formation of 99, which was then converted to the

517

[11C]acetyl chloride 100 by treatment with phthaloyl dichloride. Then, acetylation of

518

101a with 100 provided the 11C-labelled 102a in 19% radiochemical yield. As shown in

519

Scheme 15C, the synthesis of

520

also achieved by reaction between 100 and 101b, allowing the formation of 102b in 32%

521

radiochemical yield.

C-labelled 2-iodomelatonin 102a from 5-methoxy-2-iodotryptamine (101a) and

11

C-labelled 5-methoxy-2-phenyltryptamine (102b) was

522

29

523 524

Scheme 15. Synthesis of radiolabelled 2-iodomelatonin derivatives. A Synthetic

525

approach to 2-[125I]iodomelatonin (96) [82]. 96 has become the most widely used ligand

526

for the identification and study of melatonin binding sites and/or receptors in animal

527

tissues. B Structure of 2-[125I]MCA-NAT (97) reported by Molinari et al. [83]. 97 is a

528

MT2-selective ligand. C Synthetic approach to [11C]labelled 2-iodomelatonin (102a)

529

reported by Chen et al. [86].

530 531

Apart from the radiolabelled iodomelatonin analogues, melatonin can be easily

532

iodinated at C2 in the presence of N-iodosuccinimide (NIS) to provide 2-iodomelatonin

533

[51,87]. 2-Iodomelatonin, which is commercially available at a low price, is known to

534

show higher binding affinity (approximately 15 times higher) for melatonin receptors in

535

comparison to melatonin [80,88]. 2-Iodomelatonin shows agonist non-selective binding

536

affinity at MT1 and MT2 receptors [31]. 2-Iodomelatonin has been reported to prevent

537

the apoptosis of cerebellar granule neurons [89]. Further, it is known that both 2-

30

538

iodomelatonin and 2-chloromelatonin inhibit testis growth and reduced body weight

539

gain in hamsters [90]. In the rat ovulation-inhibition model, 2-iodomelatonin was found

540

to be much more potent than melatonin, and the acute toxicity of 2-iodomelatonin was

541

reported to be extremely low [91]. The methoxy and alkylamide groups of 2-

542

iodomelatonin were reported to interact with N162 and Q181 in MT1 binding site in a

543

similar manner to ramelteon [24].

544

Finaru et al. described a synthetic approach to the 2-iodoindole 111 by solid-state

545

synthesis (Scheme 16A) [92]. After linkage of o-iodoaniline (105) to a rink amide

546

resine in dioxane, the indole core was built via palladium-mediated heteroannulation of

547

the internal alkyne 107 with the o-iodoaniline derivative 106. The obtained indole 108

548

was cleaved to give 109. Treatment of 108 with 3 equivalents of NIS in

549

dichloromethane (DCM) at reflux provided the iodo derivative 110, which was cleaved

550

from the resine with TFA. It must be noted that the application of microwave irradiation,

551

instead of heating, could significantly improve the yield of some steps and shortened the

552

reaction time. 111 was later involved in various palladium-mediated reactions, such as

553

Stille, Sonogashira, Heck or Suzuki, allowing the access to various 2-substituted indoles

554

[93].

555

An alternative synthetic approach leading to a number of 2-subtituted melatonin

556

analogues was patented by Tao et al. (Scheme 16B) [87]. After iodination or

557

bromination of melatonin at position 2 to provide 112a and 112b, the halogenated

558

compounds were submitted to Suzuki reaction, allowing the formation of the 2-

559

substituted melatonin analogues 113. Different aromatic substituents were incorporated,

560

including phenyl, biphenyl, pirazol, furane and thiophene moieties.

561

31

562 563

Scheme 16. Synthetic approaches to 2-iodomelatonin analogues. 2- iodomelatonin

564

show higher binding affinity (approximately 15 times higher) for melatonin receptors in

565

comparison to melatonin A Synthetic approach to 111 reported by Finaru et al. [92].

566

Later, the same research group reported the introduction of aromatic rings at C2 by

567

palladium-mediated reactions [93]. B Synthetic approach to the 2-substituted melatonin

568

derivative 113 patented by Tao et al. [87].

569 570

The synthesis of 2-bromomelatonin was reported by Duranti et al. in 1992 [88]. The

571

synthetic approach consisted of the direct bromination of melatonin with NBS in

572

anhydrous acetic acid. In vitro studies in rabbit parietal cortex (without differentiation

573

of MT1 and MT2 receptor subtypes) demonstrated that the relative binding affinity of 232

574

bromomelatonin was about ten times higher than that of melatonin but lower than that

575

of 2-iodomelatonin (2-bromomelatonin, Ki = 0.045 nM; 2-iodomelatonin, Ki = 0.025

576

nM; melatonin, Ki = 0.410 nM). 2-Bromomelatonin was shown to behave as a potent

577

agonist in the Syrian hamster gonadal regression model. The bromination of melatonin

578

using NBS with similar reaction conditions was later patented by Fraschini et al. [51].

579

In this patent, the efficacy of 2-bromomelatonin for the treatment of circadian rhythms

580

was evaluated as well as its transdermal administration. In 2003, Doss et al. attempted

581

the direct bromination of melatonin with bromide in acetic acid, achieving 2-

582

bromomelatonin in 79% yield [94]. The obtained structure was used as the starting point

583

for further palladium-mediated acylation reactions. Mor et al. described the synthesis of

584

2,4-dibromomelatonin by treating melatonin with NBS in acetic acid to provide the

585

desired compound in 25% yield [62]. In the same article, 2,6-dibromomelatonin was

586

synthesized in 25% yield by direct bromination of 6-bromomelatonin with NBS [62].

587

Binding affinity studies indicated that the higher binding affinity of 2-bromomelatonin

588

in comparison with melatonin was partially reversed by the introduction of an additional

589

Br atom at position 6, and fully reversed when the second halogen was introduced at C4.

590

Garratt et al. reported a synthetic approach to obtain new series of 2-substituted

591

indoles (Scheme 17) [95], following similar conditions than those reported by Flaugh et

592

al. for the synthesis of melatonin [56]. In this case, the treatment of 114a-c with

593

formaldehyde and dimethylamine gave the dimethylgramines 115a-c. Methylation

594

followed by displacement of the resulting ammonium ion with sodium cyanide provided

595

the nitriles 116a-c. Reduction of 116a and 116b with lithium aluminium hydride gave

596

the corresponding amines, which were acylated to obtain the amides 117a-n and 118.

597

The 2-bromo (119a) and 2,6-dibromo (119b) derivatives were prepared from the nitrile

598

116c using a similar procedure than that reported for the synthesis of 117a-n and 118.

33

599

The affinity of the obtained compounds was determined in the Xenopus melanophores

600

assay. The derivatives with the general structure 119a were agonists, whereas the

601

derivatives 119b showed antagonist or partial agonist properties. It was observed that all

602

synthetized compounds showed lower binding affinities in comparison with melatonin.

603

Changes on the length of the amide side chain caused relevant variations on the affinity.

604

The introduction of a bromine at C2 (119a) increased the binding affinity with respect

605

compounds 117a-n and 118. However, the introduction of a second bromine atom at C6

606

(119b) did not suppose a relevant change on the affinity in comparison to that detected

607

for 119a. The highest binding affinities were obtained with compounds bearing an N-

608

butanoyl chain at C3.

609

610 611

Scheme 17. Synthetic approach to the 2-bromomelatonin analogues 117, 118 and

612

119a,b reported by Garrat et al. [95]. Derivatives with a bromo group at C2 (119a) 34

613

showed high agonist binding affinity. 119a exhibited lower binding affinity in

614

comparison to melatonin and 2-bromomelatonin.

615 616

A simple strategy for the synthesis of some 2-substituted melatonin derivatives,

617

including 2-oxomelatonin (124) and 2-chloromelatonin (126), was reported by

618

Lozinskaya et al. using p-anisidine (120) was used as the starting material (Scheme 18A)

619

[96]. Later, the same research group investigated the binding affinity of 124 and other 2-

620

oxomelatonin analogues, demonstrating that 2-oxoindole derivatives are effective

621

ligands of MT3 binding site with, in some cases, higher binding affinities in comparison

622

to melatonin [97]. The affinity for MT3 was calculated according to the inhibition of the

623

quinone reductase activity. Interestingly, 124 showed much higher binding affinity for

624

MT2 in comparison to that for MT1 (human MT1 and MT2 receptors and 2-

625

[125I]iodomelatonin were used in the screening).

626

35

627 628

Scheme 18. Synthesis of 2-oxo melatonin derivatives. A Synthetic approach to 2-

629

oxomelatonin (124) and 2-chloromelatonin (126) reported by Lozinskaya et al. [96].

630

124 showed higher affinity for MT3 in comparison to melatonin. B Synthetic approach

631

to 2-oxomelatonin analogue 131 reported by Volkova et al. [98]. 130 and 131 showed

632

low affinities for MT3.

633

36

634

Fourtillan et al. patented a synthetic approach to prepare the 2-oxomelatonin analogue

635

124 [99]. The synthetic approach consisted in the direct oxidation of melatonin in the

636

presence hydrochloric acid in dimethyl sulfoxide. Volkova et al. reported the synthesis

637

of the 2-oxomelatonin analogue 131 using aniline (127) as the starting material (Scheme

638

18B) [98]. This was transformed into the isatin 128, which was submitted to

639

Knoevenagel condensation with cyanoacetic acid to provide 129. Reduction of the

640

double-bond and decarboxylation with zinc allowed the preparation of 130. Reduction

641

of the cyano group by hydrogenation in the presence of Adam´s catalyst and acylation

642

with acetic anhydride led to the 2-oxo-5-acetamido melatonin derivative 131. Affinity

643

studies towards MT3 indicated that the deletion of the methoxy group decreased the

644

affinity almost 3-fold in comparison with melatonin. A comparison of 130 and 131

645

indicated that the shorted alkyl chain and the cyano group are preferred over the

646

elongated alkyl chain and acetyl group.

647 648

3.2.1.2. C2-Substituted melatonin analogues

649

New series of 2-[(2,3-dihydro-1H-indol-1-yl)methyl]melatonin analogues (138a-k)

650

were synthetized by Zlotos et al. (Scheme 19A) [100]. The synthetic sequence

651

commenced with the condensation of 5-methoxyindole-2-carboxylic acid (132) with 2-

652

methylindoline (133a) or indoline (133b) using EDC as the catalyst in DCM to give the

653

amides 134a,b. Aminomethylation of 134a,b using N,N-dimethylmethyleneiminium

654

iodide afforded the Mannich bases 135a,b. Treatment of 135a,b with methyl iodide in

655

DCM and heating of the resulting trimethylammonium iodides with potassium cyanide

656

provided the nitriles 136a,b. Simultaneous nitrile and amide reduction using lithium

657

aluminium hydride in diethyl ether/tetrahydrofuran (THF) afforded the ethylamines

658

137a,b, which were converted to the desired melatoninergic ligands 138a-e by N-

37

659

acylation with the corresponding agent. Starting from 139, the target compounds 138f-j

660

were prepared in a reaction sequence already applied in the first route involving the

661

condensation with the appropriate amine, simultaneous nitrile and amide reduction

662

using lithium aluminium hydride, and N-acylation of the resulting amines (Scheme

663

19B). The 6’-amino substituted 138k was prepared from the nitroacetamide 138j by

664

hydrogenation using palladium on carbon (Scheme 19C). Binding affinity studies of the

665

synthetized compounds for human MT1 and MT2 receptors using 2-[125I]iodomelatonin

666

revealed that all synthetized compounds showed lower binding affinities in comparison

667

to melatonin. The substitution pattern of the indoline caused relevant effects on the

668

binding affinity. The 5-methoxyindoline derivative 138f exerted the highest binding

669

affinity but no MT1/MT2 selectivity. The most interesting results were obtained with

670

138b (2-(indolin-yl)-melatonin), which showed an excellent affinity ratio (100-fold)

671

MT2/MT1 (138b, MT1 pKi = 6.94, MT2 pKi = 8.93; melatonin, MT1 pKi = 9.34, MT2

672

pKi = 9.02).

673

Attia et al. reported the synthesis of derivatives 138l-n (Scheme 19D) [101]. The

674

synthetic strategy of Zlotos et al. [100] was also applied in this case. Obtained

675

derivatives exhibited non-selective binding affinity towards human MT1/MT2 receptors.

676

38

677 678

Scheme 19. Synthetic approaches to C2-indolinyl melatonin derivatives. A Synthetic

679

approach to the melatonin derivatives 138a-e [100]. 138b (2-(indolin-yl)-melatonin)

680

showed 100-fold MT2/MT1 ratio. B Synthesis of the melatonin derivatives 138f-j [100].

681

138f exerted the highest binding affinity among all C2-indolinyl derivatives but no

682

MT1/MT2 selectivity. C Melatonin derivative 138k [100]. D Melatonin derivatives

683

138l-n [101].

684

39

685

Further studies by Heckman et al. described the dehydrogenation of derivatives 138a

686

and 138e with palladium on carbon to obtain 140a and 140b, which contain an indole

687

ring attached at C2 (Scheme 20A) [102]. Binding affinity of the synthetized derivatives

688

for human MT1 an MT2 using 2-[125I]iodomelatonin indicated that 140a showed 5-times

689

lower affinity for the MT2 receptor than 138b, whereas the binding affinity to MT1 was

690

almost unchanged.

691

Darwish et al. reported the synthesis of the C2-indolyl derivative 146, which is the

692

main contaminant in melatonin preparations (Scheme 20B) [103,104]. To achieve this

693

goal, 141 was reacted with the nucleophile 5-methoxyindoline (142) in the presence of

694

EDC·HCl in DCM to furnish the amide 143. Subsequent oxidation of 143 was

695

accomplished using DDQ in ethyl acetate at reflux to yield the di-indole derivative 144.

696

Reduction of the amide 144 was carried out with lithium aluminium hydride/aluminium

697

chloride. The resulting amine was reacted with 2-nitroethyl acetate in xylene at reflux to

698

give the di-nitro derivative 145, which was hydrogenated in the presence of palladium

699

on carbon and acetylated to provide the target derivative 146. A spectrofluorometric

700

method for the determination of melatonin in the presence of 146 was also developed.

701

40

702 703

Scheme 20. Synthetic approaches to C2-indolyl melatonin derivatives. A Synthetic

704

approach to 140a,b reported by Heckman et al. [102]. 140a showed 20-fold MT2/MT1

705

ratio. B Synthetic approach to 146 reported by Darwish et al. [103,104].

706 707

Heckman et al. reported the synthesis of C2-isoindolinyl and tetrahydroisoquinolinyl

708

derivatives 148a-e and 150 (Scheme 21) [102]. The synthesis was carried out starting

709

from 139, which was reacted with isoindole and tetraisoquinoline in the presence of

710

EDC·HCl to obtain the intermediates 147 and 149, respectively. These were reduced 41

711

with lithium aluminium hydride, and the resulting amines were acylated to give the

712

target derivatives 148a-e and 150. Binding affinity studies of the synthetized derivative

713

for human MT1 and MT2 receptors using 2-[125I]iodomelatonin revealed that antagonist

714

148a was 124-times more selective for the MT2 receptor that for the MT1. The binding

715

affinity of 148a for MT2 was similar to that of 138b. Ligands 148b-e and 150 did not

716

show MT2-selective binding affinity.

717

718 719

Scheme 21. Synthetic approaches to C2-substituted melatonin derivatives bearing

720

isoindoline (148a-e) and tetrahydroquinoline rings (150) [102]. 148a showed 124-times

721

higher affinity for MT2 than for MT1. 148b-e and 150 were not MT2-selective.

722 723

Di Giacomo et al. reported a synthetic approach to 154a-f, 155 and 156 starting from

724

132 (Scheme 22) [105]. This was reacted with 1-(dimethyamino)-2-nitroethylene in

725

trifluoroacetic acid to provide the nitroethene 151. This compound was converted to the 42

726

acetamino derivative 152 using sodium borohydride followed by hydrogenation over

727

Ra-Ni in THF and concomitant N-acylation with acetic anhydride. The 2-carboxylic

728

acid derivative 153, which was obtained by ester alkaline hydrolysis of 152, was

729

coupled with the appropriate hydroxyl derivative in the presence of N,N-

730

dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) to yield the

731

compounds 154b-g (n = 5, 7, 8, 9, 10 and 12) and 155. The derivatives 154a (n = 3) and

732

155 were obtained by treating 153 with a solution of DCl, and 1,3-propanediol or 9-

733

hydroxynonylbenzoate, respectively, in DMF. Binding affinity studies for human MT1

734

and MT2 using 2-[125I]iodomelatonin revealed that all synthetized compounds, 154a-g,

735

155 and 156, showed weak binding ability in comparison with melatonin. 154e and 155

736

showed moderate selectivity for MT2 receptor. Derivatives 154d (n = 8) and 154e (n = 9)

737

exhibited the highest binding affinities. 154d showed fully agonist behaviour, whereas

738

154e was found to be partial agonist/partial antagonist.

739

43

740 741

Scheme 22. Synthetic approach to the 2-substituted melatonin analogues 154a-f, 155

742

and 156 reported by Di Giacomo et al. [105]. Synthetized compounds showed low non-

743

selective binding affinities.

744 745

Markl et al. reported a synthetic strategy for the synthesis of the 2-substituted

746

melatonin derivatives 159a-f from 139 (Scheme 23A) [106]. Amide formation by

747

coupling N-substituted methylamine to 139 using EDC as the activator followed by

748

Mannich aminomethylation and substitution with sodium cyanide allowed the

749

preparation of 157a-c. However, the order of the steps was changed in order to obtain

750

the cyanides 157d-f. In first place, the C3 chain was introduced via aminomethylation

751

and subsequent substitution with cyanide. Then, the amide was formed in the presence 44

752

of EDC to provide 157d-f. To obtain the target compounds 159a-f, cyanides 157a-f

753

were reduced with lithium aluminium hydride in THF/diethyl ether and acetylated with

754

acetic anhydride. Interestingly, binding affinity studies for human MT1 and MT2

755

receptors using 2-[125I]iodomelatonin revealed that all synthetized compounds showed

756

lower affinity in comparison to melatonin. 159d, which displayed strong agonist activity,

757

was found to be 7-times more selective for MT2 than for MT1 receptor. The binding

758

affinity was relevantly decreased in compounds 159a, 159b, 159e and 159f, whereas

759

159c showed a strong non-selective affinity.

