- Email: [email protected]
Combinatorial Chemistry Online
Combinatorial Chemistry - An Online Journal 6 (2004) 13–16
Combinatorial Chemistry Online Volume 6, Issue 4, April 2004 N. K. Terrett Pfizer Global R&D, Cambridge, MA 02139, USA
1. Current literature highlights 1.1. a-Fucosidase inhibitors
RCO2H
N
+ OH
Iminocyclitols (also known aza-sugars) have attracted attention due to their inhibitory activity against various glycosidases. The glucose-type iminocyclitol, deoxynojirimycin, has been used for the treatment of non-insulin dependent diabetes, and recent studies with deoxynojirimycin and its derivatives indicate they are effective against hepatitis B and C, as well as glycosphingolipid storage disorders such as Gaucher disease. The efficacy of iminocyclitols is attributed to their mimicry of the transition state of enzymatic glycosidic cleavage. Of the members of the glycosidase family, afucosidase is involved in the hydrolytic degradation of numerous fucose-containing glycoconjugates. This enzyme is associated with a number of essential functions, and the abnormal accumulation of fuco-conjugates, resulting from the absence or deficiency of a-fucosidase, leads to the genetic neurovisceral storage disease fucosidosis. An aberrant distribution of intracellular and extracellular a-fucosidase is also found in cystic fibrosis.
NH2
E-mail: [email protected]fizer.com doi:10.1016/j.comche.2004.04.001
N
OH
OH
OH
OH
OH
R O
Scheme 1.
that the product could be used directly for screening in situ without isolation. A solution phase library of 60 fuconojirimycin derivatives was synthesised as singletons according to general Scheme 1. The a-fucosidase from bovine kidney was used for inhibition studies and a number of active compounds were identified. One of the most potent was (i) which possessed a Ki of 0.6 nM, and selectivity against related glycosidases studied was high. This work has produced the most potent and selective inhibitors reported to date against the glycosyltransfer enzyme a-fucosidase.
H
Though the physiological functions of a-fucosidase are not completely understood, potent fucosidase inhibitors may be used as probes for the study of fucosidases in various disease states, and for the development of potential therapeutic agents. To facilitate the discovery of new glycosidase inhibitors, a recent publication describes the development of a new method for rapid derivatisation of an iminocyclitol core designed for a specific glycosidase family––in this case, particular fuconojirimycin derivatives for fucosidases.1 In this approach, the compounds are synthesised without protecting group manipulation and under such conditions
H N
H
H
N
OH
OH
OH
F
HN
H N O
(i)
1.2. Human betaine inhibitors The challenge for functional genomics and proteomics is to translate sequencing data into a precise understanding of how proteins function in cells, tissues or whole organisms. Small ligands that are able to specifically interact with proteins can be effective tools in the search for proteome function. Classically, new protein ligands have been identified by SAR studies, molecular modelling or combinatorial chemistry techniques. However,
14
N. K. Terrett / Combinatorial Chemistry - An Online Journal 6 (2004) 13–16
these approaches generally use only one protein target, and given the high number of proteins in mammalian organisms, high-throughput screening procedures have been developed to handle this task. A potential drawback with such methods is that the full range of proteins the chosen ligand may interact with are not discovered if the screening is performed with only one or a few proteins. This lack of information precludes our ability to completely understand the full spectrum of effects that a ligand may have in a complex environment such as a living cell.
