- Email: [email protected]
Combinatorial Chemistry Online Volume 7, Issue 9, September 2005
Combinatorial Chemistry - An Online Journal 7 (2005) 37–40
Combinatorial Chemistry Online Volume 7, Issue 9, September 2005 N. K. Terrett Pfizer Global R&D, Cambridge, MA 02139 USA
1. Current literature highlights 1.1. Carboxamide proline derivatives as CNS agents The 5-HT7 receptor (5-HT7R) is the most recently identified subtype of the serotonin G-protein-coupled receptor superfamily, showing about 36–53% homology with other human 5-HT receptors. The 5-HT7R has been found to be positively coupled to adenylate cyclase and evaluation of the expression pattern of 5-HT7R indicates that it is present both centrally and peripherally. The prominent position of 5-HT7 receptor in the thalamus, limbic and cortical regions of the brain, as well as high affinity for several antipsychotic and antidepressant agents, suggest its involvement in such mental disorders as schizophrenia and depression. There are many different structural types of compounds active at the 5-HT7R receptor. A relatively large group of these ligands contain several fragments in common with 5-HT and other GPCR ligands (e.g. 5-HT1A, 5HT2A, D2): For example, these compounds often comprise an amine moiety (mostly 4-N-arylpiperazine, tetrahydroisoquinoline or 4-substituted tetrahydropyridine), which is connected by a variable length alkyl chain (2–5 carbon atoms) to a terminal aromatic fragment. Recently there has been a report of the application of solid phase parallel chemistry for the generation of a focussed arylpiperazine library, targeted at 5-HT7 receptors on SynPhase Lanterns solid support.1
ing to building blocks) to produce a convenient visual tagging system. The library members were evaluated for their in vitro affinity at central serotonin 5-HT7 receptors, and additionally, the affinity of 12 compounds for D2 receptors was assessed, and 17 selected compounds were tested for their ability to bind to 5HT1A receptors. The compounds selected were screened in radioligand binding assays, and one of the most potent compounds against 5-HT7 discovered was (i) which possessed a Ki of 183 nM for 5-HT7 receptors. This library also revealed a number of compounds with good potency for 5-HT1A receptors: (i) for example, displays a Ki of 29 nM for 5-HT1A. Thus this work has developed an efficient solid supported method for the synthesis of novel sulphonamide and carboxamide proline derivatives, and biological evaluation for 5-HT7 and 5-HT1A serotonin, and D2 dopamine receptor affinities has successfully been carried out.
N
H N
N O
N
O
O
(i)
The authors designed a structurally related 64-member library of sulphonamide and carboxamide L- and Dproline derivatives, carrying out the library synthesis on BAL linker functionalised polyamide SynPhase Lanterns using a split-and-pool approach. The lanterns were equipped with coloured cogs and spindles (correspond-
E-mail: nick.terrett@pfizer.com doi:10.1016/j.comche.2005.08.001
1.2. Diketopiperazines as potential inhibitors of calpain Calpains are a class of intracellular cytoplasmic nonlysosomal cysteine proteases expressed ubiquitously in mammalian cells. Among the 16 different kinds of calpain identified to date, two of the most studied are l-calpain (calpain I) and m-calpain (calpain II) which differ
38
N. K. Terrett / Combinatorial Chemistry - An Online Journal 7 (2005) 37–40
in their sensitivity toward activation by calcium ions: Calpain I is sensitive to activation by micromolar concentrations of calcium, whereas calpain II responds only to millimolar calcium concentrations. Both isoforms are heterodimers composed of identical 30 kDa subunits, but differing 80 kDa subunits. Over-activation of calpain has been implicated in many pathological conditions such as stroke and myocardial infarction. Thus, selective inhibitors of calpain are of interest as pharmacological probes and as potential therapeutic agents. Recent work has centred on the identification of selective non-peptide inhibitors of calpain.2 The authors of this paper developed a one-pot cyclisation procedure for the synthesis of diketopiperazine derivatives as calpain inhibitors. A small library of diketopiperazines was synthesised in solution and the compounds were evaluated for inhibition of calpain I in a continuous fluorescence assay, using recombinant calpain I produced by the baculovirus expression system, and SucLeu-Tyr-AMC23 as the fluorogenic substrate. When the library compounds were tested, only negligible activity against calpain I was observed: one of the most potent compounds isolated (ii) displayed an IC50 of 0.1 mM. Compounds screened possessed IC50 values in the range 0.1–1.0 mM. This work has produced a small library of 2,5-diketopiperazines,but only weakly binding calpain inhibitors were discovered from this methodology. Further work, as indicated by the authors, may proceed in this important search for calpain inhibition using structure-based methods and a high-throughput screening approach.