760

Righi et al. reported the synthesis of 2-substituted melatonin analogues using the same

761

synthetic approach previously described for the synthesis of melatonin (Scheme 7D)

762

[59]. 2-Substituted 5-methoxyindole derivatives, bearing different aliphatic chains at C2,

763

were used as the starting material. The one-step synthetic approach consisted in the

764

direct introduction of the N-acetly-2-aminoethyl chain at C3 via reaction between the

765

starting material and N-acetylaminoacetaldehyde dimethyl acetal (55) in the presence of

766

triethylsilane and trifluoroacetic acid in DCM.

767

In 2019, Luthra et al. reported an alternative synthetic strategy that allowed the

768

synthesis of 161 (Scheme 23B) [107]. The synthetic strategy was based on the one-pot

769

molecular iodine-catalyzed oxidative ring opening of the 1-aryltetrahydro-β-carboline

770

160 in the presence of t-butylhydroperoxide (TBHP) as an oxidant, and subsequent

771

imination with primary amines to obtain melatonin derivatives with the general formula

772

161. These were found to be MT1 antagonists and showed substantial antimalarial

773

properties by inhibiting the trophozoite stage of P. falciparum life cycle. The affinity of

774

the synthetized compounds was screened by molecular docking and ELISA MT1

775

melatonin receptor assay.

776

45

777 778

Scheme 23. Synthetic strategies to the melatonin derivatives 159a-f and 161. A

779

Synthetic strategy to the 2-substituted melatonin analogues 159a-f reported by Markl et

780

al. [106]. 159d showed strong 7-fold MT2-selective agonist activity. B Synthesis of 161

781

reported by Luthra et al. [107]. 161 were found to be MT1-selective antagonists and

782

showed substantial antimalarial properties by inhibiting the trophozoite stage of P.

783

falciparum life cycle.

784 785

As abovementioned, 2 different synthetic approaches to 2-substituted melatonin

786

derivatives based on the formation of the indole ring were reported: Houlihan indole

787

formation and Fischer reaction. Regarding the synthetic strategies based on Houlihan

788

indole formation, Garrat et al. described the preparation of 2-phenylmelatonin (166a)

789

using the acylated 2-methyl-4-methoxyaniline 162 as the starting material (Scheme 24A)

790

[108]. The indole 163 was formed via Houlihan reaction [78] of 162 using n-butyl

791

lithium. Formylation of the indole 163 with phosphoryl chloride and dimethyl

792

formamide followed by Henry reaction with nitromethane gave the nitroalkene 164,

46

793

which was reduced with lithium aluminium hydride to the amine 165 in 19% overall

794

yield. The amine 165 was then acylated to give the amides 166a-j. Affinity studies for

795

melatonin receptors using the Xenopus melanophores assay revealed that 166a-j are

796

agonists. Interestingly, derivatives 166a-d, which contain small C3 chains, were

797

determined to bind to the receptor more strongly than melatonin. However, the rest of

798

the derivatives (166e-j) showed weak binding affinities. In the same study, 2-

799

phenyltryptamines, lacking of methoxy group at C5, were also evaluated as

800

melatoninergic ligands. 2-Phenyltryptamines bearing small chains at C3 showed agonist

801

activity, whereas the 2-phenyltryptamines with voluminous substituents were

802

demonstrated to produce antagonist activity. All 2-phenyltryptamines showed

803

significant lower binding affinity with respect melatonin.

804

Further studies have revealed that 166a adopts a ‘tail up’ binding mode inside the MT2

805

receptor [25]. This ‘tail up’ position is forbidden in the MT1 receptor, which explains

806

the selectivity of some C2-substituted melatonin analogues towards MT2.

807

47

808 809

Scheme 24. Synthetic approaches to 2-substituted melatonin analogues based on

810

Houlihan indole formation. A Synthetic approach reported by Garrat et al. for the

811

synthesis of the 2-phenylmelatonin analogues 166a-j [108]. 166a-d, which contain

812

small chains at C3, were determined to bind to the receptor more strongly than

813

melatonin. B 2-Substituted melatonin derivatives (166k-s) studied by Spadoni et al.

814

[109]. Melatonin derivatives with methyl (166k and 166o), benzyl (166n and 166q) or

815

bromo (166r) groups at C2 improved the binding affinity of melatonin.

816 817

The same synthetic approach was later reported by Spadoni et al. (Scheme 24B) [109],

818

allowing the formation of melatonin analogues with different aliphatic chains (166k-s)

819

at C2. It was observed that the introduction of a cyclopropyl ring at the amide nitrogen

820

on the C3 side chain (166o-s) significantly decreased the binding affinity in comparison

48

821

with the derivatives with acetyl groups. On the other hand, introduction of methyl (166k

822

and 166o), benzyl (166n and 166q) or bromo (166r) groups at C2 resulted in derivatives

823

with higher binding affinity in comparison to melatonin, whereas bulky groups, such as

824

isopropyl or cyclohexyl (166l, 166m and 166p), decreased the affinity (166k, Ki =

825

0.43ffnM; 166l, Ki = 0.43ffnM; 166m, Ki = 5.3ffnM; 166o, Ki = 0.057ffnM; 166p, Ki =

826

0.63 nM; 166n, Ki = 180 nM; 166q, Ki = 0.24ffnM; 166r, Ki = 0.21 nM; 166s, Ki =

827

2.2ffnM; melatonin, Ki = 1.1ffnM). Among all molecules, only 166n and 166q, both

828

bearing a phenyl at C2, exhibited antagonist activity. These experiments were

829

performed the melatonin receptors of quail brains in competition with 2-

830

[125I]iodomelatonin (with no differentiation of MT1 and MT2 subtypes). The same

831

synthetic approach and the synthesis of the same derivatives was later patented by

832

Fraschini et al. [51].

833

Among synthetic approaches based on the formation of the indole ring via Fischer-

834

indole reaction, Nenajdenko et al. reported the preparation of a wide range of 2-

835

substituted melatonin derivatives (Scheme 25A) [110]. To achieve this goal, p-

836

substituted phenylhydrazines (167) were used as the starting material. Reaction between

837

167 and the δ-amidoketones 168a-e allowed the formation of 169a-j. The reaction was

838

performed in a mixture of hydrochloric acid and acetic acid at reflux. All 2-substituted

839

melatonin analogues were obtained in high yield except 169g. Later, the same research

840

group reported the synthesis of the indole 171, which contains the N-acetyl chain at C2

841

(Scheme 25B) [111]. It was found that the presence of ethanol in the reaction mixture,

842

instead of hydrochloric acid/acetic acid, changed the regioselectivity of the reaction,

843

obtaining 171 in moderated-high yields.

844

Kanayama et al. patented a synthetic approach based on a Fischer-indol reaction

845

between the oxidized p-methoxyphenylhydrazine 14 and 2-oxopiperidine-3-carboxylate

49

846

(13), following similar conditions than those reported by Abramovitch and Misztal

847

(Scheme 3A) [47,49,112]. In this case, compound 17 was not decarboxylated, and the

848

carboxylic acid moiety was used for the introduction different chains via amide

849

formation.

850

851 852

Scheme 25. Synthetic approaches to 2-substituted melatonin analogues based on the

853

formation of the indole ring via Fischer indole reaction. A Synthetic approach to the 2-

854

substituted melatonin derivatives 169a-j reported by Nenajdenko et al. [110]. B

855

Synthetic approach to 171 reported by Zakurdaev et al. [111].

856 857

3.2.1.3. Synthesis of luzindole

858

One of the most typical representatives of C2-modified melatonin analogues is N-

859

acetyl-2-benzyltryptamine (175), also called luzindole. 175 is one of the most important

860

melatonin receptor antagonists and it has a 25-fold higher affinity for the human MT2

861

melatonin receptor than for the MT1 receptor [113]. It constitutes a standard reference

862

compound for pharmacologists in the field. It has been reported that it is capable of 50

863

disrupting the circadian rhythm as well as producing antidepressant effects [114]. 175

864

consists of a N-acetyltryptamine core, lacking of 5-methoxy group, with a benzyl

865

moiety at C2.

866

The first synthetic approach to 175 was patented by Dubocovich et al. in 1994

867

(Scheme 26A) [115]. The synthetic approach allowed the production of not only

868

luzindole but also a number of 2-aryl N-acetyltryptamines. The synthesis of 175 was

869

achieved through a method based on a Pictet-Spengler reaction, whereby tryptamine (39)

870

underwent ring closure to the β-carboline 173 after condensation with benzaldehyde

871

(172) in the presence of sulphuric acid. The resulting pyrido[3,4-b]indole core 173 was

872

then cleaved by catalytic hydrogenation over palladium on carbon to give the 2-

873

benzyltryptamine 174, which was acetylated with acetic anhydride to produce 175 in

874

less than 8% overall yield.

875

In 2018, Chauhan et al. reported an alternative synthetic approach to 175, which

876

consisted in the ring opening of tricyclic compound 176 to provide 177 in 78% yield

877

(Scheme 26B) [116]. The oxidative ring opening of 176 was performed in the presence

878

of molecular iodine and aqueous hydrogen peroxide in ethanol as the solvent. Then, the

879

ketone 177, which was produced in 2 g scale, was reduced with sodium borohydride

880

followed by treatment with triethylsilane in the presence of trifluoroacetic acid. 175 was

881

finally purified by column chromatography to achieve the desired product.

882

51

883 884

Scheme 26. Synthetic approaches to luzindole (175) based on the formation of

885

tricycle intermediates (173 and 176). A Synthetic approach to 175 reported by

886

Dubocovich et al. [115]. B Synthetic approach to 175 reported by Chauhan et al. [116].

887 888

An alternative method leading to the precursor 174 was reported by Buzas and Merour

889

(Scheme 27A) [117]. To achieve this goal, 1-acetyl-2-arylmethylene-3-oxo-2,3-

890

dihydroindolone (179) was prepared by condensation of 1-acetyl-3-oxo-2,3-

891

dihydroindole (178) with 172 in benzene or toluene. Reduction of 179 with hydrogen

892

over

893

cyanomethylphosphonate in the presence of sodium hydride to obtain a mixture of

894

181a,b. The nitriles 181a,b could be transformed into 174 via hydrogenation over Ra-

895

Ni. This strategy allowed the formation of 174 in 9% overall yield.

palladium

provided

180,

which

was

then

treated

with

diethyl

896

A synthetic approach to 175 based on the direct introduction of the C3 side chain was

897

reported by Righi et al. [59]. The methodology consisted in the direct alkylation of 5-

898

methoxy-2-benzylindole (186) with N-acetylaminoacetaldehyde dimethyl acetal (55) in 52

899

the presence of triethylsilane and trifluoroacetic acid to give 175 in 73% yield. It must

900

be noted that the reaction was performed in 2.13 g scale. An alternative synthetic

901

strategy to 175 was reported by Soni et al. The synthetic strategy involved the

902

introduction of the chains at C2 and C3 (Scheme 27B) [118]. The synthetic approach

903

consisted in the substitution of N-protected indole 182 with toluene (183) in the

904

presence of lithium bis(trimethylsilyl)amide (LiHMDS) and catalyst 184 to provide the

905

2-substituted indole 185. After N-deprotection in the presence of sodium ethoxide to

906

give 186, the C3 allyl chain was attached following the same conditions reported by

907

Righi et al. to give 175 [59]. This 3-step synthetic approach allowed the preparation of

908

175 in 44% overall yield. In the same manuscript, Soni et al. reported the substitution of

909

182 with p-methoxytoluene, instead of 183, that allowed the formation of the

910

corresponding luzindole derivative [118].

911

53

912 913

Scheme 27. Synthetic approaches to luzindole (175) and luzindole precursor 174

914

based on the introduction of the C2 and/or C3 side chains in the indole structure. A

915

Synthetic approach to intermediate 174 reported by Buzas and Merour [117]. B

916

Synthetic approach to 175 reported by Soni et al. [118].

917 918

In 2008, Tsotinis et al. reported a synthetic strategy to obtain 175 via formation of the

919

indole ring (Scheme 28). To achieve this goal, 2-iodoaniline (187) and 3-phenyl-1-

920

propyne (188) were used as the starting materials [119]. 187 was reacted with 188 via

921

Sonogashira coupling reaction in the presence of bis(triphenylphosphine)palladium 54

922

chloride and copper(I) iodide in triethylamine/THF, obtaining the 2-(3-phenyl-1-

923

propynyl)aniline 189. Cyclization of 189 into 2-(phenylmethyl)indole (190) was

924

successfully achieved in the presence of potassium t-butoxide. Incorporation of the C3

925

side chain was effected by nitroolefination with 1-(dimethylamino)-2-nitroethylene in

926

trifluoroacetic acid/DCM to give 191, Then, reduction to 191 with lithium aluminium

927

hydride and acetylation with acetic anhydride in DCM provided target compound 175.

928

The conversion of the starting materials to 175 was effected in 52% overall yield.

929

The binding affinity of 5-methoxyluzindole was studied by Dubocovich et al.,

930

indicating that 5-methoxyluzindole is a partial agonist and shows 130 MT2/MT1 ratio

931

(5-methoxyluzindole, MT1 Ki = 32.7 nM, MT2 Ki = 0.25 nM; melatonin, MT1 Ki = 0.88

932

nM, MT2 Ki = 0.18 nM) [76]. These experiments were carried out at human MT1 and

933

MT2 receptors using 2-[125I]iodomelatonin.

934

Teh and Sugden evaluated the melatoninergic activity of luzindole derivatives bearing

935

diverse N-acyl chains [120]. All derivatives showed antagonist properties. The

936

derivative with a pentanoyl chain, also called DH97, was 90-fold selective for MT2.

937

938

55

939 940

Scheme 28. Synthetic approach to 175 based on the formation of the indole ring reported by Tsotinis et al. [119].

941 942

3.2.2. 2-Substituted indoles

943

Although melatonin is based on a 3,5-disubstituted indole, several articles can be

944

found in the literature reporting the synthesis of melatonin analogues with a 2-

945

aminoethyl chain at C2 and no side chain at C3. Interesting melatoninergic ligands were

946

obtained when the methoxy group was simultaneously moved from C5 to C4. All

947

reported synthetic strategies to these analogues employed indol-2-carboxylic acid

948

derivatives as the starting material.

949

In this field, Spadoni et al. reported the synthesis of the isomers 196a-k (Scheme 29A)

950

[121]. To achieve this goal, 192a-f were reduced with lithium aluminium hydride to

951

provide the alcohols 193a-f, which were oxidized with manganesium(IV) oxide to the

952

aldehydes 194a-f. Mannich reaction of 194a-f with nitromethane allowed the formation

953

of nitro compounds 195a-f. Finally, these were transformed into the melatonin

954

analogues 196a-f via reduction with lithium aluminium hydride and acylation with

955

either acetic or propionic anhydride. The analogues 196i and 196j were synthetized via

956

N1-acylation of 196b and 196g with methyl iodide and benzyl chloride, respectively.

957

On the other hand, 196b was brominated with NBS to provide derivative 196k. The

958

same synthetic strategy was followed to synthetize 197a-d and 198 (Scheme 29B).

959

Later, the same research group reported the synthesis of 197e-g by direct N-alkylation

960

and N-acylation of N-[(4-methoxy-1H-indol-2-yl)methyl]-propionamide (Scheme 29B)

961

[77]. Binding affinity studies revealed that all synthetized compounds exhibited lower

962

binding affinities in comparison with melatonin. The derivatives 196a-f acted as partial

963

agonists, antagonists, or putative inverse agonists at the MT1 receptor subtype

56

964

depending on the substitution pattern. An in vitro functional assay based on the specific

965

binding of [35S]GTPγS on MT1 subtype was used in these studies. It was found that the

966

N1-phenyl substitution coupled with the 2-ethylamido side chain is particularly

967

important for enhancing the affinity of the compounds. This was shown when using

968

196f and 196h, which have submicromolar affinity for the receptor and can be classified

969

as partial agonists. All the compounds with shortened chain length 197a-d behaved as

970

antagonists. On the other hand, the binding affinity of 197e-g was screened at human

971

MT1 and MT2 receptors using 2-[125I]iodomelatonin. These studies revealed that 197f,

972

also called UCM 454, displayed 100-fold higher affinity for hMT2 receptor than for

973

hMT1 (197f, MT1 pKi = <5, MT2 pKi = 5.74; melatonin, MT1 pKi = 9.54, MT2 pKi =

974

9.55).

975

57

976 977

Scheme 29. C2-Substituted melatonin analogues reported by Spadoni et al. A

978

Synthetic approach to the melatonin analogues 196a-k [121]. B Structures of the

979

melatonin derivatives 197a-g and 198 [77,121]. The antagonist derivative 197f, also

980

called UCM 454, exhibited 100-fold higher affinity for hMT2 receptor than for hMT1.

981 982

The same research group reported the preparation of the 2-substituted derivatives

983

199a-k and 200a-k (Scheme 30A and Scheme 30B, respectively). The derivatives 199a-

984

k consists of an indole core with a N1-propyl-2-aminoethyl chain, a methoxy group at

985

C6 and different functionalities at C2 [122]. Binding affinity studies at human MT1 and 58

986

MT2 receptors using 2-[125I]iodomelatonin revealed that the introduction of electro-

987

withdrawing substituents at C2, such as Br (199k) or CO2Me (199a), increased the

988

affinity with respect melatonin, whereas the introduction of hydrophilic substituents at

989

C2, such as CH2OH (199h), CONH2 (199f) or NHCONH2 (199g), significantly

990

decreased the affinity. Compound 199e, which contains a CH2CH2Ph group at C2,

991

showed high MT2/MT1 selectivity. On the other hand, the derivatives 200a-k showed a

992

C2-aminoethyl chain and different substituents at position 5 [123]. 200a-k were studied

993

as antioxidant agents. The 4-methoxy derivative 200j, which contains a methoxy group

994

at C4, showed the highest antioxidant activity.

995

996 997

Scheme 30. C2-Substituted melatonin analogues reported by Spadoni et al. [122,123].

998

A Structure of 199a-k. The introduction of electro-withdrawing substituents at C2, such

999

as Br (199k) or CO2Me (199a), increased the affinity with respect melatonin. B

1000

Structure of 200a-k, which were evaluated as antioxidant agents.

