- Email: [email protected]
Combinatorial Chemistry Online Volume 9, Issue 5, May 2007
Combinatorial Chemistry - An Online Journal 9 (2007) 21–25
Combinatorial Chemistry Online Volume 9, Issue 5, May 2007 N. K. Terrett Ensemble Discovery Corp., Cambridge, MA 02139, USA
1. Current literature highlights 1.1. Combinatorial approaches to combating multidrug resistance with antimicrobial peptides The widespread use of antibiotics throughout the world has led to bacterial resistance to many commonly used antibiotics. Development of resistance, coupled to the fact that only a few new classes of antibacterial agents have been introduced into the clinic during the last decade, has emphasised the need for novel antibiotic development. To meet this need, cationic antimicrobial peptides (CAPs) are a promising class of future antibacterial agents. They are believed less likely to induce resistance in bacteria, and this lower propensity for resistance may arise from their unique mechanism of action. Although no exact mode of action has been established, most antimicrobial peptides are thought to act on, or at least to involve, bacterial membranes. Several models have been put forward to explain the interactions between CAPs and bacterial membranes, but no common view has been reached to date.
increases in antimicrobial activity compared to control peptides. S. pyogenes was found to be the least susceptible bacterium in the test panel, while all peptides were most active against MRSE. One of the most potent peptides isolated was (ii) which possessed a MIC of 16 lM against S. pyogenes and a MIC of 4.1 lM against MRSE. In addition, the peptides were also tested for haemolytic activity against human erythrocytes. Most of the peptides were found to be non-haemolytic within the concentration range tested (up to 500 lg/mL). R O H2 N
E-mail: [email protected] doi:10.1016/j.comche.2007.04.001
N H
NH2
O HN
HN
(i) HN
Several challenges remain in the development of CAPs into drugs. However, one promising approach has been the development of small molecular weight CAPs. In a recent study, a library of tripeptide derivatives containing the unnatural amino acid 4-iodophenylalanine has been prepared using a Rink amide linker solid support.1 These novel tripeptides (i) were synthesised through Suzuki–Miyaura cross-coupling reactions, and tested for their ability to inhibit the growth of Streptococcus pyogenes, S. aureus, methicillin-resistant S. aureus (MRSA), and methicillin-resistant S. epidermidis (MRSE). The results obtained were expressed as the minimal inhibitory concentration (MIC) in lM. Of the peptides synthesised and tested, generally all of the derivatives displayed significant
O
H N
HN
NH2
O H2 N
HN HN
NH2
H N
N H
O NH2
O HN
NH2
HN
NH2
(ii)
In summary, the low haemolytic propensity of these peptides in combination with their high antimicrobial activity increases the chances that such entities could be developed into clinical candidates, allowing for the future development of drugs effective against multidrug resistant pathogens.
22
N. K. Terrett / Combinatorial Chemistry - An Online Journal 9 (2007) 21–25
1.2. Evaluation of new taxoids derived from 2-deacetoxytaxinine J
may provide an important starting material for the synthesis of new reversal agents.
Paclitaxel (Taxol) is a complex natural diterpene extracted from Taxus brevifolia. Paclitaxel and its derivative docetaxel are two of the more important anticancer agents for the treatment of ovarian and breast cancer. The use in a clinical setting of anticancer drugs such as these have revealed a number of undesirable side effects and multidrug resistance (MDR) induced by taxoid treatment in tumour cells is an obstacle to the successful application of chemotherapy.
For these reasons, the development of methods for the preparation of new bioactive taxinine analogues from DAT-J, is desirable. Recent work has reported on the preparation of a small library of DAT-J analogues (v) and their biological screening as new putative MDR-reversing agents against multidrug-resistant breast tumour cell lines.2
MDR is a phenomenon whereby tumour cells that have been exposed to one cytotoxic agent develop cross resistance to a range of structurally and functionally unrelated compounds. The drug resistance developed in cancer cells may be controlled by many mechanisms. One postulated mechanism relates to the over-expression in cancer cells of particular proteins such as P-glycoprotein (P-gp) which expel hydrophobic anticancer compounds and maintain intracellular concentrations below a cytotoxic level. Among the natural taxoids, 2-deacetoxytaxinine J (DAT-J) (iii) has emerged as an active P-gp inhibitor with a potency higher than verapamil. DAT-J is extracted in low amounts from several yew species, but it can be synthesised from the natural alkaloid 2’-deacetoxyaustropicatine (DAS) (iv) available in multigram amounts from Taxus x media Rehd. Cv. HicKsii. Additionally, unlike other cinnamates related to taxinine, DAT-J does not show cardiotoxicity, and thus
O
OAc OAc
O
O O
H
O
N
The condensation reaction of 2-amino-3-hydroxypyridine with different carboxylic acids by microwave-assisted heating has been shown to be a fast method for producing libraries based on fused 2-substituted oxazolo[4,5-b]pyridines.5
O
H
O H
(iv)
O
OAc OAc
O
R
OH
H
O
(v)
H
O
The first regiocontrolled solid-phase synthesis of a 2,6,8,9tetrasubstituted purine library has been performed through on-resin elaboration of 4,6-dichloro-2-(methylthio)-5nitropyrimidine. Most of the final purines were cleaved in good to excellent yield and purity. However it was found that bulky groups at N9 hindered cyclisation in C8-substituted derivatives.3
Various palladium-catalysed cascade reactions of O-alkylated 2-iodophenol have been explored in order to synthesise novel dihydrobenzofurans, and a small library of these compounds was prepared with a parallel organic synthesiser.4
OAc OAc O
O
2.1. Solid-phase synthesis
2.2. Solution-phase synthesis
(iii)
O
2. A summary of the papers in this month’s issue
O
H
O
Biological evaluation of DAT-J analogues of general structure (v) synthesised in this work were tested in vitro for their MDR revertant activity in human mammary carcinoma cell line MCF7-R; this cell line being resistant to paclitaxel. The compounds were tested at a non-cytotoxic concentration (1.0 and 0.1 lM) in combination with paclitaxel. The activity was expressed as an IC50 (in nM); the concentration required to cause 50% inhibition of cancer cell growth. One of the most potent compounds synthesized and tested was (vi) which possessed an IC50 of 31 nM.