phase resin via an organic spacer has been described.4 The optical purities of the N-substituted-amino ester products are superior to the solution phase DKR. Utilizing alkylation at a benzylic nitrogen-atom as a key step, a solid-phase route for synthesis of 15 N-labeled acylpolyamines has been reported.5 The derivatives were used as reference compounds for the investigation of the MS/MS behaviour of spider toxins. 2.2. Solution-phase synthesis
Approaches that study the effects of ligands in whole cells are becoming increasingly important. Screening libraries using biosensor chips or arrays grafted with proteins allows real time recording of ligand-protein interactions. Subsequent elution of these complexes can be used for protein identification by mass spectrometry. A method to discover novel protein-ligand interactions has been developed based on affinity capture principles coupled to combinatorial chemistry.2 Affinity columns were prepared containing 361 different phosphinic peptides and used to isolate all interacting proteins from crude rat liver homogenates. By applying a deconvolution process, the most specific ligand having the highest affinity towards one newly discovered protein target, betaine:homocysteine S-methyltransferase (BHMT), was identified from the library. The phosphinic peptides, which served as immobilised ligands for the isolation of rat BHMT, were then tested for their ability to inhibit human recombinant BHMT in solution. The most potent inhibitor also behaved as a selective ligand for the affinity purification of BHMT from a complex media. Further optimisation led to (ii)––a potent BHMT inhibitor that possessed an IC50 of about 1 lM. This work has demonstrated the successful application of a new and simple method for the discovery of new protein targets for artificial ligands of interest. This methodology, in combination with 2D electrophoresis and MALDI mass spectrometry holds promise as an additional method for the discovery of new specific proteinligand interactions.
Val-Phe-W½PO2 –CH2 Leu-His-NH2 ðiiÞ
2. A summary of the papers in this month’s issue 2.1. Solid-phase synthesis
A new synthesis of N-aryl- and N-heteroaryl-N 0 -(arylalkyl)piperazines using palladium-catalysed amination of aryl bromides and heteroaryl chlorides with mono Nbenzyl- or N-(arylethyl)piperazines has been reported.6 Applying an automated parallel synthesizer the preparation of a small library of potentially bioactive compounds can be easily achieved. The palladium-catalysed regioselective a-monoarylation of deoxybenzoins and, a,a-diarylation of acetophenones provides general, efficient access to 1,2,2-triarylethanones and have been conducted by means of either commercially available polymer-anchored catalysts or a very simple homogeneous catalytic system.7 A recent review evaluates the advantages, disadvantages, and effectiveness of newly developed peptide coupling reagents used in organic synthesis.8 Each reagent was classified into one of eight types including phosphonium, uronium, immonium, carbodiimide, imidazolium, organophosphorous, acid halogenating and other coupling reagents, according to the structural similarity. 2.3. Scaffolds for combinatorial libraries No papers this month. 2.4. Solid-phase supported reagents A novel polymer-supported N-heterocyclic carbene was prepared from chloromethyl polystyrene (CM PS) resin using a simple procedure, and has been used as a ligand for palladium (Pd) Suzuki cross-coupling under aqueous conditions.9 A simple and efficient method has been developed for the synthesis of a-bromoesters and ketones from bketoesters and diketones in one pot using a supported reagents system.10
A general procedure to prepare peptide thioacids by solid-phase peptide synthesis has been presented.3 The method involves the synthesis of 4-[a-(S-acetyl)mercaptobenzyl]phenoxyacetic acid, which once attached to a solid support is derivatised with the Boc-amino acid of choice after deprotection of the thiol.