1001

59

1002

Tsotinis et al. reported the synthesis of the 2-substituted indoles 205a,b and 206a,b

1003

that contain azide and isothiocyanate groups, respectively, at the C2 side chain (Scheme

1004

31) [124]. The synthesis was effected from 2-indolecarboxylic acid (201) and its 5-

1005

methoxy congener 141. The melatoninergic activity of the synthetized derivatives was

1006

studied using the Xenopus laevis melanophore assay. The C2-substituted analogues

1007

205a and 206a showed weak antagonist activity, though a small (∼40% of maximal)

1008

partial agonist action was observed for 205b and 206b. All synthetized compounds

1009

showed lower antagonist binding affinity in comparison to luzindole.

1010

1011 1012

Scheme 31. Synthetic approach to the 2-substituted melatoninergic ligands 205a,b

1013

and 206a,b reported by Tsotinis et al. [124]. 205a and 206a showed antagonist activity,

1014

whereas 205b and 206b were partial agonists/partial antagonists. All synthetized

1015

derivatives showed weak binding affinity.

1016 1017

3.3. Modifications on C3

60

1018

Some C3-modified melatonin analogues have shown interesting melatoninergic

1019

activities. It has been reported that small modifications in the acyl chain are able to alter

1020

the binding affinity for melatonin receptors. A typical modification to increase the

1021

activity consists of the introduction of an N-butanoyl chain as replacement of the acetyl

1022

group. In this sense, Depreux et al. reported a 100-fold higher affinity of 5-methoxy-N-

1023

butanoyltryptamine in comparison of that of melatonin [125]. The introduction of

1024

radioactive atoms at the C3 chain has allowed the preparation of melatonin receptor

1025

radioligands, such as [methylene-3H]melatonin or [125I]SD6. [125I]SD6 exhibits a similar

1026

pharmacological profile to that of 2-[125I]iodomelatonin with non-selective affinity for

1027

MT1 and MT2 receptors [31,126]. In few occasions, the introduction of small

1028

substituents in the 2-aminoethyl chain allowed the preparation of agonists with high

1029

MT2/MT1 ratios, whereas the derivatives with voluminous substituents in the chain were

1030

found to be antagonists. Apart from the melatoninergic activity, some C3-modified

1031

melatonin analogues have found applications as antioxidant, analgesics or

1032

neuroprotective agents.

1033

A number of synthetic strategies to afford 3-substituted melatonin analogues were

1034

described until date. The synthetic approaches can be divided into 3 different

1035

retrosynthetic analysis. A common retrosynthetic analysis is based on the derivatization

1036

of 3-susbtituted indoles. In this sense, 5 different functional groups have been used for

1037

the

1038

methoxytryptamine and methyl (2-(1H-indol-3-yl)ethyl)carbamate, aldehyde, such as

1039

indole-3-carbaldehyde, ketone, such as 3-acetylindole, carboxylic acid, such as indole-

1040

3-carboxylic acid, and cyanide, such as 5-methoxyindole-3-acetonitrile. Other synthetic

1041

approaches are based on the introduction of a C3 chain, including 3 different synthetic

1042

strategies: Vilsmeier-Haack formylation, introduction of chains under basic conditions

synthesis

of

3-substituted

melatonin

61

derivatives:

amine,

such

as

5-

1043

and introduction of chains via metal activation. Finally, the last retrosynthetic analysis

1044

involves the formation of the indole core via Fischer or Houlihan reaction.

1045

Regarding the synthetic strategies from 5-methoxytryptamine (53), Chatterjie et al.

1046

reported the synthesis of the melatonin analogue bearing valproic acid at the C3 chain

1047

[127]. The accomplishment was performed via reaction of 53 with dipropylacetyl

1048

chloride in THF. The synthetized compound exhibited neuroprotective properties and

1049

low toxicity. The synthesis of deuterated melatonin via treatment of 53 with

1050

trideuterated acetyl chloride was reported by Almeida et al. [128]. Bedini et al.

1051

described the synthesis of the pinacol aryl boronate 208 via reaction of 53 with 207

1052

(Scheme 32A) [72]. It was found that 208 exhibited lower anti-cancer effects in

1053

comparison with those shown by compound 78 (Scheme 11E). The nitric oxide (NO)-

1054

donors 209-215 were prepared by Chegaev et al. (Scheme 32B) [129]. Apart from the

1055

NO-donors, Chegaev et al. also described the synthesis of melatonin derivatives bearing

1056

propanoyl, pentanoyl, decanoyl or dodecanoyl chains linked to the 2-aminoethyl chain.

1057

The antioxidant activity and binding affinity for human MT1 and MT2 receptors (using

1058

the [35S]GTPcS binding assay) was examined. It was found that the antioxidant

1059

activities were dependent on the lipophilicity of the derivative. The lipophilic

1060

derivatives 209a,b, 211, 212, N-decanoyl- and N-dodecanoyl-5-methoxytryptamine

1061

showed the highest antioxidant activities among all synthetized compounds. Affinity

1062

studies revealed that compounds 209-212 are agonists or partial agonists, whereas 213

1063

and 215a,b exhibited antagonist or inverse agonist activities at both MT1 and MT2. The

1064

obtained compounds showed lower binding affinity in comparison with melatonin.

1065

Legros et al. reported the synthesis of SD6 and [125I]SD6 (217) from 53 (Scheme 32C)

1066

[126]. To synthesize 217, 53 was treated with bromoacetyl bromide in ethyl

1067

acetate/water to obtain the bromoacetyl derivative 216. Substitution of the bromide

62

1068

atom of 216 by refluxing in acetone with Na[125I] resulted in the iodo derivative 217.

1069

[125I]SD6 was a non-selective full agonist with similar binding affinity in comparison to

1070

2-iodomelatonin when using the [35S]-GTPγS binding assay.

1071

A novel series of melatonin analogues were obtained by fusing donepezil, a

1072

medication used to treat Alzheimer´s disease, and tryptamine [130]. Some of the

1073

synthetized compounds showed multi-target activity, including chelating activity or cell

1074

oxidative stress. Xiong et al. reported the synthesis of 5-bromo, 5-fluoro and 5-

1075

methoxytryptamines bearing salicylic acid [131]. The synthetized compounds were

1076

evaluated as antitumor agents, indicating that the derivatives with a bromo group at C5

1077

exhibited the strongest antitumor activities. Estevao et al. described the synthesis of

1078

prenylated melatonin analogues with attached phthaloyl groups, and the scavenging

1079

activity of reactive oxygen species (ROS) and reactive nitrogen species (RNS) was

1080

examined [10]. Some synthetized compounds showed higher antioxidant activity in

1081

comparison to commercial drug Trolox. Rodriguez-Franco et al. reported the synthesis

1082

of tacrine-melatonin hybrids that displayed higher radical absorbance capacity in

1083

comparison to melatonin and selective acetylcholinesterase inhibitory activity [132].

1084

Schuck et al. reported the synthesis of melatonin derivatives bearing butanoyl, hexanoyl

1085

and benzoyl chains at C3 [133]. These derivatives showed very low antimalarian

1086

activity against malaria parasite Plasmodium falciparum, indicating that the acetyl

1087

group is crucial in the melatonin antimalarian action. Luo et al. reported the synthesis of

1088

melatonin-derived

1089

multi/functional agents with cholinesterase inhibitory, antioxidant and neuroprotective

1090

activities [134].

benzylpyridinium

bromides,

1091

63

which

were

evaluated

as

1092 1093

Scheme 32. Synthesis of C3-modified melatonin analogues via derivatization of 5-

1094

methoxytryptamine (53). A Bedini et al. described the synthesis of the pinacol aryl

1095

boronate 208 [72]. This exhibited low anti-cancer activity. B Chegaev et al. reported the

1096

synthesis of melatonin analogues with NO-donors (209-215) [129]. 209-212 are

1097

agonists or partial agonists, whereas 213 and 215a,b are antagonists or inverse agonists

1098

at MT1 and MT2. The obtained compounds showed low binding affinity in comparison

1099

with melatonin. C Synthetic approach to [125I]SD6 (217) [126]. This showed non-

64

1100

selective full agonist properties and similar binding affinity in comparison to 2-

1101

iodomelatonin.

1102 1103

Piromelatine (Neu-P11, 218) is based on a 5-methoxytryptamine core bearing the

1104

comanic acid moiety attached at the C3 side chain (Scheme 33A). The synthetic

1105

methodology to prepare piromelatine (Neu-P11) was patented by Yang et al. and

1106

consisted in the direct reaction between comanic acid and 53 via amide formation [135].

1107

Neu-P11, which is under development by Neurim Pharmaceuticals, is a strong agonist

1108

for MT1/MT2 and 5-HT1A/5-HT1D receptors [136]. Further, Neu-P11 has shown anti-

1109

diabetic, antihypertensive and antidepressant effects [137].

1110

Di Giacomo et al. reported a synthetic route to dimeric melatonin ligands via reaction

1111

between 53 and either pimeloyl chloride or sebacoyl chloride, which was performed in

1112

the presence of triethylamine in THF [105]. The synthetized dimers did not show

1113

relevant binding affinity for human MT1 and MT2 in competition with 2-

1114

[125I]iodomelatonin. Han et al. reported the acylation of 53 to provide N-substituted and

1115

N,N-disubstituted melatonin analogues [138]. Results indicated that a second tryptamine

1116

core at the C3 side chain enhanced the analgesic potency.

1117

Hasan et al. reported the synthesis of the tamoxifen-melatonin hybrids 220a-e

1118

(Scheme 33B) [139]. The synthesis of 220a-e was carried out via coupling 53 with

1119

219a-e in the presence of Py in THF. 220b and 220c showed high affinity for MT1 and

1120

estrogen receptor 1. The binding affinity assay for human MT1 receptor was carried out

1121

in competition with 2-[125I]iodomelatonin. These derivatives inhibited tamoxifen-

1122

resistant MCF-7 cells (IC50 = 4-8 µM).

1123

An alternative synthetic approach to derivative 224 using 221 as the starting material

1124

was reported by Somei et al. (Scheme 33C) [55]. After methylation of 221 with methyl

65

1125

chloride to give 222, the methoxy group was introduced at C5 via treatment of 222 with

1126

methanol in acid medium. The resulting compound 223 was decarboxylated in the

1127

presence of sodium hydroxide and the (indol-3-yl)methyl moiety was introduced to

1128

provide the target compound 224.

1129

1130 1131

Scheme 33. Synthetic strategies to C3-modified melatonin analogues using 5-

1132

methoxytryptamine (53) as the starting material. A Synthetic approach to Neu-P11 (218) 66

1133

patented by Yang et al. [135]. Neu-P11 is under development by Neurim

1134

Pharmaceuticals and is a strong agonist at MT1/MT2 and 5-HT1A/5-HT1D receptors [136].

1135

B Synthetic route and chemical structure of the melatonin-tamoxifen drug conjugates

1136

220a-e [139]. 220b and 220c showed high affinity for MT1. C Synthetic route to N-

1137

(indol-3-yl)methyl-N-methyl-5-methoxytryptamine (224) described by Somei et al. [55].

1138 1139

Regarding the synthetic strategies from indole-3-carbaldehyde (225), Gurkok et al.

1140

reported the synthesis of indole hydrazine (226 and 227)/hydrazone (228) derivatives

1141

(Scheme 34A) [140-143]. The new compounds were synthetized via reaction between

1142

225 and different hydrazines/hydrazones that contained mainly aromatic structures.

1143

Later, the same synthetic strategy was employed to link N-protected amino acids into

1144

225 to obtain 229 [142]. Most synthetized compounds showed similar or higher

1145

antioxidant activity in comparison with melatonin. The indole-amino acid derivatives

1146

exhibited similar activity in comparison to melatonin in the radical-scavenging assay

1147

but more potent activities in the lipid peroxidation inhibition assay. On the other hand,

1148

Biradar et al. reported the synthesis of melatonin derivatives bearing barbitone

1149

[144,145]. The synthesis was based on the condensation of 225, or indole-3-carboxylic

1150

acid derivatives, with barbituric acid. Some synthetized compounds exhibited

1151

antioxidant and DNA cleavage activities. Yin et al. described the synthesis of gramine

1152

analogues via reaction between 225 and a wide range of cyclic amines [146]. Some

1153

synthetized compounds showed higher agonist activity at human MT1 and 5-HT1A

1154

receptors in comparison with gramine.

1155

An alternative synthetic strategy to the melatonin derivatives 234a-m and 235a-e was

1156

reported by Iakovou et al. using 3-acetylindole (230a) and N-methyl-3-acetylindole

1157

(230b) as the starting materials (Scheme 34B) [147]. The agonist and antagonist

67

1158

potency of the new analogues was assessed using the Xenopus laevis melanophores

1159

assay. None of the tested compounds exhibited any agonist action, while six of them

1160

(234d, 234e, 234l, 234m, 235a and 235b) were melatonin antagonists. The most potent

1161

antagonist was compound 235b, which also inhibited pigment aggregation. 235c and

1162

235e, which did not show any appreciable binding affinity, were found to be potent

1163

inhibitors of lipid peroxidation in rat liver microsomes.

1164

1165 1166

Scheme 34. Synthetic strategies to C3-modified melatonin analogues from indole-3-

1167

carbaldehyde (225) and 3-acetylindole (230a,b) as the starting materials. A Synthetic 68

1168

approach to the hydrazine/hydrazone derivatives 226, 227, 228 and 229 reported by

1169

Suzen et al. [140-143]. B Synthetic approach to 234a-m and 235a-e reported by

1170

Iakovou et al. [147] 234d, 234e, 234l, 243m, 235a and 235b were melatonin

1171

antagonists. 235b showed the strongest binding affinity and inhibited pigment

1172

aggregation. 235c and 235e inhibited lipid peroxidation in rat liver microsomes.

1173 1174

Regarding the synthetic strategies from indoles with carboxylic acid moieties at C3,

1175

Olgen et al. described the synthesis of C3-substituted indoles bearing 3,4-disubstituted

1176

and 2,4-disubstituted benzamines [148,149]. The benzamine derivatives were linked to

1177

indole-3-propanoic acid (236b) to form the corresponding amides. The same group also

1178

reported the reaction between indole-3-acetic acid (236a) and aliphatic amines. All

1179

reactions were performed in the presence of DCl as the catalyst in dry THF. The

1180

obtained amides showed significant antioxidant activity at low concentrations. Suzen et

1181

al. reported the linkage of aliphatic amines to methyl indole-3-propanoate [150]. The

1182

amide formation was performed by dissolving methyl indole-3-propanoate in the

1183

corresponding amine at reflux. The oxidative behaviour of the synthetized compounds

1184

was evaluated using voltammetric studies. Devender et al. employed indole-3-butyric

1185

acid, indole-3-propanoic acid (236b) and indole-3-acetic acid (236a) for the

1186

introduction of sulphonamides and triazole pharmacophores [151]. The antiplasmodial

1187

activity and cytotoxicity of the synthetized compounds was evaluated. The obtained

1188

results indicated that the sulphonamide derivatives showed higher activity in

1189

comparison to that detected for the triazole derivatives, but lower with respect

1190

antimalarial drug chloroquine.

1191

Tsotinis et al. reported the synthesis of the azides 239a,b and isothiocyanates 240a,b

1192

from 236a,b (Scheme 35A) [124]. Similarly to the properties of C2-linked azido and

69

1193

isothiocyanato derivatives 205a,b and 206a,b (Scheme 31), the obtained compounds

1194

(239a,b and 240a,b) antagonized melatonin action and showed lower binding affinity in

1195

comparison with luzindole. It was observed that the derivatives with longer side chain

1196

(239b and 240b) showed stronger affinity with respect the derivatives with shorter side

1197

chain (239a and 240a). The nature of the substituent, either azide or isothiocyanate, did

1198

not influenced the binding affinity. Ahner et al. reported the tritiation of the C3 chain of melatonin to provide [methylene-

1199 1200

3

1201

methoxyindole-3-acetonitrile (85b) was reduced with tritium gas in the presence of 5%

1202

rhodium on alumina as the catalyst to provide 241. Then, the melatonin analogue 242

1203

was achieved after acetylation of 241.

H]melatonin derivative 242 (Scheme 35B) [152]. To achieve this goal, 5-

1204

70

1205 1206

Scheme 35. Synthetic strategies to C3-modified melatonin analogues from carboxylic

1207

acid or cyanide derivatives. A Synthetic strategy to 240a,b from indole-3-acetic acid

1208

(236a) and indole-3-propanoic acid (236b), respectively, reported by Tsotinis et al.

1209

[124]. 239a,b and 240a,b antagonized melatonin action and showed lower binding

1210

affinity in comparison with luzindole. 239b and 240b showed stronger binding affinity

1211

in comparison with 239a and 240a. B Synthesis of [methylene-3H]melatonin (242)

1212

reported by Ahner et al. [152].

1213 1214

Ates-Alagoz et al. reported the synthesis of the retinoid derivative 244 (Scheme 36A)

1215

[153]. To achieve this goal, 43 was oxidized with phosphoryl chloride to give 51, which

1216

was used as precursor for the synthesis of 5-methoxytryptamine (53) using the same 71

1217

synthetic strategy described in Scheme 7C. 53 was finally reacted with 243 to produce

1218

the retinoid derivative 244. This strongly inhibited lipid peroxidation, achieving 96%

1219

inhibition at 10-4 M concentration. Furman et al. reported the synthesis of 4- and 6-

1220

substituted indole-3-carbadehydes via reaction of 4- and 6-substituted indoles with

1221

phosphoryl chloride [154]. The indole-3-carbadehydes were subsequently transformed

1222

into the corresponding tryptamine derivatives using standard reactions. Synthetized

1223

tryptamine derivatives exhibited anti-inflammatory activity.

1224

The indole-lipoic acid derivative 246 was synthetized by Gurkan et al. and the

1225

antioxidant activity against lipid peroxidation was analysed (Scheme 36B) [155]. The

1226

synthesis was carried out via treatment of 53 with racemic 245 and CDI in DMF to give

1227

the derivative 246, which exhibited 75.7% inhibition at 1 mM concentration. It must be

1228

noted that 53 was synthetized from 43 following the synthetic strategy described in

1229

Scheme 7C. 246 was later synthetized by Venkatachalam et al. following the same

1230

synthetic approach [156]. In this case, radiolysis studies indicated that the melatonin

1231

moiety of 246 reacts preferably with oxydizing agents, whereas the lipoic acid moiety

1232

reacts with reducing agents. The obtained results indicated that the conjugate 246 must

1233

be a radioprotector.