O
OAc OAc
O
A highly efficient one-pot, two-step microwave procedure has been developed for the synthesis of 4-substituted 1-heteroarylpiperazines. Microwave heating of heteroaryl chlorides with 1,4-diazabicyclo[2.2.2]octane (DABCO) yielded 1-heteroaryl-4-(2-chloroethyl)piperazines, which could be further reacted with various nucleophiles, again under microwave irradiation conditions, to give an array of 4substituted 1-heteroarylpiperazines in good to excellent yields.6 2.3. Scaffolds for combinatorial libraries
H
O
OH
H (vi)
Optimisation of coupling reactions of glycosylamines with Fmoc-protected aspartic acid, by microwave approach, has
N. K. Terrett / Combinatorial Chemistry - An Online Journal 9 (2007) 21–25
23
been described. Different reaction conditions, quantities of substrates and solvents were tested to develop simple and reproducible methodologies, and the N-glycosyl amino acids were deprotected to achieve final products for SPPS.7
tors for the treatment of type 2 diabetes. Using parallel chemistry, and protein co-crystal structural data to guide the optimisation of N-substituents, a >400 · improvement in potency over the initial hit was realised.14
Preparation of the 4 0 ,4 0 -C-diaminomethyl uridine analogue starting from the commercial uridine via 4 0 ,4 0 -C-dihydroxymethyl uridine, 4 0 ,4 0 -C-bis-trifluoromethanesulphonyloxymethyl uridine, and 4 0 ,4 0 -C-diazidomethyl uridine in total eight steps was achieved in 8% yield. The product has been used as a scaffold for library production.8
A series of heterobiaryl amides was designed and synthesised as novel mGluR5 antagonists. The synthesis using palladium catalyzed Suzuki–Miyaura cross-coupling reactions provided an array of compounds with a range of in vitro activities.15
2.4. Solid-phase supported reagents No papers this month.
In the course of a high throughput screening, a series of pyrazole compounds were identified with luteinising hormone receptor (LH-R) agonist activity. A focused pyrazole library was produced by solid-phase synthesis and key pyrazole regioisomers were obtained selectively in solution.16
2.5. Novel resins, linkers and techniques No papers this month. 2.6. Library applications Novel arylpiperazines with N-acylated amino acids, selected on the basis of a preliminary screening of two libraries previously synthesised on SynPhaseTM Lanterns, have been prepared in solution and their affinity for 5HT1A, 5-HT2A, and D2 receptors evaluated.9 A 23-member C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine5,11-dione (PBD dilactam) library has been synthesised using Suzuki coupling, and the effect of base upon racemisation at the C11a-position during the cross-coupling reaction studied. Three library members were sufficiently cytotoxic in the NCI’s preliminary screen to warrant further evaluation.10 The identification of constitutively activated STAT (Signal Transducers and Activators of Transcription) proteins in aberrant cell signalling pathways has led to investigations targeting the selective disruption of specific STAT isoforms directly associated with oncogenesis. Through the design of a library of peptidomimetic inhibitors, agents that selectively disrupt STAT1 or STAT3 homo-dimerisation at low micromolar concentrations have been discovered.11 The guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde, a CCR5 receptor ligand, was identified using high-throughput screening. Optimisation efforts led to the discovery of a novel piperidine series of CCR5 antagonists, and the 4-hydroxypiperidine derivative was a starting point for further optimisation using parallel synthesis.12 A library of potential antifungal triazole-modified b-methoxyacrylate analogues was designed and synthesised via a Cu(I)-catalyzed 1,3-dipolar alkyne-azide coupling reaction or ‘click chemistry’. Subsequent biological screening revealed that some compounds displayed low to moderate antifungal activity toward pathogenic fungi and low phytotoxicity.13 A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibi-