The novel 3-N,N-(dimethylamino)isocyanoacrylateWang-resin has been used for the synthesis of imidazole4-carboxylic acids. The syntheses are performed in a microwave reactor with reaction times of only 15 min at 220 °C in the solvent dimethoxyethane.11
The first example of a dynamic kinetic resolution (DKR) using immobilized amine nucleophiles attached to a solid
A new type of polymeric dehydrating reagent, readily prepared by the treatment of polymer-supported tri-
N. K. Terrett / Combinatorial Chemistry - An Online Journal 6 (2004) 13–16
phenylphosphine oxide with triflic anhydride, was found to be effective in a variety of dehydration reactions such as ester and amide formation.12 A new cross-linked polystyrene-supported thioanisole reagent has been reported. This reagent can be treated with methyl trifluoromethanesulphonate to form the corresponding sulphonium salt, and then deprotonated to form a polymer-supported sulphur ylide that is able to react with aldehydes and ketones to form epoxides. The thioanisole reagent can also be oxidized to form an insoluble sulphoxide reagent useful for Swern oxidation reactions.13 2.5. Novel resins, linkers and techniques A phenylmenthyl derivative, previously shown to be a very effective chiral auxiliary in diastereoselective [2+2] photocycloadditions of cyclic enones with ethylene, was attached to poly(ethylene glycol)-grafted Wang resin.14 This was used for the first example of the photochemical production of a bicyclo[4.2.0]octane derivative on solid support. The synthesis of an ionic support and its application in the preparation of a set of amides and sulphonamides has been described.15 The potential was further exemplified by the use in a one-pot multistep ionic liquid phase assisted synthesis of a tirofiban analogue. A new oxidatively activatable safety-catch linker has been developed for combinatorial solid-phase chemistry using a two-step process starting from Merrifield resin.16 A polymer-bound iminium participates in an aza Diels– Alder cycloaddition, which leads to a supported dihydroquinoline (DHQ resin). A straightforward synthesis of trityl alcohols in which one of the aryl rings is substituted with a vinyl group has been presented.17 These compounds were used to incorporate trityl linker groups into polystyrene-based organic synthesis supports. 2.6. Library applications A new noncovalent glycoarray assembly method for microplates created by simply mixing together an isocyanate-containing C14 -hydrocarbon and an aminecontaining carbohydrate has been described.18 This new array, together with the efficient methods available for synthesis of complex oligosaccharides, could become useful for the high-throughput biological evaluation of carbohydrate–protein and carbohydrate–carbohydrate interactions. A series of novel benzimidazole derivatives have been synthesized via parallel solution-phase chemistry, and many found to inhibit the growth of Staphylococcus aureus and Escherichia coli.19 Several analogues exhibited low micromolar minimal inhibitory concentrations (MIC) against both Gram-positive and Gram-negative
15
bacteria of clinical relevance and could serve as leads for further optimisations for antibacterial research. A readily automated solid-phase approach to the synthesis of diverse N-(phenylalkyl)cinnamide analogues of an NR2B antagonist, has been described.20 A 225member focused library was synthesized using a Tecan Combitec synthesizer. Inspired by structure-based design and tailored for combinatorial preparation, a series of novel cyclic peptides has been developed to yield binding ligands for the third PDZ domain (PDZ3) of PSD-95. the postsynaptic density-95 kDa protein.21 Solid-phase synthetic methods for biaryl-based compounds have been developed resulting in the construction of two 1000-member libraries.22 Numerous compounds were identified by high-throughput screening using whole cell screens to exhibit anti-microbial activity against Gram-positive bacteria. The binding of the prokaryotic tubulin analogue, FtsZ, and the membrane-anchored protein, ZipA, presents a potential target for antibacterial therapy. Based on a small molecule inhibitor of the ZipA–FtsZ interaction, a parallel synthesis of small molecules was initiated which targeted a key region of ZipA involved in FtsZ binding.23 A small library of pentapeptides containing two regions of variability was synthesized and evaluated for lectin binding.24 Specificity was observed and galectin inhibition measured with selected sequences was 2–3 times stronger than galactose. The influence of aromatic substitution on a newly discovered class of inhibitors of dipeptidyl peptidase IV has been investigated.25 A 105 -fold increase in potency was achieved by the optimisation of aromatic substituents in a parallel chemistry program. A robust method for the solid phase synthesis of a series of selective caspase-3 peptide inhibitors has been described.26 The inhibitors were obtained after cleavage from the solid support without further purification. A small focused library of 20 3,5-substituted phenylgalactosides based on two previous lead structures was prepared with the aim of developing high-affinity mono and multivalent antagonists of cholera toxin (CT) and Escherichia coli heat-labile enterotoxin (LT).27 The crystal structures of the most promising compounds bound to either CTB5 or LTB5 were also determined. A library containing 29 peptides has been prepared via catalysis by a unique ribozyme and the products analysed by mass spectrometry.28 The results implicate that this ribozyme may have potential application in peptide synthesis. In order to characterise enzymes with unknown function, a novel systems-based inhibitor design strategy,
16
N. K. Terrett / Combinatorial Chemistry - An Online Journal 6 (2004) 13–16
enabled by bioinformatic and NMR structural developments has been developed.29 This strategy employs a combinatorial library that yielded specific inhibitors for multiple oxidoreductases.