1234

Bahuguna et al. reported the introduction of side chains at C3 via Michael reaction to

1235

synthesize the melatonin precursor 249 (Scheme 37A) [157]. A nanocomposite of MoS2

1236

supported on gC3N4 nanosheets was developed and was shown to be able to catalyze the

1237

addition of nitroalkenes (248) into 5,6-substituted indoles (247) in aqueous solution to

1238

provide a wide range of 3-substituted indoles (249).

1239

72

1240 1241

Scheme 36. Synthetic strategies based on the derivatization of 5-methoxytryptamine-

1242

3-carbaldehyde (51) for the synthesis of C3-modified melatonin analogues. A Synthetic

1243

approach to retinoid derivative 244 reported by Ates-Alagoz et al. [153]. 244 inhibited

1244

lipid peroxidation at low concentrations. B Synthetic approach to the lipoic acid-

1245

melatonin analogue 246 reported by Gurkan et al. [155]. 246 inhibited lipid

1246

peroxidation.

1247 1248

Wolfard et al. reported a synthetic strategy that involved the alkylation of 5-

1249

substituted and 7-substituted indoles (250) with cyclic sulfamidates (251) (Scheme 37B)

1250

[158]. The position 3 was activated with MeMgCl in the presence of copper chloride,

1251

and then the indoles were treated with cyclic sulfamidates. The reaction was carried out

1252

at -20ºC in DCM. The synthetic methodology was used for the preparation of a number

1253

of 3,5-disubstituted indoles bearing diverse substitutions in the 2-aminoethyl chain

73

1254

(252). The synthetic approach also allowed the synthesis of agonist melatonin receptor

1255

TIK-301 (other synthetic strategies and properties of TIK-301 are described in

1256

“Modifications on C6” section).

1257

Other synthetic strategies are based on introduction of side chains at C3 under basic

1258

conditions. Buemi et al. reported the synthesis of 257b from 5-hydroxyindole (253)

1259

(Scheme 37C) [159]. After protection of the alcohol 253 with benzyl bromide in DCM

1260

to give 254, the 2-chloro-1-ethanone chain was introduced at C3 via reaction of 254

1261

with chloroacetyl chloride in the presence of Py. Then, the obtained 255 was reacted

1262

with 3,4-bis(benzyloxy)-N-piperidin-4-yl-benzamide (256) to provide 257a, which was

1263

O-deprotected with boron tribromide in DCM to give 257b. 257b was found to be a

1264

strong GluN2B/NMDA antagonist receptor ligand and showed antioxidant properties

1265

(ABTS inhibition: 94.1% at 17 µM). Later, the same research group used this synthetic

1266

strategy for the preparation of related structures [160].

1267

Hirotaki et al. reported the synthesis of the melatonin analogues 260 via reaction of

1268

substituted indoles (259) with aziridine 258 (Scheme 37D) [161]. It was found that the

1269

introduction of the Ns (o-nitrobenzenesulfonyl) group into the 2-CF3-aziridine ring

1270

enhanced the electrophilic character of the ring, allowing the base-free ring-opening

1271

reaction with indoles. The alkylation was carried out in xylene at 150ºC. 260 was

1272

produced as a racemic mixture.

1273

74

1274 1275

Scheme 37. Synthetic strategies to melatonin analogues based on the introduction of

1276

the side chain at C3. A Synthetic approach reported by Bahuguna et al. based on MoS2-

1277

catalyzed Michael addition [157]. B Metal-activated alkylation of indoles with cyclic

1278

sulfamidates reported by Wolfard et al. [158]. The synthetic approach also allowed the

1279

synthesis of agonist melatonin receptor TIK-301. C Synthetic approach to

1280

neuroprotective 257b via addition of side chain under basic conditions reported by

1281

Buemi et al. [159]. 257b was found to be a strong GluN2B/NMDA antagonist receptor

75

1282

ligand and showed antioxidant properties. D Synthetic strategy based on the akylation

1283

with aziridine reported by Hirotaki et al. [161].

1284 1285

Tsotinis et al. reported a new synthetic strategy that allowed the preparation of 265a-

1286

m using indole (261) and 5-methoxyindole (43) as the starting materials (Scheme 38A)

1287

[162]. After formation of the nitriles 262a,b by treating 43 and 261 with formaldehyde

1288

and potassium cyanide, 262a,b were N-methylated to give 263a,b. Treatment of these

1289

with potassium bis(trimethylsilyl)amide (KHMDS) followed by the appropriate

1290

dihaloalkane gave 264a-c, which were reduced to the corresponding amine and acylated

1291

to give 265a-m. A similar synthetic strategy was also used for the synthesis of the C3

1292

modified melatonin analogues 266a-e and 267a,b, which did not contain the N-methyl

1293

group (Scheme 38B) [162]. The binding affinities of the synthetized compounds at

1294

human MT1 and MT2 receptors using 2-[125I]iodomelatonin were examined. The agonist

1295

and antagonist properties were studied using the Xenopus laevis melanophores assay.

1296

Results indicated that the introduction of the N-methyl group reduced the binding

1297

affinity. Similarly, the addition of voluminous moieties at the C3 chain provided

1298

derivatives with lower binding affinity and/or changes from agonist to antagonist

1299

ligands (compounds 265g,f and 266d,e showed antagonist activity). The absence of

1300

methoxy group at C5 also produced antagonist compounds (265i-m). It was found that

1301

small incremental changes in size at N1 (addition of the N-methyl group) and C3 mainly

1302

affected the human MT1 receptor, while the human MT2 receptor remained much more

1303

tolerant. This effect provided compounds, such as 265c or 265f, which showed agonist

1304

activity and moderate-high MT2/MT1 affinity ratios. It must be noted that all derivatives

1305

showed lower binding affinities in comparison to melatonin.

1306

76

1307 1308

Scheme 38. Synthetic approaches to C3-modified melatonin derivatives based on the

1309

introduction of side chains under basic conditions. A Synthetic approach to melatonin

1310

derivatives 265a-m reported by Tsotonis et al. [162]. B Melatonin analogues 266a-e

1311

and 267a,b synthetized by Tsotonis et al. [162]. All synthetized compounds showed low

1312

binding affinities. 265c or 265f showed agonist activity and high MT2/MT1 affinity

1313

ratios.

1314

77

1315

Regarding the synthetic strategies that involve the formation of the indole ring, Marais

1316

et al. reported the synthesis of the α-amino acid 269 following the same synthetic

1317

approach described in Scheme 2D [45]. In this case, the reaction was carried out using

1318

methoxyphenylhydrazine (2) and 268 in acetic acid to provide 269 in quantitative yield

1319

(Scheme 39A).

1320

An alternative approach for the synthesis of the melatonin analogues 274a-l based on

1321

the construction of the indole ring via Bischler reaction was reported by Tsotinis et al.

1322

(Scheme 39B) [162]. After formation of the indole ring by reaction between 270 and

1323

271a-c to provide 272a-c, the amides 273a-c were obtained via reaction of 272a-c with

1324

ammonia. Then, 273a-c were reduced with lithium aluminium hydride and acylated to

1325

give 274a-l. Affinity studies using human MT1 and MT2 in competition with 2-

1326

[125I]iodomelatonin and Xenopus laevis melanophores assays revealed that all

1327

derivatives bearing a cyclopentane ring (274h-l) showed antagonist properties, whereas

1328

the compounds with methyl groups (274a-g) exhibited agonist behaviour. In general,

1329

274a-g showed higher binding affinity and higher MT2/MT1 affinity ratio in comparison

1330

to 274h-l. 274e and 274f showed 9 and 11.5 MT2/MT1 ratios, respective, and a binding

1331

affinity for MT2 slightly lower than that of melatonin.

1332

78

1333 1334

Scheme 39. Synthetic approaches to C3 melatonin analogues based on the

1335

construction of the indole ring. A Synthetic approach to 269 via Fischer reaction

1336

reported by Marais et al. [45]. B Synthetic approach to 274a-l via Bischler reaction

1337

reported by Tsotinis et al. [162]. 274h-l showed antagonist properties, whereas 274a-g

1338

exhibited agonist behaviour. 274e and 274f showed moderate-high MT2/MT1 ratios, and

1339

a binding affinity for MT2 slightly lower than that of melatonin.

1340 1341

3.4. Modifications on C4

1342

Few reports of 4-substituted melatonin analogues can be found in the literature. It

1343

must be noted that the studied 4-substituted melatonin analogues have shown weak

1344

binding affinities for MT1 and MT2 but much higher binding affinities for MT3 binding

1345

site in comparison to melatonin. It has been found that the introduction of substituents at 79

1346

C4 sometimes causes the change from agonist to potent antagonist ligands. Some 4-

1347

substituted melatonin analogues exhibited high antioxidant activities.

1348

Hayakawa et al. reported the synthesis of 4-fluoromelatonin (279) (Scheme 40A)

1349

[163]. The synthetic strategy consisted in the activation of the 4 position of indole 275

1350

using

1351

fluorobenzenesulfonimide (NFSi) to provide 276. Deprotection of the amine 276 and

1352

substitution with trimethylsilyl cyanide (TMSCN) provided the cyanide 277, which was

1353

reduced with lithium aluminium hydride to give the amine 278. N-Acetylation of 278

1354

gave the target compound 279. The electrophilic nature of position 4 was also used by

1355

Leclerc et al. for the introduction of nitro groups (Scheme 40B) [164]. Direct treatment

1356

of N-t-butoxycarbonyl (N-Boc) or N-SO2C6H5 melatonin with nitric acid in acetic

1357

anhydride provided the nitrosylation of positions 4 and 6, respectively (compounds

1358

nitrosylated in position 6 are described in “Modification on C6” section). After N-

1359

deprotection, 4-nitromelatonin (280) was obtained. Interestingly, 280 showed a

1360

considerable loss of MT1 and MT2 binding affinity compared to melatonin but a 60-fold

1361

higher affinity on the MT3 binding site, indicating that 280 is a MT3 specific ligand.

1362

Competition studies for human MT1 and MT2 with 2-[125I]iodomelatonin were used in

1363

these experiments, whereas the affinity for MT3 was screened in hamster brain

1364

preparations. N-methylation of 280, which was achieved by treating 280 with dimethyl

1365

sulfate in the presence of sodium hydroxide, provided N-methyl-4-nitromelatonin. This

1366

compound showed a similar MT3/MT2 ratio and improved the MT3/MT1 ratio compared

1367

to 280.

t-butyllithium

and

subsequent

fluorination

in

the

presence

of

N-

1368

Furman et al. reported an alternative synthetic approach to 4-substituted indole-3-

1369

carbadehydes via formylation of 4-substituted indoles [154]. Then, the resulting

1370

aldehydes were transformed into the corresponding tryptamine analogues using

80

1371

common reactions. The synthetized compounds showed strong inhibitory activity

1372

against acetyl and butyrylcholinesterases.

1373

1374 1375

Scheme 40. Derivatization of 3,5-disubstituted tryptamines to produce C4-substituted

1376

melatonin analogues. A Synthetic route to 4-fluoromelatonin (279) reported by

1377

Hayakawa et al. [163]. B 4-Nitromelatonin structure (280), which was synthetized by

1378

Leclerc et al. [164]. 280 showed 60-fold higher affinity for the MT3 binding site in

1379

comparison to melatonin.

1380 1381

Venepally et al. described the synthesis of the 4-methoxymelatonin analogues 286a-h

1382

using 2,3-dimethoxybenzaldehyde (281) as the starting material (Scheme 41) [165].

1383

This synthetic approach involved the formation of the indole core. The cytotoxic effects

1384

and the antioxidant activity of the obtained compound were examined. It was found that

1385

the derivatives with long N-acyl chains (286a-c) showed higher antioxidant activity in

81

1386

comparison to that detected for derivatives with short N-acyl chains (286d-h). In some

1387

cases, the antioxidant activity of the derivatives was similar to that detected for

1388

butylated hydrotoluene. In contrast, the highest cytotoxic results were found with

1389

compounds with short N-acyl chains. It must be noted that all synthetized compounds

1390

showed lower cytotoxicity in comparison with doxorubicin.

1391

As described in “Modifications on N1” section, Tsotinis et al. reported the synthesis

1392

of N-OMe melatonin analogues bearing a fluoro group at C4 [63]. In contrast with the

1393

results obtained with the 5-fluoro compounds, 4-fluoro compounds showed antagonist

1394

activity. Interestingly, it was found that 68 (Scheme 9B), containing a cyclopropanoyl

1395

moiety at the C3 side chain, showed 3-fold higher binding affinity than luzindole.

1396

1397 1398

Scheme 41. Synthetic approach to 4-methoxymelatonin analogues 286a-h reported by

1399

Venepally et al. [165]. 286d-h showed similar antioxidant activities in comparison to

1400

butylated hydrotoluene.

1401 1402

3.5. Modifications on C5

82

1403

C5-Modified melatonin analogues have shown singular properties as melatoninergic

1404

ligands. Among C5-modified melatonin analogues, one compound must be highlighted:

1405

5-HEAT. 5-HEAT has a unique pharmacological profile acting as a full agonist at the

1406

hMT1 receptor and antagonist at the hMT2 receptor. Some C5-modified melatonin

1407

analogues showed high binding selectivity for MT1.

1408

Some synthetic strategies are based on the derivatization of 5-substituted indoles,

1409

including C5-activated indoles or N-acetyl-5-hydroxytryptamine. Lozinska et al.

1410

reported a synthetic strategy to the donepezil-melatonin hybrids 289a-e using 3-

1411

(acetamidomethyl)-1H-indol-5-yl 4-nitrophenylcarbonate (287) as the starting material

1412

(Scheme 42A) [166]. The attachment of 288a-e into 287 was performed in the presence

1413

of DMAP as the catalyst in DCM. The inhibitory activity of 289a-e against human

1414

acetyl and butyrylcholinesterases was examined, indicating that the derivatives with

1415

long side chains at C5 (289a,b) showed higher inhibitory activity than that observed for

1416

the derivatives with short chains (289c-e).

1417

Ahern et al. described the tritiation of N-acetyl-5-hydroxytryptamine (58) with

1418

[3H]methyl iodide to provide [methoxy-3H]melatonin [152]. Similarly, Chegaev et al.

1419

reported the direct introduction of NO-donors into 58 [129]. In this case, the reaction

1420

was performed in the presence of potassium carbonate in acetonitrile. As observed for

1421

the C3-modified melatonin analogues with NO-donors (Scheme 29B), the compounds

1422

with high lipophilicity showed the highest antioxidant activity. A wide range of

1423

melatonin analogues with arylalkyl and aryloxyalkyl substituents at C5 were

1424

synthetized by Markl et al. (Scheme 42B) [167]. 290, which was used as the starting

1425

material, was submitted to hydrogenation over Ra-Ni and palladium on carbon in acetic

1426

anhydride to provide 58. Then, this was alkylated in the presence of potassium or

1427

cesium carbonate to provide derivatives 291a-c (not all synthetized derivatives are

83

1428

shown in Scheme 42B). On the other hand, reaction of 58 with 1-bromo-3-

1429

chloropropane gave the dimer 292. Affinity binding studies of 291a-c and 292 for

1430

human MT1 and MT2 using 2-[125I]iodomelatonin revealed that the alkylated derivatives

1431

bearing -O-(CH2)3-Ph (291b) and -O-(CH2)3-O-Ph (291c) chains at C5 showed high

1432

MT1/MT2 ratios (>10). Interestingly, 291a showed higher binding affinity in

1433

comparison to melatonin (291a, MT1 Ki = 0.15 nM, MT2 Ki = 0.19 nM; melatonin, MT1

1434

Ki = 0.46 nM, MT2 Ki = 0.95 nM). However, 291a did not show any relevant selectivity.

1435

Zlotos et al. reported the synthesis of the difluoroacetamide derivative 293 starting

1436

from 291c (Scheme 42C) [168]. The synthesis of 293 was carried out via N-

1437

deacetylation of 291c in the presence of potassium hydroxide, and subsequent reaction

1438

of the resulting amine with methyl 2,2-difluoroacetate. Although 293 and 291c show

1439

important structural similarities, binding affinity studies revealed that 293 exhibited no

1440

selectivity for human MT1 or MT2 receptors (2-[125I]iodomelatonin was used in the

1441

binding affinity screening).

1442

84

1443 1444

Scheme 42. Synthetic approaches to C5-modified melatonin analogues. A Synthetic

1445

strategy to 289a-e reported by Lozinska et al. [166]. 289c-e showed high inhibitory

1446

activity against human acetyl and butyrylcholinesterases. B Synthetic strategy to 291a-c

1447

and 292 reported by Markl et al. [167]. 291b and 291c showed high MT1/MT2 ratios.

1448

291a showed higher binding affinity in comparison to melatonin and no selectivity. C

1449

Structure of the difluoroacetamide analogue 293 reported by Zlotos et al. [168]. 293

1450

showed non-selective affinity for MT1 and MT2. The affinity of 293 was lower in

1451

comparison to melatonin.

85

1452 1453

Karamitri et al. reported the synthesis of the C5-modified melatonin analogues 296

1454

and 297a-e from 58 (Scheme 43A) [169]. O-alkylation of 58 using methyl 5-

1455

bromovalerate yielded the ester 294. After ester hydrolysis of 294 in basic medium to

1456

the acid 295, the monovalent melatonin analogue 296 was prepared by coupling 295

1457

with n-propylamine. On the other hand, the acid 295 was submitted to amide coupling

1458

with diaminoalkanes of different chain lengths H2N-(CH2)n-NH2 (n = 4, 6, 8, 10 and 12)

1459

using EDC as the catalyst to give the target bivalent ligands 297a-e. All synthetized

1460

derivatives showed lower binding affinity for human MT1 and MT2 receptors (2-

1461

[125I]iodomelatonin was used as the radioligand) in comparison to melatonin. The

1462

binding affinity of 297a-e increased with increasing the spacer length. The bivalent

1463

ligands 297a-e increased BRET signals of MT1 dimers up to 3-fold compared to the

1464

monomeric ligand 296, indicating the simultaneous binding of the two pharmacophores

1465

to dimeric receptors.