Inhibitors of histone deacetylase (HDAC) proteins such as suberoylanilide hydroxamic acid (SAHA) have emerged as effective therapeutic anti-cancer agents. To better understand the structural requirements of HDAC inhibitors, a small molecule library with a variety of substituents attached adjacent to the metal binding hydroxamic acid of SAHA was synthesised.17 Halopemide, which was identified by HTS to inhibit phospholipase D2 (PLD2), provided the basis for an exploratory effort to identify potent inhibitors of PLD2 for use as inflammatory mediators. Parallel synthesis and purification were used to rapidly identify orally available amide analogues derived from indole 2-carboxylic acids with superior potency versus PLD2.18 A novel series of potent dual agonists of PPARa and PPARc, the alkoxybenzylglycines, has been identified and explored using a solution-phase library approach.19 The synthesis of a selected library of heterochiral dPro-containing RGD-peptidomimetics (RpD) has been described and these compounds were investigated as inhibitors of fibronectin adhesion to SK-MEL-24 tumour cells.20 The discovery of novel antibacterial agents which were rapidly optimised utilizing a parallel chemistry approach has been described. In an effort to decrease the affinity for HSA, a series of heterocyclic analogues were prepared and these retained antibacterial activity and demonstrated reduced affinity for HSA.21 A novel, general and versatile method of diversification of the P1 0 position in phosphinic pseudodipeptides, presumable inhibitors of proteolytic enzymes, has been elaborated. The procedure was based on parallel derivatisation of the amino group in the suitably protected phosphinate building blocks with appropriate alkyl and aryl halides. The compounds were evaluated as inhibitors of cytosolic leucine aminopeptidase and aminopeptidase N.22 A series of 2-oxy-substituted 1-(1H-imidazol-1-yl)-4-phenylbutanes comprising imidazole–ketones, imidazole–dioxolanes and imidazole–alcohols substituted with halogens in the phenyl ring have been synthesised and evaluated as
24
N. K. Terrett / Combinatorial Chemistry - An Online Journal 9 (2007) 21–25
novel inhibitors of heme oxygenase which are structurally distinct from metalloporphyrins.23 The parallel acylation of N-{3-[4-(3-aminopropyl)piperazin-1-yl]propyl}-7-chloroquinolin-4-amine with polymerbound carboxylic acids has provided a straightforward access to novel aminoquinolines with activity against Plasmodium falciparum strains in vitro.24
References 1. Haug, B. E. et al. Bioorg. Med. Chem. Lett. 2007, 17 (8), 2361–2364. 2. Botta, M. et al. Bioorg. Med. Chem. Lett. 2007, 17 (6), 1579–1583. 3. Hammarstro¨m, L. G. J. et al. Tetrahedron Lett. 2007, 48 (16), 2823–2827. 4. Szlosek-Pinaud, M. et al. Tetrahedron 2007, 63 (16), 3340–3349. 5. Myllyma¨ki, M. J.; Koskinen, A. M. P. Tetrahedron Lett. 2007, 48 (13), 2295–2298. 6. Wang, H.-J.; Earl, W. G. Tetrahedron Lett. 2007, 48 (17), 3043–3046. 7. Paolini, I. et al. Tetrahedron Lett. 2007, 48 (16), 2901–2904. 8. Yu, C.-S.; Wang, R.-T. Tetrahedron Lett. 2007, 48 (17), 2979–2982. 9. Zajdel, P. et al. Bioorg. Med. Chem. 2007, 15 (8), 2907–2919. 10. Antonow, D.; Jenkins, T. C. Bioorg. Med. Chem. 2007, 15 (8), 3041–3053. 11. Gunning, P. T. et al. Bioorg. Med. Chem. Lett. 2007, 17 (7), 1875–1878. 12. Lu, S.-F. et al. Bioorg. Med. Chem. Lett. 2007, 17 (7), 1883–1887. 13. Chen, H. et al. Bioorg. Med. Chem. Lett. 2007, 17 (7), 1979–1983. 14. Backes, B. J. et al. Bioorg. Med. Chem. Lett. 2007, 17 (7), 2005–2012. 15. Kulkarni, S. S.; Newman, A. H. Bioorg. Med. Chem. Lett. 2007, 17 (7), 2074–2079. 16. Jorand-Lebrun, C. et al. Bioorg. Med. Chem. Lett. 2007, 17 (7), 2080–2085. 17. Bieliauskas, A. V.; Weerasi, S. V. W. Bioorg. Med. Chem. Lett. 2007, 17 (8), 2216–2219. 18. Monovich, L.; Mu, B. Bioorg. Med. Chem. Lett. 2007, 17 (8), 2310–2311. 19. Devasthale, P. V. et al. Bioorg. Med. Chem. Lett. 2007, 17 (8), 2312–2316. 20. Gentilucci, L. et al. Bioorg. Med. Chem. Lett. 2007, 17 (8), 2329–2333. 21. Li, J. et al. Bioorg. Med. Chem. Lett. 2007, 17 (8), 2347–2350. 22. Vassiliou, S. et al. Bioorg. Med. Chem. 2007, 15 (9), 3187–3200. 23. Roman, G. et al. Bioorg. Med. Chem. 2007, 15 (9), 3225–3234. 24. Freitag, M. et al. Bioorg. Med. Chem. 2007, 15 (7), 2782–2788.