26. Grimm, E. L.; et al. Bioorg. Med. Chem. 2004, 12 (5), 845– 851. 27. Mitchell, D. D.; et al. Bioorg. Med. Chem. 2004, 12 (5), 907–920. 28. Cui, Z.; et al. Bioorg. Med. Chem. 2004, 12 (5), 927–933. 29. Sem, D. S.; et al. Chem. Biol. 2004, 11 (2), 185–194.
References 1. Wu, C-Y.; et al. Angew. Chem., Int. Ed. Engl. 2003, 42 (38), 4661–4664. 2. Collinsova, M.; et al. Chem. Biol. 2003, 10 (2), 113–122. 3. Gaertner, H.; et al. Tetrahedron Lett. 2004, 45 (10), 2239– 2241. 4. Valenrod, Y.; et al. Tetrahedron Lett. 2004, 45 (12), 2545– 2549. 5. Manov, N.; et al. Tetrahedron 2004, 60 (10), 2387–2391. 6. Michalik, D.; et al. Tetrahedron Lett. 2004, 45 (10), 2057– 2061. 7. Churruca, F.; et al. Tetrahedron 2004, 60 (10), 2393–2408. 8. Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60 (11), 2447– 2467. 9. Byun, J.-W.; Lee, Y.-S. Tetrahedron Lett. 2004, 45 (9), 1837–1840. 10. Aoyama, T.; et al. Tetrahedron Lett. 2004, 45 (9), 1873– 1876. 11. Henkel, B. Tetrahedron Lett. 2004, 45 (10), 2219–2221. 12. Elson, K. E.; et al. Tetrahedron Lett. 2004, 45 (12), 2491– 2493. 13. Kwok Wai Choi, M.; Toy, P. H. Tetrahedron 2004, 60 (12), 2875–2879. 14. Shintani, T.; et al. Tetrahedron Lett. 2004, 45 (9), 1849– 1851. 15. de Kort, M.; et al. Tetrahedron Lett. 2004, 45 (10), 2171– 2175. 16. Arseniyadis, S.; et al. Tetrahedron Lett. 2004, 45 (10), 2251–2253. 17. Kwok Wai Choi, M.; Toy, P. H. Tetrahedron 2004, 60 (12), 2903–2907. 18. Fazio, F.; et al. Tetrahedron Lett. 2004, 45 (12), 2689– 2692. 19. He, Y.; et al. Bioorg. Med. Chem. Lett. 2004, 14 (5), 1217– 1220. 20. Weber, C.; et al. Bioorg. Med. Chem. Lett. 2004, 14 (5), 1279–1281. 21. Li, T.; et al. Bioorg. Med. Chem. Lett. 2004, 14 (6), 1385– 1388. 22. Look, G. C.; et al. Bioorg. Med. Chem. Lett. 2004, 14 (6), 1423–1426. 23. Jennings, L. D.; et al. Bioorg. Med. Chem. Lett. 2004, 14 (6), 1427–1431. 24. Arnusch, C. J.; et al. Bioorg. Med. Chem. Lett. 2004, 14 (6), 1437–1440. 25. Peters, J.-U.; et al. Bioorg. Med. Chem. Lett. 2004, 14 (6), 1491–1493.