1466

Nonno et al. reported the first synthetic approach to 5-HEAT (299) (Scheme 43B)

1467

[170]. The 5-oxyacetic acid methyl ester derivative 298 was prepared by O-alkylation of

1468

58 with methyl chloroacetate in DMF. Reduction of the ester 298 with lithium

1469

aluminium hydride gave the 5-hydroxyethoxy melatonin analogue 299. 5-HEAT

1470

showed a little selectivity for the MT1 receptor, with an affinity around five times higher

1471

than for the MT2 receptor. It was shown that 5-HEAT has an exceptional

1472

pharmacological profile acting as a full agonist at the MT1 receptor and antagonist at the

1473

MT2 receptor. 5-HEAT showed lower binding affinity in comparison with melatonin.

1474

Later, Spadoni et al. reported the synthesis of 5-HEAT derivatives with different chains

1475

at C5 (300a-k) (Scheme 43C) [171]. It was found that the substitution at C2 with

1476

bromine or phenyl groups enhanced the binding affinity. The best mixed MT1

86

1477

agonist/MT2 antagonist profile was found when using derivative 300g, which showed

1478

higher binding affinity in comparison to 5-HEAT (5-HEAT, MT1 pKi = 7.77 nM, MT2

1479

pKi = 7.12 nM; 300g, MT1 pKi = 8.84 nM, MT2 pKi = 7.70 nM; melatonin, MT1 pKi =

1480

9.69 nM, MT2 pKi = 9.52 nM). Binding affinity studies were carried out at human MT1

1481

and MT2 receptors using 2-[125I]iodomelatonin.

1482

1483 1484

Scheme 43. Synthetic approaches to C5-modified melatonin analogues. A Synthetic

1485

approach to melatonin derivatives 296 and 297a-e reported by Karamitri et al. [169]. 87

1486

297a-e exhibited higher binding affinity with respect 296, indicating the simultaneous

1487

binding of the two melatonin structures to dimeric receptors. B Synthetic approach to 5-

1488

HEAT (5-hydroxyethoxy-N-acetyltryptamine, 299) reported by Nonno et al. [170]. 5-

1489

HEAT is agonist at the MT1 receptor and antagonist at the MT2 receptor. C 5-HEAT

1490

derivatives 300a-k reported by Spadoni et al. [171]. 300g showed higher binding

1491

affinity in comparison to 5-HEAT.

1492 1493

As described in “Modifications on N1” section, Tsotinis et al. reported the synthesis

1494

of the N-OMe melatonin analogue 67, which contains a fluoro group at C5 (Scheme 9B)

1495

[63]. Although the derivatives bearing the fluoro group at C4 showed antagonist activity,

1496

the derivatives with the fluoro at C5 showed agonist activity. It must be noted that the

1497

fluoro compound 67 showed approximately 20-times less potent activity in comparison

1498

with N-OMe melatonin.

1499

Dual-acting melatonin derivatives bearing an O-arylcarbamate group at C5 (304a-c)

1500

were designed by Spadoni et al. (Scheme 44) [172]. 58, which was used as the starting

1501

material, was reacted with appropriate t-butyl (ω-bromoalkyl)carbamates in the

1502

presence of potassium carbonate to provide 301a,b. The 2-bromoindole derivative 301c

1503

was obtained by bromination of 301a with trimethylphenylammonium tribromide in

1504

THF. After N-deprotection with trimethylbromo silane, the resulting amines 302a-c

1505

were condensed with 303 to give the target melatonin analogues 304a-c. 304c showed

1506

remarkable double function as melatoninergic ligand and fatty acid amide hydrolase

1507

inhibitor. 304c showed non-selective high affinity for human MT1 and MT2 (2-

1508

[125I]iodomelatonin was used as the radioligand). Administration of 304c reduced

1509

elevated intraocular pressure in rabbits, with a longer action and improved effcacy

88

1510

compared to the reference compounds melatonin and URB597, cyclohexylcarbamic

1511

acid 3´-carbamoylbiphenyl-3-yl ester.

1512

1513 1514

Scheme 44. Synthesis of the C5-substituted melatonin derivatives 304a-c reported by

1515

Spadoni et al. [172]. 304c showed remarkable double function as melatoninergic ligand

1516

and fatty acid amide hydrolase inhibitor.

1517 1518

3.6. Modifications on C6

1519

Melatonin derivatives that contain substitutions at C6 were shown to have diverse

1520

applications as anti-inflammatory and anti-ovulatory agents, and melatoninergic ligands.

1521

All synthetized C6-substituted melatonin analogues have been obtained via introduction

1522

of small substituents and have shown non-selective full agonist properties at melatonin

1523

receptors. Three melatoninergic ligands based on C6-substituted structures must be

1524

highlighted: 6-hydroxymelatonin, 6-chloromelatonin and TIK-301 [31]. The binding 89

1525

affinity of 6-chloromelatonin for MT1 and MT2 was found to be higher than that of 6-

1526

hydroxymelatonin and similar to that of melatonin (6-chloromelatonin, MT1 Ki = 11.4

1527

nM, MT2 Ki = 0.20 nM; 6-hydroxymelatonin, MT1 Ki = 40.2 nM, MT2 Ki = 5.5 nM;

1528

melatonin, MT1 Ki = 0.88 nM, MT2 Ki = 0.18 nM). 6-Hydroxymelatonin is of particular

1529

interest due to it is a major metabolite of melatonin. In humans, most melatonin in the

1530

general circulation is converted to 6-hydroxymelatonin by the liver, which clears 92 to

1531

97% of circulating melatonin in a single pass [173]. TIK-301 was found to be more

1532

potent than melatonin at melatonin receptors MT1 and MT2 and to act as an antagonist

1533

at the serotonin 5-HT2C and 5-HT2B receptors [174]. TIK-301 was first developed by Eli

1534

Lilly and Co and is currently in advanced state of clinical studies. This section has been

1535

divided into 2 different subsections: synthesis of C6-substituted melatonin analogues

1536

(3.6.1) and synthesis of TIK-301 (3.6.2).

1537 1538

3.6.1. Synthesis of C6-substituted melatonin analogues

1539

The synthesis of 6-substituted indoles has been carried out using indole derivatives as

1540

the starting materials or via formation of the indole core. Two different synthetic

1541

approaches from 6-benzyloxy-5-methoxyindole (305) and melatonin (1) were reported

1542

for the preparation of 6-hydroxymelatonin (307). The first synthetic strategy consisted

1543

in the formylation of 305 at C3 (Scheme 45A) [175]. Subsequent Knoevenagel

1544

condensation and final O-benzyl deprotection allowed the preparation of 307. Similarly,

1545

Taborsky et al. described the introduction of the C3 side chain into 305 via Mannich

1546

reaction

1547

hydrogenation and acetylation to produce 307 [176].

with

formaldehyde

and

dimethylamine,

substitution

with

cyanide,

1548

On the other hand, Karam et al. reported an alternative synthetic route to 307 via

1549

introduction of the hydroxyl group into the melatonin core (1) (Scheme 45B) [177]. 1

90

1550

was N-protected with ethyl chloroformate to provide 308. Then, a regioselective

1551

Friedel–Crafts acylation at the 6 position of 308 using acetyl chloride and aluminium

1552

chloride afforded 309, which was submitted to Baeyer–Villiger oxidation with m-

1553

chloroperoxybenzoic acid (mCPBA) to give 310. O- and N-deprotections were

1554

accomplished under basic conditions to furnish 307.

1555

1556 1557

Scheme 45. Synthesis of 6-hydroxymelatonin (307), which is a full agonist at

1558

melatonin receptors and shows lower binding affinity in comparison with melatonin.21

1559

A Synthetic strategy to 307 based on the introduction of the C3 chain reported by Hall

1560

et al. [175]. B Synthetic strategy to 307 based on the introduction of the C6 hydroxy

1561

group reported by Karam et al. [177].

1562

91

1563

The synthesis of 6-sulphatoxymelatonin was successfully achieved by Leone et al.

1564

[178]. The synthetic approach consisted in the direct reaction between 6-

1565

hydroxymelatonin (307) and chlorosulphonic acid in DMF. Recently, Abeysuriya et al.

1566

developed a model to monitor the sleep dynamics using 6-sulphatoxymelatonin [179].

1567

As 6-hydroxymelatonin, 6-sulphatoxymelatonin occurs in nature and is one of the major

1568

metabolites of melatonin.

1569

Furman et al. reported the synthesis of 6-substituted indole-3-carbadehydes, which

1570

were subsequently transformed into the corresponding tryptamine derivatives [154].

1571

The synthetized tryptamine analogues lacked of methoxy group at C5 and were

1572

evaluated as anti-inflammatory agents. Leclerc et al. described the synthesis of 6-

1573

nitromelatonin, which was achieved via reaction of N-benzenesulfonylmelatonin with

1574

nitric acid and subsequent N-deprotection [164].

1575

Regarding the synthesis of C6-substituted melatonin analogues via formation of the

1576

indole core, Flaugh et al. reported synthesis of melatonin analogues bearing with chloro

1577

and fluoro groups at C6 (320a,b) using 5-methyl-2-nitrophenol (311) as the starting

1578

material (Scheme 46) [56]. The antiovulatory activity of the synthetized compounds

1579

was examined, indicating that the halogenation at C6 allows a relevant increase in the

1580

activity. Hugel reported a similar synthetic approach for the preparation of 6-

1581

chloromelatonin (320a) [180]. Later, Dong et al. reported the synthesis of a wide range

1582

of 6-methoxytryptamine analogues [181].

1583

Dubocovich et al. studied the binding affinity of 6-chloro-2-methylmelatonin for

1584

human MT1 and MT2 receptors using 2-[125I]iodomelatonin. The obtained results

1585

indicated that the introduction of the methyl group at C2 increased the affinity for MT1

1586

but reduced the affinity for MT2 [76].

1587

92

1588 1589

Scheme 46. Synthetic approach to the C6-substituted melatonin analogues 320a,b

1590

bearing chloro and fluoro groups at C6 [56]. 320a showed similar binding affinity for

1591

MT1 and MT2 in comparison with melatonin.

1592 1593

3.6.2. Synthesis of TIK-301

1594

Flaugh patented a synthetic approach to racemic TIK-301 (327) from 6-chloro-5-

1595

methoxyindole (319a) (Scheme 47) [182]. The condensation of 319a with Meldrum’s

1596

acid and acetaldehyde in the presence of L-proline as the catalyst gave the adduct 321,

1597

which was treated with Cu and ethanol in refluxing Py to yield 322. The reaction of 322

1598

with hydrazine at reflux afforded 323, which was treated with sodium nitrite in acetic

1599

acid to provide the tricyclic system 324. Ring-opening of 324 was successfully achieved

1600

in alkaline medium to give the amino acid 325. The decarboxylation of 325 by means of

1601

refluxing in methanesulfonic acid afforded 326, which was finally acylated with acetic 93

1602

anhydride and Py to provide the target compound 327. Recently, Stephenson et al.

1603

reported the resolution of the racemic mixture into its enantiomers via reaction of the

1604

racemate 327 with L-TA and selective crystallization [183]. It must be noted that only

1605

the R enantiomer was found to be a melatonin agonist, whereas the S enantiomer was

1606

inactive.

1607

1608 1609

Scheme 47. Synthetic route to racemic TIK-301 (327) patented by Flaugh [182]. The

1610

R enantiomer showed stronger binding affinity in comparison with melatonin and is

1611

currently in advanced state of clinical studies ((R)-327, MT1 Ki = 0.081 nM, MT2 Ki =

1612

0.042 nM).

1613 1614

Later, Flaugh patented a second synthetic approach based on the formation of the

1615

indole core that allowed the preparation of enantiomerically pure (R)-327 (Scheme 48)

1616

[184]. The reduction of pulegone (328) with hydrogen over palladium on carbon 94

1617

provided the menthol 329, which was oxidized with chromium trioxide to yield 330.

1618

Oxigenation of 330 with trifluoroperacetic acid via Baeyer-Villiger reaction allowed the

1619

formation of 331, which was treated with sodium ethoxide in ethanol to obtain the

1620

corresponding ethyl monoester 332. The reaction of 332 with diethyl carbonate afforded

1621

333. Then, this was reacted with oxalyl chloride to provide the expected acyl chloride

1622

334. The reaction of 334 with sodium azide and benzyl alcohol gave the intermediate

1623

azide that rearranged to the benzyl carbamate 335. Reductive cyclization of 335 with

1624

hydrogen over palladium on carbon yielded 336, which was condensed with the

1625

diazonium salt 337 to afford the hydrazono derivative 338. Cyclization of 338 was

1626

attempted in hot formic acid to give the tricycle 339. Ring opening, decarboxylation and

1627

final acetylation were performed as previously patented by the same research group to

1628

provide enantiomerycally pure (R)-327.

1629

95

1630 1631 1632

Scheme 48. Synthetic approach to enantiomerically pure (R)-327 patented by Flaugh [184].

1633 1634

3.7. Modifications on C7

1635

Few synthetic approaches to C7-substituted melatonin analogues can be found in the

1636

literature. All synthetic approaches were based on the introduction of the C3 side chain

1637

and only allowed the formation of melatonin analogues bearing small substituents.

1638

Obtained melatonin analogues showed decreased binding affinities in comparison with

1639

melatonin and moderate selectivity to the MT2 receptor.

1640

Leclerc et al. reported the synthesis of 7-nitromelatonin (341) from 7-nitro-5-

1641

methoxyindole (340) via introduction of the chain at C3 by Mannich reaction with

96

1642

formaldehyde and dimethylamine, and subsequent substitution with cyanide, reduction

1643

and acetylation (Scheme 49A) [164]. 341 was evaluated as melatoninergic ligand and

1644

showed stronger binding affinity for MT1 and MT2 than for MT3. Human MT1 and MT2

1645

receptors (2-[125I]iodomelatonin was used as the radioligand) and MT3 from hamster

1646

brain preparations were used in this screening. The binding affinity of 341 was 400 and

1647

100 times less potent than melatonin for MT1 and MT2, respectively. Spadoni et al. also

1648

observed a reduction in the binding affinity for human MT1 and MT2 receptors when

1649

using 5,7-dimethoxymelatonin [185].

1650

Faust et al. described the synthesis of 7-substituted melatonin analogues (344a-f and

1651

345a-f) using 7-substituted indoles (342a,b) as the starting materials (Scheme 49B)

1652

[186]. Affinity studies at human MT1 and MT2 receptors (2-[125I]iodomelatonin was

1653

used as the radioligand) and Xenopus melanophores were examined. The obtained

1654

results revealed that 7-methylmelatonin (344a), 7-bromomelatonin (344d) and 7-

1655

phenylmelatonin are 575, 42 and 1500 times less potent than melatonin in the Xenopus

1656

melanophores assay. The introduction of the N-methyl group has a rather small effect,

1657

reducing the binding affinity for MT1. In this sense, 345f showed the highest MT2/MT1

1658

ratio, 15.5. The rest of the 7-substituted melatonin analogues showed slightly higher

1659

affinity to MT2 over MT1, except for 7-phenylmelatonin that was equipotent.

1660

97

1661 1662

Scheme 49. Synthetic approaches to C7-substituted melatonin analogues. A Synthetic

1663

approach to 7-nitromelatonin (341) reported by Leclerc et al. [164]. 341 showed low

1664

binding affinity for MT1 and MT2. B Synthetic approach to melatonin analogues 344a-f

1665

and 345a-f reported by Faust et al. [186]. These showed low binding affinities at MT1

1666

and MT2. 345f showed 15.5 MT2/MT1 ratio.

1667 1668

4. Melatonin analogues based on azaindole cores

1669

Azaindoles have found diverse applications as melatoninergic ligands. Some

1670

melatonin analogues based on 4-azaindole cores have shown interesting fluorescent

1671

properties and have been used for the identification of melatonin receptors in cells. For

1672

example, [125I]S70254, which is specific for the MT2, was successfully used for

1673

autoradiography studies in rat and sheep brain and retina slices [126,187]. 4-

1674

Azamelatonin and some 7-azamelatonin analogues have shown stronger binding

1675

affinities in comparison to melatonin. EFPPEA, which is based on a 7a-azaindole core, 98

1676

was identified as a potent non-selective agonist. Although most synthetic approaches to

1677

azamelatonin analogues are based on the formation of the indole ring, some synthetic

1678

approaches to 4-aza, 7-aza and 7a-azamelatonin analogues start from commercial

1679

azaindoles.

1680 1681

4.1. 3-Azaindoles

1682

Koike et al. reported the synthesis of a number of azaindoles, including the 3-

1683

azaindole 355 (Scheme 50) [188]. The synthesis of 355 was carried out from 2,6-

1684

difluorophenylacetic acid (346), which was reduced with lithium aluminium hydride to

1685

provide the alcohol 347. After acetylation with acetyl chloride, the resulting compound

1686

348 was nitrosylated with nitric acid to give 349. Selective SNAr displacement of the

1687

fluoro group of 349 with Boc-ethylenediamine afforded 350, which was then submitted

1688

to O-deprotection with lithium hydroxide to obtain 351 after intramolecular cyclization.

1689

Hydrogenation of 351 over palladium on carbon led to the amine 352. The formation of

1690

the 3-azaindole 353 was achieved via treatment of 352 with triethyl orthobenzoate in the

1691

presence of p-toluenesulfonic acid. Finally, Boc deprotection of 353 with hydrochloric

1692

acid and acetylation with acetyl chloride allowed the formation of the target 3-azaindole

1693

355. Binding affinity studies for human MT1 and MT2 using 2-[125I]iodomelatonin

1694

receptors indicated that 355 exhibited less binding affinity compared to melatonin and

1695

other synthetized 7a-azaindoles. 355 showed no significant selectivity.

1696

99

1697 1698 1699

Scheme 50. Synthetic approach to the 3-azaindole 355 reported by Koike et al. [188]. 354 exhibited lower binding affinity compared to melatonin.