Further reading Papers on combinatorial chemistry or solid-phase synthesis from other journals Bayo-Puxan, N.; Fernandez, A.; Tulla-Puche, J.; Riego, E.; Cuevas, C.; Alvarez, M.; Albericio, F. Total solid-phase
synthesis of the azathiocoraline class of symmetric bicyclic peptides. Chemistry–A European Journal 2006, 12 (35), 9001–9009. Lehmann, F.; Lake, L.; Currier, E. A.; Olsson, R.; Hacksell, U.; Luthman, K. Design, parallel synthesis and SAR of novel urotensin II receptor agonists. European Journal of Medicinal Chemistry 2007, 42 (2), 276–285. Zameo, S.; Vauzeilles, B.; Beau, J.-M. Direct composition analysis of a dynamic library of imines in an aqueous medium. European Journal of Organic Chemistry, 2006, (24), 5441– 5444. Koenig, H. M.; Gorelik, T.; Kolb, U.; Kilbinger, A. F. M. Supramolecular PEG-co-oligo(p-benzamide)s prepared on a peptide synthesizer. Journal of the American Chemical Society 2007, 129 (3), 704–708. Liu, X.-L.; Sheng, S.-R.; Wang, Q.-Y.; Sun, W.-K.; Xin, Q.; Ao, H.-Y. A facile solid-phase synthesis of vinyl ethers using a selenium traceless linker. Journal of Chemical Research, 2006, (2), 118–120. Kamal, A.; Reddy, K. L.; Devaiah, V.; Shankaraiah, N.; Reddy, G. S. K.; Raghavan, S. Solid-phase synthesis of a library of pyrrolo [2,1-c][1,4]benzodiazepine-5,11-diones with potential antitubercular activity. Journal of Combinatorial Chemistry 2007, 9 (1), 29–42. Christensen, C. A.; Meldal, M. Solid-phase synthesis of a peptidebased P,S-ligand system designed for generation of combinatorial catalyst libraries. Journal of Combinatorial Chemistry 2007, 9 (1), 79–85. Yang, T.-M.; Liu, G. Solution-phase parallel synthesis of 3,5,6substituted indolin-2-ones. Journal of Combinatorial Chemistry 2007, 9 (1), 86–95. Trump, R. P.; Blanc, J.-B. E.; Stewart, E. L.; Brown, P. J.; Caivano, M.; Gray, D. W.; Hoekstra, W. J.; Willson, T. M.; Han, B.; Turnbull, P. Design and synthesis of an array of selective androgen receptor modulators. Journal of Combinatorial Chemistry 2007, 9 (1), 107–114. Yuan, Y.; Liu, G.; Li, L.; Wang, Z.; Wang, L. Synthesis of diverse benzo[1,4]oxazin-3-one-based compounds using 1,5-difluoro2,4-dinitrobenzene. Journal of Combinatorial Chemistry 2007, 9 (1), 158–170. Tan, T. M. C.; Yang, F.; Fu, H.; Raghavendra, M. S.; Lam, Y. Traceless solid-phase synthesis and biological evaluation of purine analogs as inhibitors of multidrug resistance protein 4. Journal of Combinatorial Chemistry 2007, 9 (2), 210–218. Verdie, P.; Subra, G.; Feliu, L.; Sanchez, P.; Berge, G.; Garcin, G.; Martinez, J. On-line synthesis of pseudopeptide library incorporating a benzodiazepinone turn mimic: Biological evaluation on MC1 receptors. Journal of Combinatorial Chemistry 2007, 9 (2), 254–262. Kiriazis, A.; Rueffer, T.; Jaentti, S.; Lang, H.; Yli-Kauhaluoma, J. Stereoselective aza Diels-Alder reaction on solid phase: a facile synthesis of hexahydrocinnoline derivatives. Journal of Combinatorial Chemistry 2007, 9 (2), 263–266. Kamal, A.; Devaiah, V.; Reddy, K. L.; Rajendar, S.; Rajesh, V. C. R. N. C.; Shankaraiah, N. Efficient solid-phase synthesis of a library of imidazo[1,2-a]pyridine-8-carboxamides. Journal of Combinatorial Chemistry 2007, 9 (2), 267–274. Matloobi, M.; Kappe, C. O. Microwave-assisted solution- and solid-phase synthesis of 2-amino-4-arylpyrimidine derivatives. Journal of Combinatorial Chemistry 2007, 9 (2), 275–284. Whiting, M.; Tripp, J. C.; Lin, Y.-C.; Lindstrom, W.; Olson, A. J.; Elder, J. H.; Sharpless, K. B.; Fokin, V. V. Rapid discovery and structure-activity profiling of novel inhibitors of human immunodeficiency virus type 1 protease enabled by the copper(I)-catalyzed synthesis of 1,2,3-triazoles and their further functionalization. Journal of Medicinal Chemistry 2006, 49 (26), 7697–7710.
N. K. Terrett / Combinatorial Chemistry - An Online Journal 9 (2007) 21–25
Naruchi, K.; Hamamoto, T.; Kurogochi, M.; Hinou, H.; Shimizu, H.; Matsushita, T.; Fujitani, N.; Kondo, H.; Nishimura, S.-I. Construction and Structural Characterization of Versatile Lactosaminoglycan-related compound library for the synthesis of complex glycopeptides and glycosphingolipids. Journal of Organic Chemistry 2006, 71 (26), 9609–9621. Oyelere, A. K.; Chen, P. C.; Yao, L. P.; Boguslavsky, N. Heterogeneous diazo-transfer reaction: a facile unmasking of azide groups on amine-functionalized insoluble supports for solid-phase synthesis. Journal of Organic Chemistry 2006, 71 (26), 9791–9796.
25
Robins, L. I.; Kurth, M. J. 1,3,5-Triazine-based mass spectral tagging of one-bead one-compound libraries. Organic Letters 2007, 9 (2), 171–173. de Greef, M.; Abeln, S.; Belkasmi, K.; Doemling, A.; Orru, R. V. A.; Wessjohann, L. A. Rapid combinatorial access to macrocyclic ansapeptoids and ansapeptides with natural-productlike core structures. Synthesis 2006, (23), 3997–4004. Chen, R.; Lee, V.; Adlington, R. M.; Baldwin, J. E. A facile synthesis of ethyl 2-acetamido-4-methylenehex-5-enoate, a versatile Diels-Alder synthon for the parallel synthesis of novel a-amino acid derivatives. Synthesis 2007, (1), 113–117.