O O
A convenient solid phase synthesis of trisubstituted imidazolidinones and pyrimidinones via microwave assisted DIC-promoted intramolecular cyclisation has been described.5 A convenient method for the synthesis of 1,5-disubstituted imidazoles has been developed on a polymeric support using base-promoted 1,3-dipolar cycloaddition reaction of p-toluenesulphonylmethyl isocyanide (TOSMIC) with immobilised imines under microwave irradiation.6 2.2. Solution-phase synthesis Diversity-oriented organic synthesis has been employed to transform a complex 7-oxanorbornene skeleton, which is readily accessible by a tandem Ugi/Diels–Alder reaction, into two heterotricycle skeletons selectively by using a tandem ROM/CM/RCM reaction. The mode of cyclisation is pre-encoded by building blocks used in the complexity-generating tandem Ugi/Diels–Alder reaction, and the approach can be extended to construct both skeleton- and appendage-diverse small molecule libraries.7 The Suzuki–Miyaura coupling reaction of a-bromocycloalkenones with arylboronic acids has been developed by using microwave heating, and provides a simple and rapid construction of small molecule libraries of a-arylcycloalkenones with high efficiency.8 The synthesis of linear and branched di-, tri- and tetramannosides on a commercially available hyperbranched polyester as a soluble, high loading support has been described. Glycosylation products were isolated in 26– 63% yield as mixtures of anomers after total hydrolytic degradation of the polymer.9 2.3. Scaffolds for combinatorial libraries
HN NH
O
O (ii)
2. A summary of the papers in this month’s issue
A simple, efficient, and general two-step synthesis to bromo-pyridine carbaldehyde scaffolds suitable for combinatorial chemistry has been described.10 2.4. Solid-phase supported reagents The 2-nitrobenzenesulphonamide cleavage using a solidphase thiophenolate reagent gives simple 2-(alkylamino)-pyrroles without the presence of the competing nucleophilic substitution product.11
2.1. Solid-phase synthesis 2.5. Novel resins, linkers and techniques The preparation of Wang resin-bound a-diazo-b-ketoesters has been described, and these highly useful intermediates used for the synthesis of a series of heterocycle libraries.3 The solid-phase synthesis of a series of model dipeptides containing various 3-(quinoxalin-6-yl)alanine analogues has been described. The method involves formation of a quinoxaline heterocycle by condensation between an adicarbonyl compound and a b-(3,4-diaminophenyl)alanine residue, immobilised on a solid support.4
The blue organic dye, 2,6-dichloroindophenol (DCIP), has been immobilised on PEGylated Merrifield resin after a chlorination step followed by a nucleophilic substitution reaction, using microwave-assisted methodology. The final product was a blue pigmented resin that can be reversibly reduced by ascorbic acid and changes colour from blue to light yellow.12 The attachment of two aniline-based chromophores, Disperse Black 3 and Pararosaniline, to beaded con-
N. K. Terrett / Combinatorial Chemistry - An Online Journal 7 (2005) 37–40
trolled pore glass (CPG) and their testing as fibre optic based pH sensors has been described.13 The chemical synthesis of peptide nucleic acid (PNA) monomers was accomplished using various combinations of the o-nitroveratryloxycarbonyl (NVOC) group (N-aminoethylglycine backbone) and base labile acyltype nucleobase protecting groups (anisoyl for adenine and cytosine; isobutyryl for guanine). These monomers offer a photolithographic solid-phase PNA synthetic strategy compatible with photolithographic oligonucleotide synthesis conditions allowing the in situ synthesis of PNA microarrays.14 A synthesis of labelled oligonucleotides incorporating a new chemically cleavable linker via a two-step method has been described.15 2.6. Library applications 4-Amino-2-arylbutylbenzamides have been identified as micromolar MCH 1 receptor (MCH1R) antagonists, and subsequent lead optimisation efforts using solidphase parallel synthesis has resulted in the defined structure–activity relationships and the identification of 4-amino-2-biarylbutylureas as potent single digit nanomolar MCH1R antagonists.16 An encoded combinatorial library based on aryl and biaryl piperidine scaffolds has been designed and synthesised. Screening of this library resulted in the discovery of high-nanomolar biaryl piperidine-based MCH1 receptor antagonists, and follow-up optimisation using a parallel synthesis provided potent, single digit nanomolar antagonists.17 Using adenovirus as a model non-enveloped virus, it has been determined that an eight-residue cyclic D ,L -a-peptide, selected from a directed combinatorial library, can specifically prevent the development of low pH in endocytic vesicles, arrest the escape of virions from the endosome, and abrogate adenovirus infection without an apparent adverse effect on cell viability.18 A chemistry-based capture-release-tag method for isolation of complex phospho-Ser/Thr-containing peptides by liquid b-elimination combined with solid-phase Michael addition has been reported. The free thiol groups of 6-(mercapto-acetylamino)-hexanoic acid functionalised resin have been used as immobilised Michael donors to capture dehydro-serine/threonine peptides. After an acid-mediated release step, phospho-peptides are labelled with a 6-(2-mercapto-acetylamine)-hexanoic amide tag at phosphorylated sites. This method has been employed to analyse the phosphorylation status of microtubule-associated proteins.19 The thiobenzylmethylketone warhead on the aspartate residue of caspase 3 inhibitors has been conveniently generated through solid-phase synthesis. This approach allows modification in the P3 region that eventually led to simpler derivatives with increased potency against caspase 3.20
39
High-throughput screening of an array of biphenylmethylamines synthesised by high-throughput solidphase chemistry resulted in the identification of compounds with high-affinity for the 5-HT5A receptor.21 Solid-phase synthesis of a library based on the natural product anisomycin has been described, and the library tested against a panel of bacterial and fungal targets.22 A focussed virtual library of fully nonsymmetrical cyclic urea inhibitors of aspartic protease of HIV-1 has been designed.23 References 1. Zajdel, P. Bioorg. Med. Chem. 2005, 13 (8), 3029–3035. 2. Zeng, Y. et al. Bioorg. Med. Chem. Lett. 2005, 15 (12), 3034–3038. 3. Yamashita, M. et al. Tetrahedron Lett. 2005, 46 (33), 5495–5498. 4. Staszewska, A. et al. Tetrahedron Lett. 2005, 46 (33), 5525–5528. 5. Wang, X. et al. Tetrahedron Lett. 2005, 46 (34), 5747–5750. 6. Samanta, S. K. et al. Bioorg. Med. Chem. Lett. 2005, 15 (16), 3717–3719. 7. Oikawa, M. et al. Tetrahedron Lett. 2005, 46 (35), 5863–5866. 8. Song, Y. S. et al. Tetrahedron Lett. 2005, 46 (36), 5987–5990. 9. Kantchev, E. A. B. et al. Tetrahedron 2005, 61 (35), 8329–8338. 10. Mandal, A. B. et al. Tetrahedron Lett. 2005, 46 (36), 6033–6036. 11. De Rosa, M. et al. Tetrahedron Lett. 2005, 46 (33), 5715–5717. 12. Siu, M. et al. Tetrahedron Lett. 2005, 46 (33), 5543–5545. 13. Wong, L. S.; Bradley, M. Tetrahedron Lett. 2005, 46 (34), 5731–5734. 14. Liu, Z.-C. et al. Tetrahedron 2005, 61 (33), 7967–7973. 15. Mahajan, S. et al. Tetrahedron Lett. 2005, 46 (36), 6149–6153. 16. Guo, T. et al. Bioorg. Med. Chem. Lett. 2005, 15 (16), 3691–3695. 17. Guo, T. et al. Bioorg. Med. Chem. Lett. 2005, 15 (16), 3696–3700. 18. Horne, W. S. et al. Bioorg. Med. Chem. 2005, 13 (17), 5145–5153. 19. Tseng, H.-C. et al. Chem. Biol. 2005, 12 (7), 769–777. 20. Mellon, C. et al. Bioorg. Med. Chem. Lett. 2005, 15 (17), 3886–3890. 21. Corbett, D. F. et al. Bioorg. Med. Chem. Lett. 2005, 15 (18), 4014–4018. 22. Shi, S. et al. Bioorg. Med. Chem. Lett. 2005, 15 (18), 4151–4154. 23. Frecer, V. et al. Bioorg. Med. Chem. 2005, 13 (18), 5492–5501.