1700 1701

4.2. 3a-Azaindoles

1702

El Kazzouli et al. reported a synthetic approach to a novel class of melatonin receptor

1703

ligands based on 3a-azamelatonin cores (363 and 364) (Scheme 51) [189]. To achieve

1704

this goal, 2-amino-5-bromopyridine (356) was treated with 2-bromoacetone and sodium

1705

bicarbonate to give 357. The methoxy group was then introduced at C5 using methanol

1706

in the presence of copper iodide to lead 358. Treatment of 358 with N2CH2CO2CH2CH3

1707

and copper in refluxing toluene allowed the formation of the ester 359. The alcohol 360

1708

was obtained after reduction of 359 with sodium borohydride. Then, the intermediate

1709

360 was converted to the azide 361 by treatment with sodium azide in the presence of

1710

triphenylphosphine. 361 was reduced in the presence of hydrogen over palladium on 100

1711

carbon and the resulting amine 362 was acetylated with acetic anhydride to give the

1712

desired melatonin analogue 363. The melatonin derivative 364 was prepared from

1713

intermediate 358. The binding affinities of the synthetized compounds at human MT1

1714

and MT2 were determined using 2-[125I]iodomelatonin as the radioligand, indicating that

1715

363 and 364 showed lower binding affinities in comparison with melatonin. 363 showed

1716

moderate selective binding affinity for receptor MT2, 18.7 MT2/MT1 ratio.

1717

1718 1719

Scheme 51. Synthetic approaches to 3a-azamelatonin analogues reported by El

1720

Kazzouli et al. [189]. A Synthetic approach to derivative 363. This showed selective

1721

binding affinity to receptor MT2. B Synthetic approach to derivative 364. Both 363 and

1722

364 showed low binding affinities.

1723

101

1724

The synthesis of the 3a-azaindole 368 was attempted by Koike et al. using 2,3-

1725

dihydrofuro[3,2-b]pyridin-5-amine (365) as the starting material (Scheme 52) [188].

1726

This was coupled with α-bromoacetophenone in the presence of p-toluenesulfonic acid

1727

to give 366. Mannich reaction of 366 with formaldehyde and dimethylamine provided

1728

the amine 367, which was converted to the target compound 368 after quarternization of

1729

the Mannich base, substitution with a cyanide, hydrogenation and final acetylation.

1730

Affinity studies for human MT1 and MT2 receptors using 2-[125I]iodomelatonin

1731

indicated that 368 exhibits low binding affinity for MT2 (approximately 30 times lower

1732

in comparison to melatonin), whereas the binding affinity (Ki) for MT1 was higher than

1733

100 nM and was not determined.

1734

1735 1736 1737

Scheme 52. Synthetic approach to the 3-azaindole 368 reported by Koike et al. [188]. 367 exhibited low binding affinity for MT1 and MT2.

1738 1739

4.3. 4-Azaindoles

1740

The 3-substituted-4-azaindoles 371a,b were synthetized from pyridilacetonitriles

1741

369a,b in a 2-step route (Scheme 53A) [190]. The synthetic approach consisted in the

1742

alkylation of 369a,b via Michael addition or Knoevenagel condensation to give 370a,b

1743

followed by hydrogenation over palladium on carbon to produce the indoles 371a,b.

102

1744

The synthetic strategy allowed the introduction of a number of different substituents at

1745

C3, such as methyl, benzyl, p-substituted benzyl groups, n-propyl, naphthyl or

1746

cyanomethyl, which was used for the synthesis of 4-azamelatonin (376) by reduction

1747

and acetylation.

1748

The synthesis of 376 was also reported by Mazeas et al. (Scheme 53B) [191]. To

1749

achieve

this

goal,

2-methoxy-5-nitropyridine

1750

chlorophenoxyacetonitrile and potassium t-butoxide in THF at -10ºC to give 373.

1751

Elaboration to 374 was accomplished by catalytic hydrogenation of 373 using palladium

1752

on carbon. Introduction of the formyl group at C3 via formylation and subsequent

1753

standard reactions gave 376 in 4% overall yield. The binding affinity of 376 at human

1754

MT1 and MT2 using 2-[125I]iodomelatonin was later studied, demonstrating that 376

1755

exhibited agonist properties and stronger binding affinity in comparison to melatonin at

1756

both melatonin receptors (376, MT1 Ki = 0.2 nM, MT2 Ki = 0.3 nM; melatonin, MT1 Ki

1757

= 0.25 nM, MT2 Ki = 0.34 nM) [192]. 376 showed no selectivity.

1758

103

(372)

was

treated

with

4-

1759 1760

Scheme 53. Synthetic approaches to 4-azamelatonin analogues based on the formation

1761

of the indole ring. A Synthetic approach to 371a,b reported by Jeanty et al. [190]. B

1762

Synthetic approach to 4-azamelatonin (376) reported by Mazeas et al. [191]. The

1763

agonist 376 exhibited stronger binding affinity in comparison with melatonin for MT1

1764

and MT2.

1765 1766

Viault et al. reported the synthesis of the 2-substituted indoles 380a,b and 381a,b,

1767

which show fluorescent properties (Scheme 54A) [193]. Iodination of the 4-

1768

azamelatonin (376) was carried out in the presence of NIS and occurred at C2. The

1769

iodinated compound 377 was committed in a Suzuki-Miyaura reaction with the

1770

corresponding

1771

tetrakis(triphenylphosphine)palladium (0) to afford the cyano compounds 378a,b. The

cyanophenylboronic

acid

104

in

the

presence

of

1772

cyano groups were then reduced to the amines 379a,b under Ra-Ni-catalyzed

1773

hydrogenation.

1774

yl)aminoethyl (NDB, 380a,b) and boron-dipyrromethene (BODIPY, 381a,b) dyes.

1775

Viault et al. also described the preparation of the 4-azamelatonines 384 and 386

1776

(Scheme 54B and 54C) [193]. To synthesize 384, 2-cyano-4-azamelatonin (382) was

1777

obtained via palladium-catalyzed addition of potassium cyanide into 377. Then, the key

1778

amine 383 was synthesized by reduction of 382 with lithium aluminium hydride.

1779

Condensation of 383 with 4(dimethylamino)phthalic acid led to the phthalimide 384.

1780

The amine 383 was also used for the preparation of 386 via methylation/SNAr sequence

1781

to introduce the 7-nitrobenzofurazan (NBD) fluorophore at C2. The photophysical

1782

properties and binding affinities at human MT1 and MT2 receptors using 2-

1783

[125I]iodomelatonin were evaluated. Most synthetized ligands were more selective for

1784

the MT2 receptor, with the exceptions of compounds 381b and 384. The most promising

1785

MT2 selective fluorescent probes, 380b and 386, both composed with the NBD

1786

fluorophore, showed high selectivity but low brightness intensity. In contrast, 381a with

1787

a BODIPY fluorophore was brighter but not selective. Although Viault et al. also

1788

reported the synthesis of N1 and C5-substituted 4-azamelatonines bearing fluorescent

1789

groups, mentioned analogues showed low non-selective binding affinities.

379a,b

were

tagged

1790

105

with

2-(4-nitro-2,1,3-benzoxadiazol-7-

1791 1792

Scheme 54. Synthetic approaches to the fluorescent 4-azamelatonin analogues 380a,b,

1793

381a,b, 384 and 386 reported by Viault et al. [193]. The synthetic approaches were

1794

based on the iodination of 4-azamelatonin (375). A Synthesis of 380a,b and 381a,b. B

1795

Synthesis of 384. C Synthesis of 386. Most synthetized ligands were more selective for

1796

the MT2 receptor, with the exceptions of 381b and 384. 380b and 386, both composed

1797

with the NBD fluorophore, showed 115 and >140 MT2/MT1 ratios, respectively.

106

1798 1799

A synthetic approach to the fluorescent 4-azamelatonin analogues 388 and 390 was

1800

developed by Gbahou et al. (Scheme 55) [194]. The synthetic approach to 388 was

1801

based on the direct attachment of Cy3.29, Cy3 cyanin acid chloride, into 387 N1 in the

1802

presence of N,N-diisopropylethylamine (DIPEA) and O-(N-succinimidyl)-N,N,N′,N′-

1803

tetramethyluronium tetrafluoroborate (TSTU) in DMF. The cellular penetration in

1804

human and mouse cells was monitored, indicating that 388 is able to activate MT1 and

1805

MT2 receptors exclusively at the cell surface. 388 showed from partial to full agonist

1806

properties and enabled to discriminate between signalling events initiated at the cell

1807

surface and in intracellular compartments. On the other hand, Gbahou et al. reported the

1808

attachment of fluorescent BODIPY into the amine 389 to provide 390 (Scheme 55B)

1809

[194]. The reaction was carried out in the presence of TSTU and DIPEA. In contrast

1810

with the N1-substituted melatonin 388, 390 showed cell permeability.

1811

107

1812 1813

Scheme 55. Synthetic approaches to the fluorescent melatonin analogues 388 and 390

1814

reported by Gbahou et al. [194]. A Synthesis of 388. This showed from partial to full

1815

agonist properties and was not able to penetrate the cell membrane. B Synthesis of 390.

1816

This showed cell permeability.

1817 1818

To develop new radioligands, Legros et al. reported the synthesis of S70254 (394)

1819

(Scheme 56) [126,187]. The synthesis was carried out from the C2-naphthyl derivative

1820

391, which was N-deacetylated in the presence of potassium hydroxide to provide the

1821

amine 392. This was reacted with bromoacetyl bromide in DCM to give the

1822

bromoacetyl derivative 393. The target compound 394 was obtained via treatment of

1823

393 with sodium iodide. S70254 showed partial agonist properties for MT2 and no 108

1824

affinity for MT1. Affinity screening was carried out at human MT1 and MT2 receptors

1825

using 2-[125I]iodomelatonin and [methoxy-3H]melatonin as radioligands.

1826

1827 1828 1829

Scheme 56. Synthetic approach to S70254 (394) [126,187]. S70254 is a partial MT2 agonist with no affinity for MT1 receptor.

1830 1831

Larraya et al. reported the synthesis of the 4-azaindole dimers 400a-c (Scheme 57)

1832

[195]. After synthesis of 374 following the synthetic approach described by Mazeas et

1833

al. (Scheme 53) [191], this was reacted with benzenesulfonyl chloride in the presence of

1834

sodium hydroxide and benzyltriethylammonium chloride in DCM to provide the

1835

corresponding sulphonamide 395. Treatment of 395 with aluminum chloride in DCM at

1836

reflux led to the pyridone 396, which was alkylated with alkyl-dibromide in the

1837

presence of potassium carbonate in DMF to give the O-alkylated derivatives 397a-c.

1838

Dimers 398a-c were prepared by treating 397a-c in basic medium. Subsequent N-

1839

deprotection and N-methylation allowed the formation of 399a-c. The introduction of

1840

the side chain at C3 was achieved via formylation of the indole ring with phosphoryl 109

1841

chloride in DMF, subsequent Knoevenagel condensation with nitromethane, reduction

1842

and acetylation to provide the target dimers 400a-c. The binding affinity of 400a-c for

1843

human MT1 and MT2 receptors was studied using 2-[125I]iodomelatonin and compared

1844

with dimeric melatonin ligand S26284, which is based on naphthalene dimers. The

1845

obtained results indicated that S26284 exhibits stronger binding affinity in comparison

1846

to 400a-c. The most interesting results were obtained with the dimer 400c that showed a

1847

20 MT1/MT2 affinity ratio.

1848

1849 1850 1851

Scheme 57. Synthetic approach to the dimeric 4-azamelatonin analogues 400a-c reported by Larraya et al. [195]. 400c showed moderate selectivity for MT1.

1852 1853

Van de Poel et al. described the synthesis of the 4-azamelatonin analogues 406a,b

1854

starting from 374 (Scheme 58) [196]. This was prepared following the synthetic 110

1855

approach reported by Mazeas et al. (Scheme 53) [191]. Alkylation of 374 with 1,4-

1856

dibromobutane in the presence of sodium hydride in DMF gave 401. Formylation of

1857

401 under Vilsmeier–Haack conditions provided 402, which was submitted to

1858

intramolecular

1859

azobisisobutyronitrile (AIBN) to provide tricyclic ring system 403a. On the other hand,

1860

tricyclic ring system 403b was synthetized following 2 different synthetic approaches.

1861

The shortest one consisted in the intramolecular cyclization of 404 using sodium

1862

hydride to give 405. Then, this was formylated in the presence of phosphoryl chloride in

1863

DMF to provide 403b. 403a and 403b were used as precursors for the preparation of

1864

target compounds 406a,b using standard reaction conditions.

cyclization

in

the

presence

of

tributyltin

hydride

and

1865

1866 1867 1868

Scheme 58. Synthetic approach to the 4-azamelatonin analogues 406a,b reported by Van de Poel et al. [196].

1869 111

1870

4.4. 6-Azaindoles

1871

Mazeas et al. reported the synthesis of 6-azamelatonin (413) using 5-amino-2-

1872

methoxypyridine (407) as the starting material (Scheme 59) [191]. The first step

1873

involved the N-protection of 407 with pivaloyl chloride to furnish 408. Iodination of

1874

408 was performed via lithium activation and subsequent treatment with iodine to give

1875

409, which was N-deprotected with sulfuric acid under reflux to afford the amine 410.

1876

This was then submitted to Sonogashira's reaction, involving sp2-sp palladium coupling

1877

of acetylene, to provide 411. Ring closure was carried out in refluxing DMF in the

1878

presence of two equivalents of copper(I) iodide under inert atmosphere to give 5-

1879

methoxy-6-azaindole (412). Introduction of the chain at C3 was achieved via standard

1880

procedures that involved formylation with phosphoryl chloride/DMF, condensation of

1881

nitromethane, reduction and acetylation and allowed the preparation of 413 in 1.4%

1882

overall yield. Although this is the unique synthetic approach to the 6-azamelatonin

1883

structure, Mazeas et al. [191] did not examined the biological properties of 413.

1884

1885

112

1886 1887

Scheme 59. Synthetic approach to 6-azamelatonin (413) reported by Mazeas et al. [191].

1888 1889

4.5. 7-Azaindoles

1890

Mazeas et al. reported the synthesis of 7-azamelatonin (419) using 7-azaindole (414)

1891

as the starting material (Scheme 60A) [191]. The first step consisted in the halogenation

1892

of 414 with bromine in a mixture of 1-butanol and water to provide the tribromo

1893

derivative 415. This was then reduced with zinc in acetic acid to furnish 416. Reduction

1894

of the amide 416 was realised with a borane-THF complex, and the resulting indoline

1895

was oxidised with manganese triacetate in acetic acid to give 417. This was

1896

methoxylated with sodium methoxide in the presence of copper(I) bromide to provide

1897

418. This derivative was subjected to formylation with phosphoryl chloride/DMF,

1898

condensation of nitromethane, reduction and acetylation to obtain 419. Later, Jeanty et

1899

al. described the synthesis of a number of 7-azaindole derivatives, including 420a-c,

1900

421a,b, 422 and 423a-g. The binding affinity of these derivatives for human MT1 and

1901

MT2 was examined using 2-[125I]iodomelatonin and compared with the binding affinity

1902

of melatonin (1), 7-azamelatonin (419) and 4-azamelatonin (374) (Scheme 60B) [192].

1903

The obtained results indicated that 420a-c and 422 were strong MT1 and MT2 receptor

1904

agonists. The presence of amines at C3 (423a-g) was detrimental to the binding

1905

affinities. Although 419 showed very low binding affinities, 420b and 420c showed

1906

higher binding affinities for MT2 in comparison to melatonin (420b, MT1 Ki = 3.3 nM,

1907

MT2 Ki = 0.28 nM; 420c, MT1 Ki = 1.3 nM, MT2 Ki = 0.3 nM; melatonin, MT1 Ki = 0.25

1908

nM, MT2 Ki = 0.34 nM). Interestingly, 420b showed 11.8 MT2/MT1 ratio. Similarly,

1909

compound 422 showed 13.2 MT2/MT1 ratio but a binding affinity 2-fold lower than

1910

melatonin.

113

1911

1912 1913

Scheme 60. Synthesis of 7-azamelatonin analogues. A Synthesis of 7-azamelatonin

1914

(419) reported by Mazeas et al. [191]. B Structures of 7-azamelatonin derivatives 420a-

1915

c, 421a,b, 422 and 423a-g described by Jeanty et al. [192]. 420b and 420c showed

1916

higher binding affinities for MT2 in comparison to melatonin. 420b and 422 showed

1917

moderate-high MT2/MT1 ratios.

1918 1919

Larraya et al. described the preparation the dimeric 7-azamelatonin analogues 428a-c

1920

starting from the indole 424 (Scheme 61) [195]. The methoxy group was introduced at 114

1921

C5 via treatment of 424 with methanol in the presence of copper(I) bromide and the

1922

resulting methoxide was N-protected with methyl iodide to obtain 425. Reaction of 425

1923

with boron tribromide in DCM generated alcohol 426. The formation of the dimers was

1924

performed using different alkyl dibromides in the presence of potassium bicarbonate to

1925

provide the target compounds 427a-c. 427a-c were formylated at C3, condensed with

1926

nitromethane, reduced and acetylated to give the target dimeric analogues 428a-c. The

1927

binding affinity of 428c for human MT1 and MT2 was evaluated using 2-

1928

[125I]iodomelatonin. It was found that compound 428c showed lower binding affinities

1929

compared to S26284 and the 4-azamelatonin dimers 400a-c (Scheme 57).

1930

1931 1932 1933

Scheme 61. Synthesis of the dimeric 7-azamelatonin analogues 428a-c reported by Larraya et al. [195]. 428c showed low binding affinity for MT1 and MT2.

1934 1935

4.6. 7a-Azaindoles

1936

A synthetic approach to the 2-substituted 7a-azamelatonin analogues 433a-f was

1937

reported by Elsner et al. (Scheme 62A) [197]. These were synthetized from O-(2,4-

1938

dinitrophenyl)hydroxylamine, which was converted to the N-aminopyridinium salt 429.

1939

1,3-Dipolar cycloaddition between 429 and methyl propiolate or ethyl phenylpropiolate 115

1940

under oxidative conditions provided 430a and 430b, respectively. Subsequent

1941

hydrolysis and decarboxylation of 430a,b with sulphuric acid furnished the

1942

pyrazolo[1,5-a]pyridine derivatives 431a,b. Formylation of 431a,b using Vilsmeier-

1943

Haack conditions gave aldehydes 432a,b, respectively. The target compounds 433a-f

1944

were finally obtained via Knoevenagel condensation with nitroethane followed by

1945

reduction with sodium borohydride and acylation. Elsner et al. also described the

1946

synthesis of the 7a-azamelatonin derivative 436 (Scheme 62B). Binding affinity

1947

screening of the 7a-aza analogues 433a-f and 436 was carried out using the human MT1

1948

and MT2 receptors in competition with 2-[125I]iodomelatonin and Xenopus laevis

1949

melanophores assays. All synthetized compounds were agonists. 433d showed similar

1950

affinity in comparison to melatonin and no selectivity for MT1/MT2, whereas

1951

compounds 433c and 436 showed 14.6- and 76-fold selectivity towards MT2. 433c

1952

showed similar binding affinity for MT2 compared to melatonin.