Combinatorial Chemistry Online Volume 9, Issue 5, May 2007 N. K. Terrett Ensemble Discovery Corp., Cambridge, MA 02139, USA
1. Current literature highlights 1.1. Combinatorial approaches to combating multidrug resistance with antimicrobial peptides The widespread use of antibiotics throughout the world has led to bacterial resistance to many commonly used antibiotics. Development of resistance, coupled to the fact that only a few new classes of antibacterial agents have been introduced into the clinic during the last decade, has emphasised the need for novel antibiotic development. To meet this need, cationic antimicrobial peptides (CAPs) are a promising class of future antibacterial agents. They are believed less likely to induce resistance in bacteria, and this lower propensity for resistance may arise from their unique mechanism of action. Although no exact mode of action has been established, most antimicrobial peptides are thought to act on, or at least to involve, bacterial membranes. Several models have been put forward to explain the interactions between CAPs and bacterial membranes, but no common view has been reached to date.
increases in antimicrobial activity compared to control peptides. S. pyogenes was found to be the least susceptible bacterium in the test panel, while all peptides were most active against MRSE. One of the most potent peptides isolated was (ii) which possessed a MIC of 16 lM against S. pyogenes and a MIC of 4.1 lM against MRSE. In addition, the peptides were also tested for haemolytic activity against human erythrocytes. Most of the peptides were found to be non-haemolytic within the concentration range tested (up to 500 lg/mL). R O H2 N
E-mail: [email protected] doi:10.1016/j.comche.2007.04.001
N H
NH2
O HN
HN
(i) HN
Several challenges remain in the development of CAPs into drugs. However, one promising approach has been the development of small molecular weight CAPs. In a recent study, a library of tripeptide derivatives containing the unnatural amino acid 4-iodophenylalanine has been prepared using a Rink amide linker solid support.1 These novel tripeptides (i) were synthesised through Suzuki–Miyaura cross-coupling reactions, and tested for their ability to inhibit the growth of Streptococcus pyogenes, S. aureus, methicillin-resistant S. aureus (MRSA), and methicillin-resistant S. epidermidis (MRSE). The results obtained were expressed as the minimal inhibitory concentration (MIC) in lM. Of the peptides synthesised and tested, generally all of the derivatives displayed significant
O
H N
HN
NH2
O H2 N
HN HN
NH2
H N
N H
O NH2
O HN
NH2
HN
NH2
(ii)
In summary, the low haemolytic propensity of these peptides in combination with their high antimicrobial activity increases the chances that such entities could be developed into clinical candidates, allowing for the future development of drugs effective against multidrug resistant pathogens.
22
N. K. Terrett / Combinatorial Chemistry - An Online Journal 9 (2007) 21–25
1.2. Evaluation of new taxoids derived from 2-deacetoxytaxinine J
may provide an important starting material for the synthesis of new reversal agents.
Paclitaxel (Taxol) is a complex natural diterpene extracted from Taxus brevifolia. Paclitaxel and its derivative docetaxel are two of the more important anticancer agents for the treatment of ovarian and breast cancer. The use in a clinical setting of anticancer drugs such as these have revealed a number of undesirable side effects and multidrug resistance (MDR) induced by taxoid treatment in tumour cells is an obstacle to the successful application of chemotherapy.
For these reasons, the development of methods for the preparation of new bioactive taxinine analogues from DAT-J, is desirable. Recent work has reported on the preparation of a small library of DAT-J analogues (v) and their biological screening as new putative MDR-reversing agents against multidrug-resistant breast tumour cell lines.2
MDR is a phenomenon whereby tumour cells that have been exposed to one cytotoxic agent develop cross resistance to a range of structurally and functionally unrelated compounds. The drug resistance developed in cancer cells may be controlled by many mechanisms. One postulated mechanism relates to the over-expression in cancer cells of particular proteins such as P-glycoprotein (P-gp) which expel hydrophobic anticancer compounds and maintain intracellular concentrations below a cytotoxic level. Among the natural taxoids, 2-deacetoxytaxinine J (DAT-J) (iii) has emerged as an active P-gp inhibitor with a potency higher than verapamil. DAT-J is extracted in low amounts from several yew species, but it can be synthesised from the natural alkaloid 2’-deacetoxyaustropicatine (DAS) (iv) available in multigram amounts from Taxus x media Rehd. Cv. HicKsii. Additionally, unlike other cinnamates related to taxinine, DAT-J does not show cardiotoxicity, and thus
O
OAc OAc
O
O O
H
O
N
The condensation reaction of 2-amino-3-hydroxypyridine with different carboxylic acids by microwave-assisted heating has been shown to be a fast method for producing libraries based on fused 2-substituted oxazolo[4,5-b]pyridines.5
O
H
O H
(iv)
O
OAc OAc
O
R
OH
H
O
(v)
H
O
The first regiocontrolled solid-phase synthesis of a 2,6,8,9tetrasubstituted purine library has been performed through on-resin elaboration of 4,6-dichloro-2-(methylthio)-5nitropyrimidine. Most of the final purines were cleaved in good to excellent yield and purity. However it was found that bulky groups at N9 hindered cyclisation in C8-substituted derivatives.3
Various palladium-catalysed cascade reactions of O-alkylated 2-iodophenol have been explored in order to synthesise novel dihydrobenzofurans, and a small library of these compounds was prepared with a parallel organic synthesiser.4
OAc OAc O
O
2.1. Solid-phase synthesis
2.2. Solution-phase synthesis
(iii)
O
2. A summary of the papers in this month’s issue
O
H
O
Biological evaluation of DAT-J analogues of general structure (v) synthesised in this work were tested in vitro for their MDR revertant activity in human mammary carcinoma cell line MCF7-R; this cell line being resistant to paclitaxel. The compounds were tested at a non-cytotoxic concentration (1.0 and 0.1 lM) in combination with paclitaxel. The activity was expressed as an IC50 (in nM); the concentration required to cause 50% inhibition of cancer cell growth. One of the most potent compounds synthesized and tested was (vi) which possessed an IC50 of 31 nM.