Further reading Papers on combinatorial chemistry or solid-phase synthesis from other journals Paterson, I.; Gottschling, D.; Menche, D. Towards the combinatorial synthesis of spongistatin fragment libraries by using asymmetric aldol reactions on solid support.
40
N. K. Terrett / Combinatorial Chemistry - An Online Journal 7 (2005) 37–40
Chemical Communications (Cambridge, United Kingdom), 2005 (28), 3568–3570. van Gerven, P. C. M.; Elemans, J. A. A. W.; Gerritsen, J. W.; Speller, S.; Nolte, R. J. M.; Rowan, A. E. Dynamic combinatorial olefin metathesis: templated synthesis of porphyrin boxes. Chemical Communications (Cambridge, United Kingdom) 2005, 3535–3537. Mendez, L.; Delpiccolo, C. M. L.; Mata, E. G. Efficient solidphase synthesis of 1,3,4-trisubstituted b-thiolactams. Synlett 2005, 1563–1566. Langereis, S.; Dirksen, A.; De Waal, B. F. M.; Van Genderen, M. H. P.; De Lussanet, Q. G.; Hackeng, T. M.; Meijer, E. W. Solid-phase synthesis of a cyclic NGR-functionalized GdIIIDTPA complex. European Journal of Organic Chemistry 2005, 2534–2538. Marfil, M.; Albericio, F.; Alvarez, M. Chloromethoxymethyl polystyrene (CMM resin), an acid labile resin for anchoring/cleavage of N-heterocycles and oxygen aromatic compounds. Letters in Organic Chemistry 2005, 2 (4), 371–373. Riester, D.; Wirsching, F.; Salinas, G.; Keller, M.; Gebinoga, M.; Kamphausen, S.; Merkwirth, C.; Goetz, R.; Wiesenfeldt, M.; Stuerzebecher, J.; Bode, W.; Friedrich, R.; Thuerk, M.; Schwienhorst, A. Thrombin inhibitors identified by computer-assisted multiparameter design. Proceedings of the National Academy of Sciences of the United States of America 2005, 102 (24), 8597–8602. Rajpal, A.; Beyaz, N.; Haber, L.; Cappuccilli, G.; Yee, H.; Bhatt, R. R.; Takeuchi, T.; Lerner, R. A.; Crea, R. A general method for greatly improving the affinity of antibodies by using combinatorial libraries. Proceedings of the National Academy of Sciences of the United States of America 2005, 102 (24), 8466–8471. Liu, J.; Dang, Q.; Wei, Z.; Zhang, H.; Bai, X. Parallel solutionphase synthesis of a 2,6,8,9-tetrasubstituted purine library via a sulfur intermediate. Journal of Combinatorial Chemistry 2005, 7 (4), 627–636. Acharya, J.; Shakya, P. D.; Pardasani, D.; Palit, M.; Dubey, D. K.; Gupta, A. K. Surface-mediated solid phase reactions: A simple, efficient and base-free synthesis of phosphonates and phosphates on Al2O3. Journal of Chemical Research 2005, 194–196.
Eba, H.; Sakurai, K. Combinatorial fluorescence XAFS imaging of manganese complex oxides. Chemistry Letters 2005, 34 (6), 872–873. Dalicsek, Z.; Pollreisz, F.; Goemoery, A.; Soos, T. Recoverable fluorous CBS methodology for asymmetric reduction of ketones. Organic Letters 2005, 7 (15), 3243–3246. Bianco, A. Efficient solid-phase synthesis of fullero-peptides using Merrifield strategy. Chemical Communications (Cambridge, United Kingdom) 2005, 3174–3176. Moon, B.; Han, S.; Kim, D. Efficient synthesis of highly functionalized cyclic aminimides. Organic Letters 2005, 7 (15), 3359–3361. Barluenga, J.; de Prado, A.; Santamaria, J.; Tomas, M. Polymer-bound Fischer tungsten carbene complexes: synthesis and reactivity. Organometallics 2005, 24 (15), 3614–3617. Werner, S.; Iyer, P. S. Microwave-assisted synthesis of pyrrole2-carboxamides. Synlett, 2005 (9), 1405–1408. Manku, S.; Curran, D. P. Fluorous mixture synthesis of fusedtricyclic hydantoins. Use of a redundant tagging strategy on fluorinated substrates. Journal of Organic Chemistry 2005, 70 (11), 4470–4473. Chen, C.; Li, X.; Neumann, C. S.; Lo, M. M.-C.; Schreiber, S. L. Convergent diversity-oriented synthesis of small-molecule hybrids. Angewandte Chemie, International Edition 2005, 44 (15), 2249–2252. Parrish, B.; Breitenkamp, R. B.; Emrick, T. PEG- and peptidegrafted aliphatic polyesters by click chemistry. Journal of the American Chemical Society 2005, 127 (20), 7404–7410. Moulin, E.; Zoete, V.; Barluenga, S.; Karplus, M.; Winssinger, N. Design, synthesis, and biological evaluation of HSP90 inhibitors based on conformational analysis of radicicol and its analogues. Journal of the American Chemical Society 2005, 127 (19), 6999–7004. Horton, D. A.; Severinsen, R.; Kofod-Hansen, M.; Bourne, G. T.; Smythe, M. L. A versatile synthetic approach to peptidyl privileged structures using a Ôsafety-catchÕ linker. Journal of Combinatorial Chemistry 2005, 7 (3), 421–435. Ilyin, A. P.; Trifilenkov, A. S.; Kurashvili, I. D.; Krasavin, M.; Ivachtchenko, A. V. One-step construction of peptidomimetic 5-carbamoyl-4-sulfonyl-2-piperazinones. Journal of Combinatorial Chemistry 2005, 7 (3), 360–363.
Combinatorial Chemistry Online Volume 7, Issue 9, September 2005 N. K. Terrett Pfizer Global R&D, Cambridge, MA 02139 USA
1. Current literature highlights 1.1. Carboxamide proline derivatives as CNS agents The 5-HT7 receptor (5-HT7R) is the most recently identified subtype of the serotonin G-protein-coupled receptor superfamily, showing about 36–53% homology with other human 5-HT receptors. The 5-HT7R has been found to be positively coupled to adenylate cyclase and evaluation of the expression pattern of 5-HT7R indicates that it is present both centrally and peripherally. The prominent position of 5-HT7 receptor in the thalamus, limbic and cortical regions of the brain, as well as high affinity for several antipsychotic and antidepressant agents, suggest its involvement in such mental disorders as schizophrenia and depression. There are many different structural types of compounds active at the 5-HT7R receptor. A relatively large group of these ligands contain several fragments in common with 5-HT and other GPCR ligands (e.g. 5-HT1A, 5HT2A, D2): For example, these compounds often comprise an amine moiety (mostly 4-N-arylpiperazine, tetrahydroisoquinoline or 4-substituted tetrahydropyridine), which is connected by a variable length alkyl chain (2–5 carbon atoms) to a terminal aromatic fragment. Recently there has been a report of the application of solid phase parallel chemistry for the generation of a focussed arylpiperazine library, targeted at 5-HT7 receptors on SynPhase Lanterns solid support.1
ing to building blocks) to produce a convenient visual tagging system. The library members were evaluated for their in vitro affinity at central serotonin 5-HT7 receptors, and additionally, the affinity of 12 compounds for D2 receptors was assessed, and 17 selected compounds were tested for their ability to bind to 5HT1A receptors. The compounds selected were screened in radioligand binding assays, and one of the most potent compounds against 5-HT7 discovered was (i) which possessed a Ki of 183 nM for 5-HT7 receptors. This library also revealed a number of compounds with good potency for 5-HT1A receptors: (i) for example, displays a Ki of 29 nM for 5-HT1A. Thus this work has developed an efficient solid supported method for the synthesis of novel sulphonamide and carboxamide proline derivatives, and biological evaluation for 5-HT7 and 5-HT1A serotonin, and D2 dopamine receptor affinities has successfully been carried out.