1953

116

1954 1955

Scheme 62. Synthetic approaches to 7a-azamelatonin analogues reported by Elsner et

1956

al. [197]. A Synthetic approach to 433a-f. 433c showed strong selective binding affinity

1957

for MT2. 433d showed similar affinity in comparison to melatonin and no selectivity for

1958

MT1/MT2. B Synthetic approach to 436. This showed high selectivity towards MT2.

1959 1960

Koike et al. reported a synthetic strategy for the synthesis of the 7a-azamelatonin

1961

analogues 443a-i (Scheme 63A) [188]. The furopyridine 437, which was used as the

1962

starting material, was treated with O-(2,4-dinitrophenyl)hydroxylamine in acetonitrile to

1963

give the N-aminopyridinium salt 438. Then, 1,3-dipolar cycloaddition reaction of 438

1964

with various alkyne esters gave 439a-e. Reduction of the esters 439a-e, and subsequent

1965

cyanation using TMSCN and boron trifluoride etherate afforded the nitriles 441a-e. The

1966

target compounds 443a-i were finally obtained through hydrogenation over Ra-Co

117

1967

followed by acylation with either acetic or propionic anhydride. Binding affinity studies

1968

for human MT1 and MT2 using 2-[125I]iodomelatonin revealed that the 7a-aza

1969

derivatives 443a-i exhibited stronger binding affinity in comparison with the 3-

1970

azaderivatives 355 (Scheme 50) and 3a-azaderivatives 368 (Scheme 52). 443d, which

1971

showed higher affinity than melatonin for MT1 (443d, MT1 Ki = 0.062 nM, MT2 Ki =

1972

0.420 nM; melatonin, MT1 Ki = 0.24 nM, MT2 Ki = 0.21 nM), was identified as a potent

1973

MT1/MT2 agonist. Compound 443d, also called EFPPEA, exhibited good oral

1974

absorption in rats, and its sleep-promoting effects were confirmed in cats. The

1975

interesting properties of 443d encouraged Haoshi et al. to develop an alternative

1976

synthetic approach to obtain this compound from the pyridone 444 (Scheme 63B) [198].

1977

118

1978 1979

Scheme 63. Synthetic approaches to the tricyclic 7a-azamelatonin analogues 443a-i.

1980

A Synthetic approach to the tricyclic melatonin derivatives 443a-i reported by Koike et

1981

al. [188]. B Synthetic approach to 443d reported by Haoshi et al. [198].

1982 1983

5. Polycyclic melatonin analogues

1984

Melatonin analogues bearing rings fused to the [a], [b], [cd] and [hi] faces of the

1985

indole ring can be found in the literature (Scheme 64). The most interesting properties

119

1986

were found when using melatonin analogues with rings fused to the [a] face of the

1987

indole ring. In this sense, IIK7, a MT2-selective agonist, is an [a]-fused polycyclic

1988

melatonin analogues and has been used to examine the role of each MT receptor type in

1989

the modulation of sleep architecture [31]. IIK7 was reported to reduce NREM sleep

1990

onset latency and transiently increase the time spent in NREM sleep in rats without

1991

altering NREM sleep latency or the amount of NREM sleep. Mainly, the synthetic

1992

strategies to polycyclic melatonin analogues are based on the derivatization of indoles

1993

or on the formation of the indole core by Fischer reaction.

1994

1995 1996 1997

Scheme 64. Melatonin analogues with rings fused to the [a], [b], [cd] and [hi] faces of the indole ring.

1998 1999

5.1. [a]-Fused polycyclic melatonin analogues

2000

[a]-Fused polycyclic melatonin analogues were classified depending on the fused

2001

structure: tricyclic, bicyclic, 6-membered or 5-membered structures. Regarding the

2002

derivatives with a fused tricyclic structure, Attia et al. reported the synthesis of the

2003

diindole melatonin analogues 454a,b using the racemic indoline-2-carboxylic acids

2004

450a,b as the starting materials (Scheme 65) [199]. Self-coupling of 450a,b using DCC

2005

in THF afforded the lactams 451a,b. Reduction of the amides 451a,b was performed

2006

with borane in THF to provide 452a,b. Selective monodehydrogenation was achieved 120

2007

by heating 452a,b in the presence of palladium on carbon to give 453a,b. The chain at

2008

C3 was introduced by Mannich reaction with dimethylmethyleneammonium iodide and

2009

subsequent quaternization of the Mannich base, substitution with cyanide and reduction

2010

with lithium aluminium hydride to provide the melatonin derivatives 454a,b. Both 454a

2011

and 454b showed low binding affinity human MT1 and MT2 using 2-[125I]iodomelatonin.

2012

The affinity of 454b was 4.4-fold higher for MT2 than for MT1. The same research

2013

group described a similar synthetic approach to obtain 455a-e [200]. The analogues

2014

455a-e showed low non-selective binding affinities. 455c showed the most interesting

2015

profile exhibiting 5-times higher affinity for MT1 than for MT2.

2016

2017 2018

Scheme 65. Synthetic approaches to melatonin analogues bearing a tricyclic structure

2019

fused to the [a] face of the indole ring. A Synthetic route to melatonin analogue 454a,b

2020

[199]. These showed low non-selective binding affinity for MT1 and MT2. B Structure

121

2021

of melatonin analogues 455a-e [200]. These showed low non-selective binding affinity

2022

for MT1 and MT2.

2023 2024

Faust et al. reported the synthesis of melatonin analogues 459a,b from the N-acetyl

2025

tryptamine 456 (Scheme 66A) [201]. After N-alkylation of 456 with 2-bromobenzyl

2026

bromide

2027

tetrakis(triphenylphosphine)palladium(0) to give the derivatives with general formula

2028

459. 459a (known as IIK7) and 459b (known as K185), were found to be agonist and

2029

antagonist, respectively, and exhibited MT2-selective potent binding affinities. It must

2030

be noted that 459a showed stronger binding affinity for MT2 in comparison to

2031

melatonin (459a, MT1 Ki = 4.07 nM, MT2 Ki = 0.20 nM; melatonin, MT1 Ki = 0.66 nM,

2032

MT2 Ki = 0.33 nM). The affinities were screened using human MT1 and MT2 receptors

2033

in competition with 2-[125I]iodomelatonin and Xenopus laevis melanophores assays. The

2034

obtained results indicated that the presence of a butanoyl chain at C3 and a methoxy

2035

group at C5 are important features to achieve a high binding affinity.

2036

(457),

the

resulting

N-alkyl

indoles

458

were

cyclized

with

Kozikowski et al. reported a similar synthetic approach to obtain 462a-c (Scheme 66B)

2037

[202]. Indole-3-acetic acid (460), which was used as the starting material, was

2038

converted to the corresponding amide 461 via treatment with either dipropyl or

2039

dihexylamine and subsequent N1-alkylation. Palladium(0)-mediated ring closure gave

2040

462a-c. In contrast with the derivatives with a ring fused at the [b] and [cd] faces of the

2041

indole ring, 462a-c showed high binding affinity for mitochondrial diazepam binding

2042

inhibitor (DBI) receptor complex. The highest affinity was observed for structures 462a

2043

and 462c, wherein the linker group is comprised of a single methylene group.

2044

Osyanin et al. described a one-step synthetic route to obtain 466a-c (Scheme 66C)

2045

[203]. The 2-bromomelatonin analogues 463a,b, which were used as the starting

122

2046

material, were coupled with the phenols 464a-c to provide 466a-c. The reaction

2047

proceeded via formation of o-methylenequinone, which alkylates the bromomelatonin

2048

molecule at the nitrogen atom, to give intermediate 465 and further cyclization with

2049

evolution of HBr molecules.

2050

2051 2052

Scheme 66. Synthetic approaches to melatonin analogues bearing a bicyclic structure

2053

fused to the [a] face of the indole ring. A Synthetic approach to melatonin analogue 459

123

2054

reported by Faust et al. [201]. 459a (known as IIK7) and 459b (known as K185), were

2055

found to be agonist and antagonist, respectively, and exhibited MT2-selective potent

2056

binding affinities. B Synthetic approach to 462a-c reported by Kozikowski et al. [202].

2057

462a and 462c showed high binding affinity for mitochondrial DBI receptor complex. C

2058

Synthetic strategy to 466a-c reported by Osyanin et al. [203].

2059 2060

Thireau et al. reported the synthesis of the fluorescent melatonin analogues 468a-d

2061

based on the fusion of melatonin and BODIPY structures (Scheme 67) [204]. 2-

2062

Iodomelatonin (112a), which was used as the starting material, was converted into 2-

2063

formylmelatonin (467) by a palladium catalyzed carbonylative coupling reaction in the

2064

presence of tributyltin hydride. Condensation of 467 with the appropriate pyrrole in the

2065

presence of boron trifluoroborate etherate allowed the formation of the target structures

2066

468a-d. Synthetized compounds exhibited fluorescent properties compatible with cell

2067

observation. 468a-d showed high affinity for human MT1 and MT2 receptors in

2068

competition with 2-[125I]iodomelatonin. Ligand 468b was slightly more selective for the

2069

MT2 receptor, whereas 468c was slightly more selective for the MT1 receptor.

2070

2071

124

2072

Scheme 67. Synthetic approach to the melatonin analogues 468a-d based on the

2073

fusion of melatonin and BODIPY structures [204]. 468a-d showed high affinity for

2074

MT1 and MT2 receptors and fluorescent properties compatible with cell observation.

2075 2076

Tsotinis et al. reported the synthesis of the tricyclic melatonin derivative 472 from the

2077

indole 469 (Scheme 68A) [205]. This was N-alkylated with 1,4-dibromobutane in the

2078

presence of potassium hydroxide in DMF to give 470. The tricyclic structure 471 was

2079

formed upon treatment of 470 with tributyltin hydride under radical conditions. Then,

2080

471 was selectively formylated at C3 and modified using standard reaction conditions to

2081

obtain the melatonin analogue 472. In agreement with previous affinity studies using

2082

C2-substituted melatonin analogues, derivatives without methoxy group at C5 were

2083

antagonist, whereas the derivatives with a methoxy group at C5 were found to be

2084

agonist in the Xenopus laevis melanophores model. The antagonist properties of the

2085

desmethoxy derivatives was weaker in comparison to luzindole. In agreement with the

2086

results reported by Faust et al. (Scheme 66A) [201], the presence of a butanoyl group

2087

and a methoxy at C5 provided the derivative with the highest binding affinity.

2088

Mentioned derivative showed similar affinity in comparison to melatonin.

2089

Tsotinis et al. reported the synthesis of 473a-d and 474a-d, which contain

2090

modifications on the β carbon of the C3 chain (Scheme 68B) [206]. The desmethoxy

2091

derivatives 473a,b were partial agonist/partial antagonist, whereas derivatives 473c,d,

2092

which contain a methoxy group at C5, showed agonist properties in the Xenopus laevis

2093

melanophore model. 473a-d showed lower affinity in comparison to melatonin. 473a,b

2094

showed higher binding affinity in comparison to 473c,d. In contrast, the behaviour of

2095

474a-d was fully antagonist, obtaining the highest binding affinity, which was higher

2096

than that of luzindole, when using 474c.

125

2097

2098 2099

Scheme 68. Synthetic approaches to melatonin analogues bearing a 6-membered ring

2100

fused to the [a] face of the indole ring. A Synthetic approach to melatonin analogue 472

2101

reported by Tsotinis et al. [205]. The derivative with butanoyl chain and methoxy at C5

2102

showed agonist properties and similar affinity in comparison to melatonin in the

2103

Xenopus laevis melanophores model. B The melatonin analogues 473a-d and 474a-d

126

2104

reported by Tsotinis et al. [206]. Antagonist 474c showed stronger intrinsic affinity in

2105

comparison to luzindole in the Xenopus laevis melanophores model. C Synthetic

2106

strategy to 480a-c reported by Markl et al. [106]. 480b showed non-selective high

2107

binding affinity slightly for MT1 and MT2.

2108 2109

Markl et al. reported the synthesis of 480a-c, which consists of a tetrahydropirazo[1,2-

2110

a]indole (Scheme 68C) [106]. Binding affinity studies for human MT1 and MT2 using 2-

2111

[125I]iodomelatonin revealed that 480a-c showed non-selective affinity. Derivative 480b,

2112

which showed the highest affinity among synthetized compounds, showed a binding

2113

affinity slightly lower than melatonin.

2114

Doss et al. reported the synthesis of the imidazoindoles 481 and 482, triazinoindoles

2115

483a,b and thiadiazoloindole 484 (Scheme 69A) [94]. All derivatives were synthetized

2116

from melatonin and were found to be agonist in the Xenopus laevis melanophore assay.

2117

Interestingly, compound 483a showed higher agonist affinity in comparison to

2118

melatonin (483a, EC50 = 1.31 nM; melatonin, EC50 = 282 nM).

2119

Elmegeed et al. attempted the synthesis of 485a,b, 486 and 487 using 484 as the

2120

starting material (Scheme 69B) [207,208]. 485a and 487 showed anti-mutagenic

2121

activity, which was attributed to their antioxidant activity. Elmegeed et al. also

2122

described the synthesis of 488, 489, 490a,b and 491 using melatonin as the starting

2123

material (Scheme 69C) [209]. 489 showed stronger anti-inflammatory activity in

2124

comparison to melatonin. 489 and 491 exhibited higher anti-nociceptive ability with

2125

respect melatonin.

2126

127

2127 2128

Scheme 69. Synthetic approach to melatonin derivatives bearing a 5-membered ring

2129

fused to the [a] face of the indole ring. A Structures of the melatonin derivatives 481,

2130

482, 483a,b and 484 reported by Doss et al. [94]. The agonist 483a showed higher

2131

binding activity in comparison to melatonin in the Xenopus laevis melanophore assay. B

2132

Structures of the melatonin derivatives 485a,b, 486 and 487 reported by Elmegeed et al.

2133

[207]. 485a and 487 showed anti-mutagenic activities. C Structures of the melatonin

128

2134

derivatives 488, 489, 490a,b and 491 reported by Elmegeed et al. [209]. 489 showed

2135

stronger anti-inflammatory and anti-nociceptive activities in comparison to melatonin.

2136 2137

5.2. [b]-Fused polycyclic melatonin analogues

2138

Three different types of [b]-fused polycyclic melatonin analogues were found in the

2139

literature: derivatives wherein the amine is involved in the fused ring, C3-substituted

2140

and C4-substituted tetrahydropyrido[3,4-b]indoles.

2141

Kozikowski et al. reported the synthesis of the conformationally constrained analogue

2142

496 from 1,4-naphthoquinone (492) (Scheme 70A) [202]. The α-keto lactam 494 was

2143

obtained by reaction of 492 with sodium azide in sulfuric acid followed by catalytic

2144

hydrogenation over palladium on carbon. Then, Fischer-indole reaction between the α-

2145

keto lactam 494 and phenylhydrazine (495) provided the target compound 496. This

2146

analogue showed no binding affinity for mitochondrial DBI receptor complex.

2147

Fourtillan et al. patented the synthesis of the β-carbolines 498 and 500 (Scheme 70B)

2148

[210]. The synthesis was performed via Bischler-Napieralski cyclization reaction of 497

2149

and 499 to provide 498 and 500, respectively. The reactions were carried out in the

2150

presence of phosphoryl chloride in toluene. The hypnotic and sedative effects of the

2151

synthetized derivatives were examined and compared with those of three reference

2152

products: diazepam, sodium pentobarbital and melatonin. Most synthetized derivatives

2153

showed higher effects in comparison to the reference products.

2154

129

2155 2156

Scheme 70. Synthetic approaches to melatonin analogues bearing a bicyclic structure

2157

fused to the [b] face of the indole ring. A Synthetic approach to 496 reported by

2158

Kozikowski et al. [202]. This showed no binding affinity for mitochondrial DBI

2159

receptor complex. B Synthetic approach to 498 and 500 patented by Fourtillan et al.

2160

[210]. These showed hypnotic and sedative effects.

2161 2162

A synthetic approach to obtain the tetrahydropyrrolo[2,3-b]indole 501 was described

2163

by Siwicka et al. (Scheme 71A) [211]. To achieve this goal, melatonin (1) was treated

2164

with oxygen in the presence of Py and halogen lamp irradiation to give the target

2165

compound 501. The reaction took place throughout formation of an epoxide in the [b]

2166

face and subsequent intramolecular cyclization.

2167

Other synthetic approaches consisted in the reaction of melatonin, serotonin or

2168

tryptamine with aldehydes in acidic conditions via Pictet-Spengler reaction to form

2169

tetrahydropyrido[3,4-b]indole structures (502) (Scheme 71B). In this field, Bi et al. 130

2170

described the synthesis of tetrahydropyrido[3,4-b]indoles bearing 1,3-dioxane moieties

2171

attached at C1 [212]. The 1,3-dioxane derivatives were synthetized from melatonin or

2172

tryptamine. Interestingly, the melatonin analogues manifested potent anti-inflammatory

2173

and antioxidant effects, and exerted a protective effect against skeletal muscle injury

2174

and associated lung injury. Similarly, Somei et al. reported the reaction of serotonin

2175

with acetaldehyde and benzaldehyde in acidic conditions to provide the corresponding

2176

C6-hydroxy tricyclic systems [213,214]. Similarly, Rinehart et al. reported the

2177

formation of the fused ring of 6-bromotryptamine via Pictet-Spengler reaction with

2178

glyoxilic acid and subsequent decarboxylation to provide 7-bromotetrahydropyrido[3,4-

2179

b]indole [215]. In the same manuscript, Rinehart et al. described the synthesis of C1-

2180

substituted β-carbolines and tetrahydropyrido[3,4-b]indoles via derivatization of the

2181

suitable β-carbolines and tetrahydropyrido[3,4-b]indoles from the Caribbean tunicate

2182

Eudistoma olivaceum. The obtained tricycles were evaluated for the antiviral activity

2183

against herpes simplex virus (HSV) and the antimicrobial activity against Bacillus

2184

subtilis, Escherichia coli, Saccharomyces cerevisiae and Penicillum atrovenetum.