O
OAc OAc
O
A highly efficient one-pot, two-step microwave procedure has been developed for the synthesis of 4-substituted 1-heteroarylpiperazines. Microwave heating of heteroaryl chlorides with 1,4-diazabicyclo[2.2.2]octane (DABCO) yielded 1-heteroaryl-4-(2-chloroethyl)piperazines, which could be further reacted with various nucleophiles, again under microwave irradiation conditions, to give an array of 4substituted 1-heteroarylpiperazines in good to excellent yields.6 2.3. Scaffolds for combinatorial libraries
H
O
OH
H (vi)
Optimisation of coupling reactions of glycosylamines with Fmoc-protected aspartic acid, by microwave approach, has
N. K. Terrett / Combinatorial Chemistry - An Online Journal 9 (2007) 21–25
23
been described. Different reaction conditions, quantities of substrates and solvents were tested to develop simple and reproducible methodologies, and the N-glycosyl amino acids were deprotected to achieve final products for SPPS.7
tors for the treatment of type 2 diabetes. Using parallel chemistry, and protein co-crystal structural data to guide the optimisation of N-substituents, a >400 · improvement in potency over the initial hit was realised.14
Preparation of the 4 0 ,4 0 -C-diaminomethyl uridine analogue starting from the commercial uridine via 4 0 ,4 0 -C-dihydroxymethyl uridine, 4 0 ,4 0 -C-bis-trifluoromethanesulphonyloxymethyl uridine, and 4 0 ,4 0 -C-diazidomethyl uridine in total eight steps was achieved in 8% yield. The product has been used as a scaffold for library production.8
A series of heterobiaryl amides was designed and synthesised as novel mGluR5 antagonists. The synthesis using palladium catalyzed Suzuki–Miyaura cross-coupling reactions provided an array of compounds with a range of in vitro activities.15
2.4. Solid-phase supported reagents No papers this month.
In the course of a high throughput screening, a series of pyrazole compounds were identified with luteinising hormone receptor (LH-R) agonist activity. A focused pyrazole library was produced by solid-phase synthesis and key pyrazole regioisomers were obtained selectively in solution.16
2.5. Novel resins, linkers and techniques No papers this month. 2.6. Library applications Novel arylpiperazines with N-acylated amino acids, selected on the basis of a preliminary screening of two libraries previously synthesised on SynPhaseTM Lanterns, have been prepared in solution and their affinity for 5HT1A, 5-HT2A, and D2 receptors evaluated.9 A 23-member C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine5,11-dione (PBD dilactam) library has been synthesised using Suzuki coupling, and the effect of base upon racemisation at the C11a-position during the cross-coupling reaction studied. Three library members were sufficiently cytotoxic in the NCI’s preliminary screen to warrant further evaluation.10 The identification of constitutively activated STAT (Signal Transducers and Activators of Transcription) proteins in aberrant cell signalling pathways has led to investigations targeting the selective disruption of specific STAT isoforms directly associated with oncogenesis. Through the design of a library of peptidomimetic inhibitors, agents that selectively disrupt STAT1 or STAT3 homo-dimerisation at low micromolar concentrations have been discovered.11 The guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde, a CCR5 receptor ligand, was identified using high-throughput screening. Optimisation efforts led to the discovery of a novel piperidine series of CCR5 antagonists, and the 4-hydroxypiperidine derivative was a starting point for further optimisation using parallel synthesis.12 A library of potential antifungal triazole-modified b-methoxyacrylate analogues was designed and synthesised via a Cu(I)-catalyzed 1,3-dipolar alkyne-azide coupling reaction or ‘click chemistry’. Subsequent biological screening revealed that some compounds displayed low to moderate antifungal activity toward pathogenic fungi and low phytotoxicity.13 A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibi-