Further Reading Papers on combinatorial chemistry or solid-phase synthesis from other journals Ohno, H.; Tanaka, H.; Takahashi, T. Solid-phase synthesis of N-alkylated naltrindoles using a 3-nitrobenzyl safety-catch linker. Synlett 2004, (3), 508–511. Amaya, T.; Tanaka, H.; Takahashi, T. Solid-phase synthesis of carbohydrate cluster on tree-type linker with three types of orthogonally cleavable part. Synlett 2004, (3), 503–507. Amaya, T.; Tanaka, H.; Takahashi, T. Combinatorial synthesis of carbohydrate cluster on tree-type linker with orthogonally cleavable parts. Synlett 2004, (3), 497–502. Olsen, C. A.; Witt, M.; Jaroszewski, J. W.; Franzyk, H. Diols as building blocks in solid-phase synthesis of polyamine toxins by fukuyama-mitsunobu alkylation. Synlett 2004, (3), 473–476. Oliver, M.; Jorgensen, M. R.; Miller, A. D. Solid-phase assisted N-1 functionalization of azamacrocycles. Synlett 2004, (3), 453–456. Mei, Y.; Beers, K. L.; Byrd, H. C. M.; VanderHart, D. L.; Washburn, N. R. Solid-phase ATRP synthesis of peptidepolymer hybrids. Journal of the American Chemical Society 2004, 126 (11), 3472–3476. Lee, J. H.; Nandy, S. K.; Lawrence, D. S. A highly potent and selective PKCa inhibitor generated via combinatorial modification of a peptide scaffold. Journal of the American Chemical Society 2004, 126 (11), 3394–3395. de Koning, M. C.; Filippov, D. V.; van der Marel, G. A.; van Boom, J. H.; Overhand, M. Synthesis of peptide-PNApeptide conjugates by semi-solid-phase chemical ligation combined with deactivation/capture of excess reactants. European Journal of Organic Chemistry 2004, (4), 850–857. Parr, N. J.; McKeown, S. C.; Lindvall, M. K.; Lorthioir, O. E.; Congreve, M. S.; Watson, S. P. The application of quantitative analytical constructs for chemistry optimization, monomer rehearsal and reactivity prediction in solid phase library synthesis. Letters in Organic Chemistry 2004, 1 (1), 87–92. Juskowiak, G. L.; Stachel, S. J.; Tivitmahaisoon, P.; Van Vranken, D. L. Fluorogenic peptide sequences-transformation of short peptides into fluorophores under ambient photooxidative conditions. Journal of the American Chemical Society 2004, 126 (2), 550–556.
Combinatorial Chemistry Online Volume 6, Issue 4, April 2004 N. K. Terrett Pfizer Global R&D, Cambridge, MA 02139, USA
1. Current literature highlights 1.1. a-Fucosidase inhibitors
RCO2H
N
+ OH
Iminocyclitols (also known aza-sugars) have attracted attention due to their inhibitory activity against various glycosidases. The glucose-type iminocyclitol, deoxynojirimycin, has been used for the treatment of non-insulin dependent diabetes, and recent studies with deoxynojirimycin and its derivatives indicate they are effective against hepatitis B and C, as well as glycosphingolipid storage disorders such as Gaucher disease. The efficacy of iminocyclitols is attributed to their mimicry of the transition state of enzymatic glycosidic cleavage. Of the members of the glycosidase family, afucosidase is involved in the hydrolytic degradation of numerous fucose-containing glycoconjugates. This enzyme is associated with a number of essential functions, and the abnormal accumulation of fuco-conjugates, resulting from the absence or deficiency of a-fucosidase, leads to the genetic neurovisceral storage disease fucosidosis. An aberrant distribution of intracellular and extracellular a-fucosidase is also found in cystic fibrosis.