N
H N
N O
N
O
O
(i)
The authors designed a structurally related 64-member library of sulphonamide and carboxamide L- and Dproline derivatives, carrying out the library synthesis on BAL linker functionalised polyamide SynPhase Lanterns using a split-and-pool approach. The lanterns were equipped with coloured cogs and spindles (correspond-
E-mail: nick.terrett@pfizer.com doi:10.1016/j.comche.2005.08.001
1.2. Diketopiperazines as potential inhibitors of calpain Calpains are a class of intracellular cytoplasmic nonlysosomal cysteine proteases expressed ubiquitously in mammalian cells. Among the 16 different kinds of calpain identified to date, two of the most studied are l-calpain (calpain I) and m-calpain (calpain II) which differ
38
N. K. Terrett / Combinatorial Chemistry - An Online Journal 7 (2005) 37–40
in their sensitivity toward activation by calcium ions: Calpain I is sensitive to activation by micromolar concentrations of calcium, whereas calpain II responds only to millimolar calcium concentrations. Both isoforms are heterodimers composed of identical 30 kDa subunits, but differing 80 kDa subunits. Over-activation of calpain has been implicated in many pathological conditions such as stroke and myocardial infarction. Thus, selective inhibitors of calpain are of interest as pharmacological probes and as potential therapeutic agents. Recent work has centred on the identification of selective non-peptide inhibitors of calpain.2 The authors of this paper developed a one-pot cyclisation procedure for the synthesis of diketopiperazine derivatives as calpain inhibitors. A small library of diketopiperazines was synthesised in solution and the compounds were evaluated for inhibition of calpain I in a continuous fluorescence assay, using recombinant calpain I produced by the baculovirus expression system, and SucLeu-Tyr-AMC23 as the fluorogenic substrate. When the library compounds were tested, only negligible activity against calpain I was observed: one of the most potent compounds isolated (ii) displayed an IC50 of 0.1 mM. Compounds screened possessed IC50 values in the range 0.1–1.0 mM. This work has produced a small library of 2,5-diketopiperazines,but only weakly binding calpain inhibitors were discovered from this methodology. Further work, as indicated by the authors, may proceed in this important search for calpain inhibition using structure-based methods and a high-throughput screening approach.
O O
A convenient solid phase synthesis of trisubstituted imidazolidinones and pyrimidinones via microwave assisted DIC-promoted intramolecular cyclisation has been described.5 A convenient method for the synthesis of 1,5-disubstituted imidazoles has been developed on a polymeric support using base-promoted 1,3-dipolar cycloaddition reaction of p-toluenesulphonylmethyl isocyanide (TOSMIC) with immobilised imines under microwave irradiation.6 2.2. Solution-phase synthesis Diversity-oriented organic synthesis has been employed to transform a complex 7-oxanorbornene skeleton, which is readily accessible by a tandem Ugi/Diels–Alder reaction, into two heterotricycle skeletons selectively by using a tandem ROM/CM/RCM reaction. The mode of cyclisation is pre-encoded by building blocks used in the complexity-generating tandem Ugi/Diels–Alder reaction, and the approach can be extended to construct both skeleton- and appendage-diverse small molecule libraries.7 The Suzuki–Miyaura coupling reaction of a-bromocycloalkenones with arylboronic acids has been developed by using microwave heating, and provides a simple and rapid construction of small molecule libraries of a-arylcycloalkenones with high efficiency.8 The synthesis of linear and branched di-, tri- and tetramannosides on a commercially available hyperbranched polyester as a soluble, high loading support has been described. Glycosylation products were isolated in 26– 63% yield as mixtures of anomers after total hydrolytic degradation of the polymer.9 2.3. Scaffolds for combinatorial libraries
HN NH
O
O (ii)
2. A summary of the papers in this month’s issue
A simple, efficient, and general two-step synthesis to bromo-pyridine carbaldehyde scaffolds suitable for combinatorial chemistry has been described.10 2.4. Solid-phase supported reagents The 2-nitrobenzenesulphonamide cleavage using a solidphase thiophenolate reagent gives simple 2-(alkylamino)-pyrroles without the presence of the competing nucleophilic substitution product.11
2.1. Solid-phase synthesis 2.5. Novel resins, linkers and techniques The preparation of Wang resin-bound a-diazo-b-ketoesters has been described, and these highly useful intermediates used for the synthesis of a series of heterocycle libraries.3 The solid-phase synthesis of a series of model dipeptides containing various 3-(quinoxalin-6-yl)alanine analogues has been described. The method involves formation of a quinoxaline heterocycle by condensation between an adicarbonyl compound and a b-(3,4-diaminophenyl)alanine residue, immobilised on a solid support.4
The blue organic dye, 2,6-dichloroindophenol (DCIP), has been immobilised on PEGylated Merrifield resin after a chlorination step followed by a nucleophilic substitution reaction, using microwave-assisted methodology. The final product was a blue pigmented resin that can be reversibly reduced by ascorbic acid and changes colour from blue to light yellow.12 The attachment of two aniline-based chromophores, Disperse Black 3 and Pararosaniline, to beaded con-
N. K. Terrett / Combinatorial Chemistry - An Online Journal 7 (2005) 37–40
trolled pore glass (CPG) and their testing as fibre optic based pH sensors has been described.13 The chemical synthesis of peptide nucleic acid (PNA) monomers was accomplished using various combinations of the o-nitroveratryloxycarbonyl (NVOC) group (N-aminoethylglycine backbone) and base labile acyltype nucleobase protecting groups (anisoyl for adenine and cytosine; isobutyryl for guanine). These monomers offer a photolithographic solid-phase PNA synthetic strategy compatible with photolithographic oligonucleotide synthesis conditions allowing the in situ synthesis of PNA microarrays.14 A synthesis of labelled oligonucleotides incorporating a new chemically cleavable linker via a two-step method has been described.15 2.6. Library applications 4-Amino-2-arylbutylbenzamides have been identified as micromolar MCH 1 receptor (MCH1R) antagonists, and subsequent lead optimisation efforts using solidphase parallel synthesis has resulted in the defined structure–activity relationships and the identification of 4-amino-2-biarylbutylureas as potent single