Inhibitors of histone deacetylase (HDAC) proteins such as suberoylanilide hydroxamic acid (SAHA) have emerged as effective therapeutic anti-cancer agents. To better understand the structural requirements of HDAC inhibitors, a small molecule library with a variety of substituents attached adjacent to the metal binding hydroxamic acid of SAHA was synthesised.17 Halopemide, which was identified by HTS to inhibit phospholipase D2 (PLD2), provided the basis for an exploratory effort to identify potent inhibitors of PLD2 for use as inflammatory mediators. Parallel synthesis and purification were used to rapidly identify orally available amide analogues derived from indole 2-carboxylic acids with superior potency versus PLD2.18 A novel series of potent dual agonists of PPARa and PPARc, the alkoxybenzylglycines, has been identified and explored using a solution-phase library approach.19 The synthesis of a selected library of heterochiral dPro-containing RGD-peptidomimetics (RpD) has been described and these compounds were investigated as inhibitors of fibronectin adhesion to SK-MEL-24 tumour cells.20 The discovery of novel antibacterial agents which were rapidly optimised utilizing a parallel chemistry approach has been described. In an effort to decrease the affinity for HSA, a series of heterocyclic analogues were prepared and these retained antibacterial activity and demonstrated reduced affinity for HSA.21 A novel, general and versatile method of diversification of the P1 0 position in phosphinic pseudodipeptides, presumable inhibitors of proteolytic enzymes, has been elaborated. The procedure was based on parallel derivatisation of the amino group in the suitably protected phosphinate building blocks with appropriate alkyl and aryl halides. The compounds were evaluated as inhibitors of cytosolic leucine aminopeptidase and aminopeptidase N.22 A series of 2-oxy-substituted 1-(1H-imidazol-1-yl)-4-phenylbutanes comprising imidazole–ketones, imidazole–dioxolanes and imidazole–alcohols substituted with halogens in the phenyl ring have been synthesised and evaluated as
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novel inhibitors of heme oxygenase which are structurally distinct from metalloporphyrins.23 The parallel acylation of N-{3-[4-(3-aminopropyl)piperazin-1-yl]propyl}-7-chloroquinolin-4-amine with polymerbound carboxylic acids has provided a straightforward access to novel aminoquinolines with activity against Plasmodium falciparum strains in vitro.24
References 1. Haug, B. E. et al. Bioorg. Med. Chem. Lett. 2007, 17 (8), 2361–2364. 2. Botta, M. et al. Bioorg. Med. Chem. Lett. 2007, 17 (6), 1579–1583. 3. Hammarstro¨m, L. G. J. et al. Tetrahedron Lett. 2007, 48 (16), 2823–2827. 4. Szlosek-Pinaud, M. et al. Tetrahedron 2007, 63 (16), 3340–3349. 5. Myllyma¨ki, M. J.; Koskinen, A. M. P. Tetrahedron Lett. 2007, 48 (13), 2295–2298. 6. Wang, H.-J.; Earl, W. G. Tetrahedron Lett. 2007, 48 (17), 3043–3046. 7. Paolini, I. et al. Tetrahedron Lett. 2007, 48 (16), 2901–2904. 8. Yu, C.-S.; Wang, R.-T. Tetrahedron Lett. 2007, 48 (17), 2979–2982. 9. Zajdel, P. et al. Bioorg. Med. Chem. 2007, 15 (8), 2907–2919. 10. Antonow, D.; Jenkins, T. C. Bioorg. Med. Chem. 2007, 15 (8), 3041–3053. 11. Gunning, P. T. et al. Bioorg. Med. Chem. Lett. 2007, 17 (7), 1875–1878. 12. Lu, S.-F. et al. Bioorg. Med. Chem. Lett. 2007, 17 (7), 1883–1887. 13. Chen, H. et al. Bioorg. Med. Chem. Lett. 2007, 17 (7), 1979–1983. 14. Backes, B. J. et al. Bioorg. Med. Chem. Lett. 2007, 17 (7), 2005–2012. 15. Kulkarni, S. S.; Newman, A. H. Bioorg. Med. Chem. Lett. 2007, 17 (7), 2074–2079. 16. Jorand-Lebrun, C. et al. Bioorg. Med. Chem. Lett. 2007, 17 (7), 2080–2085. 17. Bieliauskas, A. V.; Weerasi, S. V. W. Bioorg. Med. Chem. Lett. 2007, 17 (8), 2216–2219. 18. Monovich, L.; Mu, B. Bioorg. Med. Chem. Lett. 2007, 17 (8), 2310–2311. 19. Devasthale, P. V. et al. Bioorg. Med. Chem. Lett. 2007, 17 (8), 2312–2316. 20. Gentilucci, L. et al. Bioorg. Med. Chem. Lett. 2007, 17 (8), 2329–2333. 21. Li, J. et al. Bioorg. Med. Chem. Lett. 2007, 17 (8), 2347–2350. 22. Vassiliou, S. et al. Bioorg. Med. Chem. 2007, 15 (9), 3187–3200. 23. Roman, G. et al. Bioorg. Med. Chem. 2007, 15 (9), 3225–3234. 24. Freitag, M. et al. Bioorg. Med. Chem. 2007, 15 (7), 2782–2788.
Further reading Papers on combinatorial chemistry or solid-phase synthesis from other journals Bayo-Puxan, N.; Fernandez, A.; Tulla-Puche, J.; Riego, E.; Cuevas, C.; Alvarez, M.; Albericio, F. Total solid-phase
synthesis of the azathiocoraline class of symmetric bicyclic peptides. Chemistry–A European Journal 2006, 12 (35), 9001–9009. Lehmann, F.; Lake, L.; Currier, E. A.; Olsson, R.; Hacksell, U.; Luthman, K. Design, parallel synthesis and SAR of novel urotensin II receptor agonists. European Journal of Medicinal Chemistry 2007, 42 (2), 276–285. Zameo, S.; Vauzeilles, B.; Beau, J.-M. Direct composition analysis of a dynamic library of imines in an aqueous medium. European Journal of Organic Chemistry, 2006, (24), 5441– 5444. Koenig, H. M.; Gorelik, T.; Kolb, U.; Kilbinger, A. F. M. Supramolecular PEG-co-oligo(p-benzamide)s prepared on a peptide synthesizer. Journal of the American Chemical Society 2007, 129 (3), 704–708. Liu, X.-L.; Sheng, S.-R.; Wang, Q.-Y.; Sun, W.-K.; Xin, Q.; Ao, H.-Y. A facile solid-phase synthesis of vinyl ethers using a selenium traceless linker. Journal of Chemical Research, 2006, (2), 118–120. Kamal, A.; Reddy, K. L.; Devaiah, V.; Shankaraiah, N.; Reddy, G. S. K.; Raghavan, S. Solid-phase synthesis of a library of pyrrolo [2,1-c][1,4]benzodiazepine-5,11-diones with potential antitubercular activity. Journal of Combinatorial Chemistry 2007, 9 (1), 29–42. Christensen, C. A.; Meldal, M. Solid-phase synthesis of a peptidebased P,S-ligand system designed for generation of combinatorial catalyst libraries. Journal of Combinatorial Chemistry 2007, 9 (1), 79–85. Yang, T.-M.; Liu, G. Solution-phase parallel synthesis of 3,5,6substituted indolin-2-ones. Journal of Combinatorial Chemistry 2007, 9 (1), 86–95. Trump, R. P.; Blanc, J.-B. E.; Stewart, E. L.; Brown, P. J.; Caivano, M.; Gray, D. W.; Hoekstra, W. J.; Willson, T. M.; Han, B.; Turnbull, P. Design and synthesis of an array of selective androgen receptor modulators. Journal of Combinatorial Chemistry 2007, 9 (1), 107–114. Yuan, Y.; Liu, G.; Li, L.; Wang, Z.; Wang, L. Synthesis of diverse benzo[1,4]oxazin-3-one-based compounds using 1,5-difluoro2,4-dinitrobenzene. Journal of Combinatorial Chemistry 2007, 9 (1), 158–170. Tan, T. M. C.; Yang, F.; Fu, H.; Raghavendra, M. S.; Lam, Y. Traceless solid-phase synthesis and biological evaluation of purine analogs as inhibitors of multidrug resistance protein 4. Journal of Combinatorial Chemistry 2007, 9 (2), 210–218. Verdie, P.; Subra, G.; Feliu, L.; Sanchez, P.; Berge, G.; Garcin, G.; Martinez, J. On-line synthesis of pseudopeptide library incorporating a benzodiazepinone turn mimic: Biological evaluation on MC1 receptors. Journal of Combinatorial Chemistry 2007, 9 (2), 254–262. Kiriazis, A.; Rueffer, T.; Jaentti, S.; Lang, H.; Yli-Kauhaluoma, J. Stereoselective aza Diels-Alder reaction on solid phase: a facile synthesis of hexahydrocinnoline derivatives. Journal of Combinatorial Chemistry 2007, 9 (2), 263–266. Kamal, A.; Devaiah, V.; Reddy, K. L.; Rajendar, S.; Rajesh, V. C. R. N. C.; Shankaraiah, N. Efficient solid-phase synthesis of a library of imidazo[1,2-a]pyridine-8-carboxamides. Journal of Combinatorial Chemistry 2007, 9 (2), 267–274. Matloobi, M.; Kappe, C. O. Microwave-assisted solution- and solid-phase synthesis of 2-amino-4-arylpyrimidine derivatives. Journal of Combinatorial Chemistry 2007, 9 (2), 275–284. Whiting, M.; Tripp, J. C.; Lin, Y.-C.; Lindstrom, W.; Olson, A. J.; Elder, J. H.; Sharpless, K. B.; Fokin, V. V. Rapid discovery and structure-activity profiling of novel inhibitors of human immunodeficiency virus type 1 protease enabled by the copper(I)-catalyzed synthesis of 1,2,3-triazoles and their further functionalization. Journal of Medicinal Chemistry 2006, 49 (26), 7697–7710.
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Naruchi, K.; Hamamoto, T.; Kurogochi, M.; Hinou, H.; Shimizu, H.; Matsushita, T.; Fujitani, N.; Kondo, H.; Nishimura, S.-I. Construction and Structural Characterization of Versatile Lactosaminoglycan-related compound library for the synthesis of complex glycopeptides and glycosphingolipids. Journal of Organic Chemistry 2006, 71 (26), 9609–9621. Oyelere, A. K.; Chen, P. C.; Yao, L. P.; Boguslavsky, N. Heterogeneous diazo-transfer reaction: a facile unmasking of azide groups on amine-functionalized insoluble supports for solid-phase synthesis. Journal of Organic Chemistry 2006, 71 (26), 9791–9796.
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Robins, L. I.; Kurth, M. J. 1,3,5-Triazine-based mass spectral tagging of one-bead one-compound libraries. Organic Letters 2007, 9 (2), 171–173. de Greef, M.; Abeln, S.; Belkasmi, K.; Doemling, A.; Orru, R. V. A.; Wessjohann, L. A. Rapid combinatorial access to macrocyclic ansapeptoids and ansapeptides with natural-productlike core structures. Synthesis 2006, (23), 3997–4004. Chen, R.; Lee, V.; Adlington, R. M.; Baldwin, J. E. A facile synthesis of ethyl 2-acetamido-4-methylenehex-5-enoate, a versatile Diels-Alder synthon for the parallel synthesis of novel a-amino acid derivatives. Synthesis 2007, (1), 113–117.