2185

Bird et al. reported the synthesis of the 3-aminotetrahydrocarbazoles 506a,b (Scheme

2186

71C) [216]. The synthesis was carried out from the 3-hydroxytetrahydropyrido[3,4-

2187

b]indoles 503a,b. 503a,b were activated after treatment with p-toluenesulphonyl

2188

chloride to give 504a,b. Substitution of 504a,b with sodium azide in dimethylsulfoxide

2189

(DMSO) allowed the preparation of the azides 505a,b. Final hydrogenation of 505a,b

2190

over palladium on carbon in methanol provided the target structures 506a,b.

2191

131

2192 2193

Scheme 71. Synthesis of melatonin analogues bearing a ring fused to the [b] face of

2194

the indole ring. A Synthetic approach to 501 reported by Siwicka et al. [211]. B

2195

Synthesis of tetrahydropyrido[3,4-b]indole structures (502) via Pictet-Spengler reaction

2196

between melatonin, serotonin or tryptamine and aldehydes [212-215]. Some synthetized

2197

tetrahydropyrido[3,4-b]indoles

2198

antimicrobial activities. C Synthetic approach to 506a,b via derivatization of 503a,b

2199

reported by Bird et al. [216].

showed

inflammatory,

antioxidant,

antiviral

or

2200 2201

Garrat et al. attempted the synthesis of the 3-amino-1,2,3,4-tetrahydrocarbazoles

2202

509a,b and 514a,b, which contain substitutions in 3 and 4 positions of the tricyclic

2203

system (Scheme 72) [217]. The tricycles 508a,b were constructed by Fischer reaction

2204

between the phenylhydrazines 2 and 495, and 4-acetyloxycyclohexanone (507). Then,

2205

508a,b were saponified in the presence of sodium hydroxide and the resulting alcohol

2206

was activated with MsCl. Subsequent substitution with sodium azide, reduction with 132

2207

lithium aluminium hydride and acylation with a variety of acid halides or anhydrides

2208

gave target compounds 509a,b. On the other hand, the 4-substituted l,2,3,4-

2209

tetrahydrocarbazoles 514a,b were also prepared by Garrat et al. [217]. Bischler reaction

2210

between anilines 510a,b and 2-bromo-carboethoxycyclohexanone (511) in the presence

2211

of zinc chloride gave 512a,b. Then, 512a,b were converted to the corresponding amides

2212

513a,b via ester hydrolysis and subsequent treatment with ammonia. 513a,b were then

2213

reduced by treatment with boron hydride-THF complex to the corresponding amines,

2214

which were acylated to provide 514a,b. Intrinsic affinity studies using the Xenopus

2215

laevis assay revealed that the 6-methoxycarbazoles 509a,b and 514a,b were melatonin

2216

agonists or partial agonists. In general, derivatives of the general formula 509b and

2217

514b exhibited higher affinities in comparison with the derivatives of formula 509a and

2218

514a, and 514a,b showed higher affinities with respect 509a,b. The introduction of a

2219

propanoyl chain at position 3 of 509a,b or a butanoyl at position 4 of 514a,b provided

2220

the derivatives with the highest binding affinities. Interestingly, the derivative of

2221

structure 514b with a butanoyl chain showed binding affinities slightly higher in

2222

comparison to melatonin (N-butanoyl 514b, Ki = 0.378 nM; melatonin, Ki = 0.59 nM).

2223

Later, Sugden et al. resolved racemic 514b with an acetyl group at the C4 side chain

2224

into its enantiomers [218]. The obtained results indicated that the (-)-enantiomer was

2225

130-fold and 230-fold more potent than the (+)-enantiomer in competition with 2-

2226

[125I]iodomelatonin in chiken brain receptors (with no differentiation of MT1 and MT2

2227

receptors) and Xenopus laevis melanophores assays, respectively.

2228

Similarly, Davies et al. reported a synthetic strategy based on a Bischler reaction to

2229

form the fused ring [219]. In this case, the synthetic strategy was used for the synthesis

2230

of melatonin derivatives with cyclopentane and cycloheptane rings fused to the [b] face

2231

of the indole ring. The synthetized derivatives were analogous to 514a,b and presented

133

2232

a aminomethyl chain at the C3 and C5 of the tricyclic system, respectively. Mentioned

2233

derivatives showed lower affinities in comparison to the analogues 514a,b.

2234

2235 2236

Scheme 72. Synthesis of melatonin derivatives bearing a 6-membered ring fused to

2237

the [b] face of the indole ring reported by Garrat et al. [217]. A Synthetic approach to

2238

the 3-substituted carbazoles 509a,b. B Synthetic approach to the 4-substituted

2239

carbazoles 514a,b. 509a,b and 514a,b showed agonist or partial agonist properties.

2240

Interestingly, 514b with a butanoyl chain showed binding affinities slightly higher in

2241

comparison to melatonin.

2242

134

2243

5.3. [cd]-Fused polycyclic melatonin analogues

2244

Two different types of [cd]-fused polycyclic melatonin analogues can be found in the

2245

literature: derivatives wherein the amine is involved in the fused ring and C3-substituted

2246

tetrahydropyrido[3,4-b]indoles.

2247

Somei et al. reported a synthetic route to the tricyclic systems 515a,b (Scheme 73)

2248

[213,214]. The synthesis was performed via Pictet-Spengler reaction of serotonin (57)

2249

with either benzaldehyde or acetaldehyde in basic conditions. In contrast (as mentioned

2250

in “[b]-Fused polycyclic melatonin analogues” section), the reaction of 57 with

2251

aldehydes in acid conditions provided tricyclic melatonin analogues that contained a

2252

ring fused to the [b] face of the indole ring.

2253

2254 2255 2256

Scheme 73. Synthetic approach to tricyclic analogues 515a,b reported by Somei et al. [213,214].

2257 2258

Spadoni et al. reported the synthesis of the tricyclic systems 521, 523 and 524, which

2259

contain substituents at C3 (Scheme 74) [220]. Palladium-catalyzed coupling, Heck

2260

reaction, of the 4-bromo-5-methoxyindole derivatives 516a,b with methyl or benzyl

2261

acrylate, respectively, gave the derivatives 517a,b. These were converted to the acids

2262

518a,b by catalytic hydrogenation over palladium on carbon and hydrolysis in the

2263

presence of potassium hydroxide. The acids 518a,b were then cyclized in PPA to the

2264

ketones 519a,b. The ketone 519a was transformed in two steps, condensation with

2265

benzylamine and catalytic hydrogenation over palladium on carbon, to the crude amine

2266

intermediate 520. This was acylated with acetic anhydride/triethylamine, obtaining the 135

2267

desired compound 521 in 15% overall yield. The ketone 519b was converted to the

2268

corresponding

2269

triisopropylbenzenesulfonyl hydrazide. The resulting hydrazone was then transformed,

2270

without any previous purification, into the cyano ethyl ester derivative 522 by heating in

2271

ethanol with potassium cyanide. By reduction of 522 with hydrogen over Ra-Ni in the

2272

presence of acetic anhydride, compound 523 was obtained. The derivative 524 was

2273

prepared by ester hydrolysis of 523 followed by decarboxylation of the corresponding

2274

acid in boiling quinoline in the presence of copper powder. Later, Bedini et al. studied

2275

the binding affinity of 521, 523 and 524 for human MT1 and MT2 receptors and quail

2276

optic tecta melatonin receptors using 2-[125I]iodomelatonin [221]. The derivatives 521

2277

and 524 were only tested for quail optic tecta melatonin receptors and showed low

2278

binding affinities. On the other hand, 523 showed similar binding affinity in the quail

2279

optic tecta assay compared to melatonin, demonstrating the relevance of the substituent

2280

at C2. The obtained results indicated that 523 exhibits high non-selective binding

2281

affinity for MT1 and MT2 receptors.

2,4,6-triisopropyl

hydrazone

2282

136

by

reaction

with

2,4,6-

2283 2284

Scheme 74. Synthetic approach to the C3-substituted tricyclic melatonin analogues

2285

521, 523 and 524 reported by Spadoni et al. [220]. 521 and 524 showed low binding

2286

affinity. 523 showed non-selective binding affinity comparable to that of melatonin.

2287 2288

5.4. [hi]-Fused polycyclic melatonin analogues

2289

Tsotinis et al. reported the synthesis of the melatonin derivatives 529a-e, 530a-e, 531

2290

and 532a,b from 1,2,3,4-tetrahydroquinoline (525) (Scheme 75) [222]. This was

2291

nitrosated with sodium nitrite in the presence of hydrogen chloride to the N-nitroso 137

2292

analogue 526, which was then converted to the hydrazine 527 via reduction with lithium

2293

aluminium hydride in THF. Condensation of 527 with α-ketoglutaric acid in hydrogen

2294

chloride/glacial acetic acid afforded the tricyclic system 528. This was used as precursor

2295

for the synthesis of the melatonin derivatives 529a-e via formation of the corresponding

2296

amide with ammonia, amide reduction with lithium aluminium hydride and final N-

2297

acylation. The analogues 530a-e, 531 and 532a,b were also synthetized from 525. The

2298

affinity of the synthetized compounds was screened at human MT1 and MT2 receptors

2299

using 2-[125I]iodomelatonin and Xenopus laevis melanophores. 529a-e, 530a-e and

2300

532a,b were found to be antagonist, whereas derivative 531 showed partial

2301

agonist/partial antagonist activity. Derivatives 530a-e showed similar binding affinity in

2302

comparison to luzindole and no significant MT1/MT2 selectivity. On the other hand,

2303

derivative 532a,b, which showed slightly lower affinity with respect luzindole,

2304

exhibited high selectivity for MT2 (>10 MT2/MT1).

2305

2306 2307

Scheme 75. Synthesis of the melatonin derivatives 529a-e, 530a-e, 531 and 532a,b,

2308

which contain rings fused at the [hi] face of the indole ring [222]. The antagonists 530a-

138

2309

e showed similar binding affinity in comparison to luzindole and no significant

2310

MT1/MT2 selectivity. The antagonists 532a,b showed slightly lower affinity with

2311

respect luzindole and exhibited high selectivity for MT2.

2312 2313

6. Conclusion

2314

Although a number of modifications on the melatonin structure were reported until

2315

date, there are still abundant non-studied combinations. It must be noted that most

2316

reported analogues are based on modifications at N1, C2 or C3, whereas modifications

2317

on the rest of the positions have been poorly examined.

2318

Regarding N1-substituted melatonin analogues, the introduction of small substituents,

2319

such as a methoxy group, resulted in strong non-selective agonist melatonin analogues,

2320

whereas the introduction of big substituents, such as phenethyl, resulted in antagonists.

2321

The introduction of ethyl or i-propyl chains at N1 provided strong lipid peroxidation

2322

inhibitors, whereas the exchange of the 2-aminoethyl chain from C3 to N1 resulted in

2323

strong agonist melatoninergic ligands. The halogenation at C2 allowed the preparation

2324

of strong non-selective agonists. This technique has been widely used for the production

2325

of radio-labelled ligands or intermediates for the introduction of aromatic rings. In

2326

general, the introduction of small substituents at C2, such as methyl, ethyl or phenyl,

2327

resulted in strong agonists, whereas the introduction of voluminous substituents or the

2328

exchange of the 2-aminoethyl chain from C3 to C2 produced MT2-selective antagonists

2329

or partial agonists. Regarding the modifications on C3, the introduction of substituents

2330

in the tryptamine structure has been shown to be an interesting strategy to create

2331

melatonin analogues with diverse pharmacological profiles. The replacement of the C3

2332

amine for azide or isothiocyante resulted in weak antagonists melatoninergic ligands.

2333

The introduction of substituents at the C1 of the side chain allowed the preparation of

139

2334

MT2-selective agonists, except for the introduction of keto and hydroxy groups that

2335

produced antagonist ligands. The introduction of small substituents at the C2 of the side

2336

chain resulted in strong MT2-selective agonists, whereas the introduction of cycles

2337

produced antagonists. The presence of a nitro group at C4 resulted in strong MT3-

2338

selective ligands, whereas 4-fluoro compounds showed antagonist activity. The

2339

introduction of alkoxy chains as a replacement of the C5-methoxy group provided MT1-

2340

selective ligands. Among C5-modified derivatives, 5-HEAT must be highlighted since

2341

it has a unique pharmacological profile acting as a full agonist at the MT1 receptor and

2342

antagonist at the MT2 receptor. The absence of the methoxy group at C5 was shown to

2343

produce antagonist ligands, such as luzindole. Substitutions on C6 with chloro, fluoro

2344

and hydroxy groups have been studied, obtaining the highest non-selective agonist

2345

binding affinity when introducing the chloro group. The introduction of small

2346

substituents at C7, such as methyl or bromo, allowed the preparations of MT2-selective

2347

ligands.

2348

Regarding the melatonin analogues based on azaindole structures, the most interesting

2349

results were obtained when using 4-azaindoles. For example, 4-azamelatonin showed

2350

higher binding affinity for melatonin receptors in comparison to melatonin. In general,

2351

the melatoninergic activities of the derivatives depended on the substitutions on the

2352

azaindole core and were in agreement with the effects produced by the same

2353

modifications on the indole structure. In this sense, 2-substituted 4-azaindoles bearing

2354

voluminous side chains showed MT2-selectivity, whereas C5-modified derivatives were

2355

MT1-selective.

2356

Polycyclic melatonin analogues bearing rings fused to the [a] face of the indole core

2357

showed interesting melatoninergic properties. In this sense, IIK7, which contains a

2358

bicyclic structure fused to the indole ring, showed strong MT2-selective agonist activity.

140

2359

On the other hand, most derivatives with a ring fused to the [b] face showed low

2360

binding affinities, expect the C4-substituted tetrahydropyrido[3,4-b]indole 514b.

2361

Derivatives bearing a [hi]-fused ring mainly showed antagonist properties.

2362

Researchers have been successful at discovering high-affinity and selective ligands for

2363

the MT2 receptor. However, the MT2 selective ligands available are mainly antagonists

2364

or partial agonists. Further, there is a lack of selective MT1 receptor ligands with high

2365

efficacy, and the reported ones mainly show antagonist or partial agonist properties. The

2366

development of selective melatoninergic ligands with agonist properties is necessary in

2367

order to overcome the limitations of the current commercial drugs for the treatment of

2368

insomnia and clarify the respective roles of MT1 and MT2 receptors. On the other hand,

2369

although melatonin has shown a number of different biological applications, most

2370

derivatives have been only studied as melatoninergic ligands, limiting the use of

2371

melatonin derivatives in other fields.

2372 2373

Acknowledgements

2374

This study was supported by the National Natural Science Foundation of China 2375

(31850410485 and 81803407), Nantong Applied Research Program (MS12017023-8), 2376

the Natural Science Research Project of Jiangsu Higher Education Institutions 2377

(18KJB180023) and the China Postdoctoral Science Foundation (2018M642240). 2378 2379

Abbreviations

2380

Aromatic

ring,

Ar;

azobisisobutyronitrile,

AIBN;

benzotriazol-1-yl-

2381

oxytripyrrolidinophosphonium hexafluorophosphate, PyBOP; 2-(1H-benzotriazole-1-

2382

yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, TBTU; benzyl chloroformate, Cbz;

2383

bioluminescence

resonance

energy

141

transfer,

BRET;

1,1´-

2384

bis(diphenylphosphino)ferrocene,

dppf;

2385

dipyrromethene, BODIPY; concentrated, conc.; 1,4-diazabicyclo[2.2.2]octane, DABCO;

2386

1,8-diazabicyclo[5.4.0]undec-7-ene, DBU; diazepam binding inhibitor, DBI; 2,3-

2387

dichloro-5,6-dicyano-1,4-benzoquinone,

2388

dichloromethane, DCM; diisopropyl azodicarboxylate, DIAD; dimethylacetamide,

2389

DMA;

2390

dimethylformamide dimethyl acetal, DMFDMA; dimethylsulfoxide, DMSO; dimethyl

2391

urea, DMU; t-butoxycarbonyl, Boc; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,

2392

EDC; gC3N4 nanosheets, GCN; G-protein-coupled receptors, GPCR; herpes simplex

2393

virus, HSV; hexamethylenetetramineinacetone, HMTA; hydroxybenzotriazole, HOBt;

2394

mesyl, Ms; m-chloroperoxybenzoic acid, mCPBA; 5-methoxycarbonylamino-N-

2395

acetyltryptamine,

2396

fluorobenzenesulfonimide, NFSi; N-iodosuccinimide, NIS; N-methyl-D-aspartate,

2397

NMDA;

2398

dicyclohexylcarbodiimide,

2399

methylmorfoline, NMM; non-rapid eye movement, NREM; N,N,N′,N′-tetramethyl-O-

2400

(N-succinimidyl)uronium

2401

phosphanetriyltris(benzenesulfonic acid) trisodium salt, tppts; polyphosphoric acid,

2402

PPA; pyridine, Py; raney, Ra; protecting group, PG; p-toluensulfonic acid, PTSA; room

2403

temperature, r.t.; tartaric acid, TA; t-butyldimethylsilyl, TBDMS; t-butylhydroperoxide,

2404

TBHP; tetrabutylammonium bromide, TBAB; tetrabutylammonium hydroxide, TBAHS;

2405

tetrahydrofuran,

2406

triisopropylbenzenesulfonyl hydrazide, TPSH; trimethylsilyl, TMS; triisopropylsilyl

2407

ether, TIPS.

DDQ;

4-dimethylaminopyridine,

DMAP;

5-MCA-NAT;

7-nitrobenzofurazan,

THF;

N,N-diisopropylethylamine,

trifluoroacetic

2408 2409

References 142

DCE;

dimethylformamide,

N,N′-carbonyldiimidazole,

Ts;

boron-

1,2-dichloroethene,

tetrafluoroborate,

tosyl,

HMDS;

N-bromosuccinimide,

NBD;

DCC;

bis(trimethylsilyl)amide,

NBS;

N-

DCl;

N,N′-

DIPEA;

TSTU;

acid,

DMF;

N-

3,3′,3″-

TFA;

2,4,6-

2410

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Highlights - A dispersed topic with high number of articles per year was covered for first time. - The synthetic routes to indole-based melatonin analogues were analyzed. - The effects of structural modifications on the biological properties were described. - New insights for the design of selective melatoninergic drugs were proposed.

Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: