Synthesis of aromatic-linked polyamine macrocyclic derivatives as HIV-1 entry inhibitors

Chinese Chemical Letters 18 (2007) 1166–1168 www.elsevier.com/locate/cclet

Synthesis of aromatic-linked polyamine macrocyclic derivatives as HIV-1 entry inhibitors Jing Su a, Yao Liu b, Zhi Bing Zheng c, Jun Hai Xiao c, Hong Lu d, Wu Zhong c, Li Li Wang c, Shi Bo Jiang d, Song Li c,* a

School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China b School of Pharmacy, Jilin University, Changchun 130021, China c Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China d Lindsley F. Kimball Research Institute, the New York Blood Center, New York, NY 10021, USA Received 13 June 2007

Abstract A series of novel aromatic-linked polyamine macrocyclic derivatives have been synthesized. Their structures were confirmed by MS and 1H NMR. These compounds exhibited potent anti-HIV-1 activities. # 2007 Published by Elsevier B.V. on behalf of Chinese Chemical Society. Keywords: HIV-1 entry inhibitors; Aromatic-linked polyamine; Macrocyclic derivatives; Synthesis

The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) transmembrane subunit gp41 plays an important role in fusion of viral and target cell membranes and HIV-1 entry [1]. Peptides derived from the HIV-1 gp41 C-terminal heptad repeat region, SJ-2176 [2] and T-20 [3], are potent HIV-1 fusion inhibitors. T-20 (brand name: Fuzeon) was licensed by FDA in 2003 as the first member of the new class of antiviral drugs—HIV entry inhibitor [4]. However, the clinical application of T-20 is limited due to its lack of oral bioavailability and high cost of production. Therefore, small molecule HIV entry inhibitors are more preferable than the peptidic drugs. Jiang et al. [5] have identified several small molecule compounds that inhibit HIV-1 entry by targeting the hydrophobic pocket in the gp41 N-helix trimer and blocking the six-helix bundle formation. Douglas et al. [6] have reported that a small molecule VP-14637 is highly potent in inhibiting entry of human respiratory syncytial virus (RSV) by binding to the hydrophobic pocket in the inner core of RSV F protein which has similar structure and function as the HIV-1 gp41. A bicyclam compound named AMD3100 was found to be potent HIV-1 entry inhibitor by targeting the HIV-1 coreceptor, CXCR4 [7]. Notably, VP-14637 and AMD3100 share some common features in docking to the HIV-1 gp41 pocket, suggesting that based on the structure of these two compounds, a novel HIV-1 entry inhibitor by targeting both gp41 and CXCR4 may be designed. Here, we synthesized a series of aromatic-linked polyamine macrocyclic derivatives as described in Scheme 1 and tested their anti-HIV-1 activity. Bromo-substituted benzaldehyde 2, as the starting materials, was protected with neopentyl glycol to afford 3. Then 3 undergone reaction with n-butyllithium to effect a halogen–alkali metal exchange, an alkyl ester was added to the * Corresponding author. E-mail address: [email protected] (S. Li). 1001-8417/$ – see front matter # 2007 Published by Elsevier B.V. on behalf of Chinese Chemical Society. doi:10.1016/j.cclet.2007.08.021

J. Su et al. / Chinese Chemical Letters 18 (2007) 1166–1168

1167

Scheme 1. Synthesis of aromatic-linked polyamine macrocyclic derivatives. Reagents and conditions: (a) Benzene, neopentyl glycol, pyridinium ptoluenesulfonate, reflux, 6 h, >90%; (b) (i) THF, n-butylLi, 78 8C, 1 h, (ii) Ar-COOCH3, 0 8C, 3 h, 60–70%; (c) Formic acid, reflux, 10 h, 50–60%; (d) THF, LiAlH4, 1 h, 70–90%; (e) 1,4-dioxane, PBr3 r.t., overnight, 60–70%; (f) 8, CH3CN, K2CO3, reflux, 24 h, 70–80%; (g) CH3COOH/ hydrobromic acid (3/2), reflux, 24–48 h, 50–60%.

reaction mixture under 78 8C yielding triphenylcarbinol 4. Then 4 were deprotected with formic acid to give alkyl aldehyde derivatives 5, which were converted to 6 by reduction of the aldehyde group with LiAlH4. Then 6 were followed by bromination with PBr3 [8] to provide bis-brominated intermediates 7. N-Alkylation of 7 with the intermediate 8 in the presence of K2CO3 gave fully tosyl-protected dimer 9. Deprotection of 9 was suitably carried out

Scheme 2. Synthesis of intermediate 8. Reagents and conditions: (a) THF, TsCl, r.t., overnight, 80%; (b) CH3CN, TsOCH2CH2OTs, K2CO3, reflux, 72 h, 62%; (c) (i) 90%H2SO4, 100 8C, 48 h, (ii) NaOH, 86%; (d) CHCl3, TsCl, r.t., overnight, 92%.

1168

J. Su et al. / Chinese Chemical Letters 18 (2007) 1166–1168

Table 1 Analytical data of the compounds 1a–h Link position

Mp (8C)

FAB-MS (m/z)

1

1a

3,30

228–230

683.3

1b

3,30

222–224

687.4

1c

3,30

230–232

703.4

1d

4,40

240–242

669.3

1e

4,40

233–235

683.2

1f

4,40

228–230

687.2

1g

4,40

232–234

703.2

1h

4,40

233–235

747.2

2.14–2.26 (br m, 8H), 2.52 (s, 3H), 3.28–3.52 (br m, 32H), 4.24 (s, 4H), 5.93 (s, 1H), 7.36–7.66 (m, 12H) 1.91 (br, 8H), 2.99–3.26 (br m, 32H), 4.07 (s,4H), 5.63 (s,1H), 6.95–7.29 (m, 12H) 1.96–2.00 (br m, 8H), 3.06–3.33 (br m, 32H), 4.14 (s, 4H), 5.72 (s, 1H), 7.20–7.39 (m, 12H) 1.87–2.00 (br m, 8H), 3.11–3.32 (br m, 32H), 4.13 (s, 4H), 5.60 (s, 1H), 7.18–7.27 (m, 13H) 1.85–1.96 (br m, 8H), 2.12 (s3, H), 3.09–3.44 (br m, 32H), 4.13 (s, 4H), 5.53 (s, 1H), 6.98–7.24 (m, 12H) 1.73–1.99 (br m, 8H), 3.09–3.50 (br m, 32H), 4.11 (s, 4H), 5.60 (s, 1H), 6.94–7.28 (m, 12H) 1.84–1.98 (br m, 8H), 3.08–3.29 (br m, 32H), 4.11 (s, 4H), 5.60 (s, 1H), 6.99–7.25 (m, 12H) 1.98–2.08 (br m, 8H), 3.05–3.41(br m, 32H), 4.03 (s, 4H), 5.80 (s, 1H), 7.13–7.49 (m, 12H)

Compound

Ar

H NMR (400 MHz, D2O, d ppm, J Hz)

Table 2 Anti-HIV-1 activity data for the compounds 1a–h and AMD3100 Compound

AMD3100

1a

1b

1c

1d

1e

1f

1g

1h

IC50 (mmol/L)

0.025

0.168

0.321

0.346

0.984

0.974

0.438

0.649

0.426

in a mixture of aqueous HBr and acetic acid to give compounds 1a–h. An optimized synthetic method of the intermediate 8 was shown in Scheme 2 [9]. Sulfonylation of bis(3-aminopropyl)ethylene diamine 10 with ptoluenesulfonyl chloride gave 11. Cyclization of 11 with ethylenebis( p-toluenesulphonate) gave 12, which was deprotected with 90% concentrated sulfuric acid and then alkalized with sodium hydroxide to give 13 (Cyclam). Then 13 was subject to tri-tosyl protection with p-toluenesulfonyl chloride to yield the intermediate 8. In total, we have synthesized eight new compounds, whose structures were confirmed by MS and 1H NMR (data shown in Table 1). The inhibitory activity of the compounds 1a–h on infection by the laboratory-adapted HIV-1 strain IIIB was determined as previously described [5]. As shown in Table 2, all of the compounds displayed anti-HIV-1 with IC50 values ranging from 0.1 to 1 mM. Further studies on the mechanism of action of these compounds are in progress. Acknowledgments This work was supported by the National Basic Research Program of China (973 project: No. 2004CB518908) and the National Natural Science Foundation of China (No. 30472093) to SL and the Outstanding Overseas Chinese Scholars Fund of Chinese Academy of Sciences (No. 2005-2-6) to S.J. References [1] [2] [3] [4] [5] [6] [7] [8] [9]

D.C. Chan, P.S. Kim, Cell 93 (1998) 681. S. Jiang, K. Lin, et al. Nature 365 (1993) 113. C.T. Wild, D.C. Shugars, et al. Proc. Natl. Acad. Sci. U.S.A. 91 (1994) 9770. J.P. Lalezari, K. Henry, et al. N. Engl. J. Med. 348 (2003) 2175. S. Jiang, S.W. Liu, et al. Antimicrob. Agents Chemother. 48 (2004) 4349. J.L. Douglas, et al. Antimicrob. Agents Chemother. 49 (2005) 2460. G.A. Donzella, et al. Nat. Med. 4 (1998) 72. T. Kamada, N. Wasada, Synthesis 10 (1990) 967. J. Su, S. Li, et al. Chinese J. Pharm. 38 (2007) 398.