NH2
E-mail: [email protected]fizer.com doi:10.1016/j.comche.2004.04.001
N
OH
OH
OH
OH
OH
R O
Scheme 1.
that the product could be used directly for screening in situ without isolation. A solution phase library of 60 fuconojirimycin derivatives was synthesised as singletons according to general Scheme 1. The a-fucosidase from bovine kidney was used for inhibition studies and a number of active compounds were identified. One of the most potent was (i) which possessed a Ki of 0.6 nM, and selectivity against related glycosidases studied was high. This work has produced the most potent and selective inhibitors reported to date against the glycosyltransfer enzyme a-fucosidase.
H
Though the physiological functions of a-fucosidase are not completely understood, potent fucosidase inhibitors may be used as probes for the study of fucosidases in various disease states, and for the development of potential therapeutic agents. To facilitate the discovery of new glycosidase inhibitors, a recent publication describes the development of a new method for rapid derivatisation of an iminocyclitol core designed for a specific glycosidase family––in this case, particular fuconojirimycin derivatives for fucosidases.1 In this approach, the compounds are synthesised without protecting group manipulation and under such conditions
H N
H
H
N
OH
OH
OH
F
HN
H N O
(i)
1.2. Human betaine inhibitors The challenge for functional genomics and proteomics is to translate sequencing data into a precise understanding of how proteins function in cells, tissues or whole organisms. Small ligands that are able to specifically interact with proteins can be effective tools in the search for proteome function. Classically, new protein ligands have been identified by SAR studies, molecular modelling or combinatorial chemistry techniques. However,
14
N. K. Terrett / Combinatorial Chemistry - An Online Journal 6 (2004) 13–16
these approaches generally use only one protein target, and given the high number of proteins in mammalian organisms, high-throughput screening procedures have been developed to handle this task. A potential drawback with such methods is that the full range of proteins the chosen ligand may interact with are not discovered if the screening is performed with only one or a few proteins. This lack of information precludes our ability to completely understand the full spectrum of effects that a ligand may have in a complex environment such as a living cell.
phase resin via an organic spacer has been described.4 The optical purities of the N-substituted-amino ester products are superior to the solution phase DKR. Utilizing alkylation at a benzylic nitrogen-atom as a key step, a solid-phase route for synthesis of 15 N-labeled acylpolyamines has been reported.5 The derivatives were used as reference compounds for the investigation of the MS/MS behaviour of spider toxins. 2.2. Solution-phase synthesis
Approaches that study the effects of ligands in whole cells are becoming increasingly important. Screening libraries using biosensor chips or arrays grafted with proteins allows real time recording of ligand-protein interactions. Subsequent elution of these complexes can be used for protein identification by mass spectrometry. A method to discover novel protein-ligand interactions has been developed based on affinity capture principles coupled to combinatorial chemistry.2 Affinity columns were prepared containing 361 different phosphinic peptides and used to isolate all interacting proteins from crude rat liver homogenates. By applying a deconvolution process, the most specific ligand having the highest affinity towards one newly discovered protein target, betaine:homocysteine S-methyltransferase (BHMT), was identified from the library. The phosphinic peptides, which served as immobilised ligands for the isolation of rat BHMT, were then tested for their ability to inhibit human recombinant BHMT in solution. The most potent inhibitor also behaved as a selective ligand for the affinity purification of BHMT from a complex media. Further optimisation led to (ii)––a potent BHMT inhibitor that possessed an IC50 of about 1 lM. This work has demonstrated the successful application of a new and simple method for the discovery of new protein targets for artificial ligands of interest. This methodology, in combination with 2D electrophoresis and MALDI mass spectrometry holds promise as an additional method for the discovery of new specific proteinligand interactions.