digit nanomolar MCH1R antagonists.16 An encoded combinatorial library based on aryl and biaryl piperidine scaffolds has been designed and synthesised. Screening of this library resulted in the discovery of high-nanomolar biaryl piperidine-based MCH1 receptor antagonists, and follow-up optimisation using a parallel synthesis provided potent, single digit nanomolar antagonists.17 Using adenovirus as a model non-enveloped virus, it has been determined that an eight-residue cyclic D ,L -a-peptide, selected from a directed combinatorial library, can specifically prevent the development of low pH in endocytic vesicles, arrest the escape of virions from the endosome, and abrogate adenovirus infection without an apparent adverse effect on cell viability.18 A chemistry-based capture-release-tag method for isolation of complex phospho-Ser/Thr-containing peptides by liquid b-elimination combined with solid-phase Michael addition has been reported. The free thiol groups of 6-(mercapto-acetylamino)-hexanoic acid functionalised resin have been used as immobilised Michael donors to capture dehydro-serine/threonine peptides. After an acid-mediated release step, phospho-peptides are labelled with a 6-(2-mercapto-acetylamine)-hexanoic amide tag at phosphorylated sites. This method has been employed to analyse the phosphorylation status of microtubule-associated proteins.19 The thiobenzylmethylketone warhead on the aspartate residue of caspase 3 inhibitors has been conveniently generated through solid-phase synthesis. This approach allows modification in the P3 region that eventually led to simpler derivatives with increased potency against caspase 3.20
39
High-throughput screening of an array of biphenylmethylamines synthesised by high-throughput solidphase chemistry resulted in the identification of compounds with high-affinity for the 5-HT5A receptor.21 Solid-phase synthesis of a library based on the natural product anisomycin has been described, and the library tested against a panel of bacterial and fungal targets.22 A focussed virtual library of fully nonsymmetrical cyclic urea inhibitors of aspartic protease of HIV-1 has been designed.23 References 1. Zajdel, P. Bioorg. Med. Chem. 2005, 13 (8), 3029–3035. 2. Zeng, Y. et al. Bioorg. Med. Chem. Lett. 2005, 15 (12), 3034–3038. 3. Yamashita, M. et al. Tetrahedron Lett. 2005, 46 (33), 5495–5498. 4. Staszewska, A. et al. Tetrahedron Lett. 2005, 46 (33), 5525–5528. 5. Wang, X. et al. Tetrahedron Lett. 2005, 46 (34), 5747–5750. 6. Samanta, S. K. et al. Bioorg. Med. Chem. Lett. 2005, 15 (16), 3717–3719. 7. Oikawa, M. et al. Tetrahedron Lett. 2005, 46 (35), 5863–5866. 8. Song, Y. S. et al. Tetrahedron Lett. 2005, 46 (36), 5987–5990. 9. Kantchev, E. A. B. et al. Tetrahedron 2005, 61 (35), 8329–8338. 10. Mandal, A. B. et al. Tetrahedron Lett. 2005, 46 (36), 6033–6036. 11. De Rosa, M. et al. Tetrahedron Lett. 2005, 46 (33), 5715–5717. 12. Siu, M. et al. Tetrahedron Lett. 2005, 46 (33), 5543–5545. 13. Wong, L. S.; Bradley, M. Tetrahedron Lett. 2005, 46 (34), 5731–5734. 14. Liu, Z.-C. et al. Tetrahedron 2005, 61 (33), 7967–7973. 15. Mahajan, S. et al. Tetrahedron Lett. 2005, 46 (36), 6149–6153. 16. Guo, T. et al. Bioorg. Med. Chem. Lett. 2005, 15 (16), 3691–3695. 17. Guo, T. et al. Bioorg. Med. Chem. Lett. 2005, 15 (16), 3696–3700. 18. Horne, W. S. et al. Bioorg. Med. Chem. 2005, 13 (17), 5145–5153. 19. Tseng, H.-C. et al. Chem. Biol. 2005, 12 (7), 769–777. 20. Mellon, C. et al. Bioorg. Med. Chem. Lett. 2005, 15 (17), 3886–3890. 21. Corbett, D. F. et al. Bioorg. Med. Chem. Lett. 2005, 15 (18), 4014–4018. 22. Shi, S. et al. Bioorg. Med. Chem. Lett. 2005, 15 (18), 4151–4154. 23. Frecer, V. et al. Bioorg. Med. Chem. 2005, 13 (18), 5492–5501.
Further reading Papers on combinatorial chemistry or solid-phase synthesis from other journals Paterson, I.; Gottschling, D.; Menche, D. Towards the combinatorial synthesis of spongistatin fragment libraries by using asymmetric aldol reactions on solid support.
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N. K. Terrett / Combinatorial Chemistry - An Online Journal 7 (2005) 37–40
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