Val-Phe-W½PO2 –CH2 Leu-His-NH2 ðiiÞ
2. A summary of the papers in this month’s issue 2.1. Solid-phase synthesis
A new synthesis of N-aryl- and N-heteroaryl-N 0 -(arylalkyl)piperazines using palladium-catalysed amination of aryl bromides and heteroaryl chlorides with mono Nbenzyl- or N-(arylethyl)piperazines has been reported.6 Applying an automated parallel synthesizer the preparation of a small library of potentially bioactive compounds can be easily achieved. The palladium-catalysed regioselective a-monoarylation of deoxybenzoins and, a,a-diarylation of acetophenones provides general, efficient access to 1,2,2-triarylethanones and have been conducted by means of either commercially available polymer-anchored catalysts or a very simple homogeneous catalytic system.7 A recent review evaluates the advantages, disadvantages, and effectiveness of newly developed peptide coupling reagents used in organic synthesis.8 Each reagent was classified into one of eight types including phosphonium, uronium, immonium, carbodiimide, imidazolium, organophosphorous, acid halogenating and other coupling reagents, according to the structural similarity. 2.3. Scaffolds for combinatorial libraries No papers this month. 2.4. Solid-phase supported reagents A novel polymer-supported N-heterocyclic carbene was prepared from chloromethyl polystyrene (CM PS) resin using a simple procedure, and has been used as a ligand for palladium (Pd) Suzuki cross-coupling under aqueous conditions.9 A simple and efficient method has been developed for the synthesis of a-bromoesters and ketones from bketoesters and diketones in one pot using a supported reagents system.10
A general procedure to prepare peptide thioacids by solid-phase peptide synthesis has been presented.3 The method involves the synthesis of 4-[a-(S-acetyl)mercaptobenzyl]phenoxyacetic acid, which once attached to a solid support is derivatised with the Boc-amino acid of choice after deprotection of the thiol.
The novel 3-N,N-(dimethylamino)isocyanoacrylateWang-resin has been used for the synthesis of imidazole4-carboxylic acids. The syntheses are performed in a microwave reactor with reaction times of only 15 min at 220 °C in the solvent dimethoxyethane.11
The first example of a dynamic kinetic resolution (DKR) using immobilized amine nucleophiles attached to a solid
A new type of polymeric dehydrating reagent, readily prepared by the treatment of polymer-supported tri-
N. K. Terrett / Combinatorial Chemistry - An Online Journal 6 (2004) 13–16
phenylphosphine oxide with triflic anhydride, was found to be effective in a variety of dehydration reactions such as ester and amide formation.12 A new cross-linked polystyrene-supported thioanisole reagent has been reported. This reagent can be treated with methyl trifluoromethanesulphonate to form the corresponding sulphonium salt, and then deprotonated to form a polymer-supported sulphur ylide that is able to react with aldehydes and ketones to form epoxides. The thioanisole reagent can also be oxidized to form an insoluble sulphoxide reagent useful for Swern oxidation reactions.13 2.5. Novel resins, linkers and techniques A phenylmenthyl derivative, previously shown to be a very effective chiral auxiliary in diastereoselective [2+2] photocycloadditions of cyclic enones with ethylene, was attached to poly(ethylene glycol)-grafted Wang resin.14 This was used for the first example of the photochemical production of a bicyclo[4.2.0]octane derivative on solid support. The synthesis of an ionic support and its application in the preparation of a set of amides and sulphonamides has been described.15 The potential was further exemplified by the use in a one-pot multistep ionic liquid phase assisted synthesis of a tirofiban analogue. A new oxidatively activatable safety-catch linker has been developed for combinatorial solid-phase chemistry using a two-step process starting from Merrifield resin.16 A polymer-bound iminium participates in an aza Diels– Alder cycloaddition, which leads to a supported dihydroquinoline (DHQ resin). A straightforward synthesis of trityl alcohols in which one of the aryl rings is substituted with a vinyl group has been presented.17 These compounds were used to incorporate trityl linker groups into polystyrene-based organic synthesis supports. 2.6. Library applications A new noncovalent glycoarray assembly method for microplates created by simply mixing together an isocyanate-containing C14 -hydrocarbon and an aminecontaining carbohydrate has been described.18 This new array, together with the efficient methods available for synthesis of complex oligosaccharides, could become useful for the high-throughput biological evaluation of carbohydrate–protein and carbohydrate–carbohydrate interactions. A series of novel benzimidazole derivatives have been synthesized via parallel solution-phase chemistry, and many found to inhibit the growth of Staphylococcus aureus and Escherichia coli.19 Several analogues exhibited low micromolar minimal inhibitory concentrations (MIC) against both Gram-positive and Gram-negative
15
bacteria of clinical relevance and could serve as leads for further optimisations for antibacterial research. A readily automated solid-phase approach to the synthesis of diverse N-(phenylalkyl)cinnamide analogues of an NR2B antagonist, has been described.20 A 225member focused library was synthesized using a Tecan Combitec synthesizer. Inspired by structure-based design and tailored for combinatorial preparation, a series of novel cyclic peptides has been developed to yield binding ligands for the third PDZ domain (PDZ3) of PSD-95. the postsynaptic density-95 kDa protein.21 Solid-phase synthetic methods for biaryl-based compounds have been developed resulting in the construction of two 1000-member libraries.22 Numerous compounds were identified by high-throughput screening using whole cell screens to exhibit anti-microbial activity against Gram-positive bacteria. The binding of the prokaryotic tubulin analogue, FtsZ, and the membrane-anchored protein, ZipA, presents a potential target for antibacterial therapy. Based on a small molecule inhibitor of the ZipA–FtsZ interaction, a parallel synthesis of small molecules was initiated which targeted a key region of ZipA involved in FtsZ binding.23 A small library of pentapeptides containing two regions of variability was synthesized and evaluated for lectin binding.24 Specificity was observed and galectin inhibition measured with selected sequences was 2–3 times stronger than galactose. The influence of aromatic substitution on a newly discovered class of inhibitors of dipeptidyl peptidase IV has been investigated.25 A 105 -fold increase in potency was achieved by the optimisation of aromatic substituents in a parallel chemistry program. A robust method for the solid phase synthesis of a series of selective caspase-3 peptide inhibitors has been described.26 The inhibitors were obtained after cleavage from the solid support without further purification. A small focused library of 20 3,5-substituted phenylgalactosides based on two previous lead structures was prepared with the aim of developing high-affinity mono and multivalent antagonists of cholera toxin (CT) and Escherichia coli heat-labile enterotoxin (LT).27 The crystal structures of the most promising compounds bound to either CTB5 or LTB5 were also determined. A library containing 29 peptides has been prepared via catalysis by a unique ribozyme and the products analysed by mass spectrometry.28 The results implicate that this ribozyme may have potential application in peptide synthesis. In order to characterise enzymes with unknown function, a novel systems-based inhibitor design strategy,
16
N. K. Terrett / Combinatorial Chemistry - An Online Journal 6 (2004) 13–16
enabled by bioinformatic and NMR structural developments has been developed.29 This strategy employs a combinatorial library that yielded specific inhibitors for multiple oxidoreductases.
26. Grimm, E. L.; et al. Bioorg. Med. Chem. 2004, 12 (5), 845– 851. 27. Mitchell, D. D.; et al. Bioorg. Med. Chem. 2004, 12 (5), 907–920. 28. Cui, Z.; et al. Bioorg. Med. Chem. 2004, 12 (5), 927–933. 29. Sem, D. S.; et al. Chem. Biol. 2004, 11 (2), 185–194.
References 1. Wu, C-Y.; et al. Angew. Chem., Int. Ed. Engl. 2003, 42 (38), 4661–4664. 2. Collinsova, M.; et al. Chem. Biol. 2003, 10 (2), 113–122. 3. Gaertner, H.; et al. Tetrahedron Lett. 2004, 45 (10), 2239– 2241. 4. Valenrod, Y.; et al. Tetrahedron Lett. 2004, 45 (12), 2545– 2549. 5. Manov, N.; et al. Tetrahedron 2004, 60 (10), 2387–2391. 6. Michalik, D.; et al. Tetrahedron Lett. 2004, 45 (10), 2057– 2061. 7. Churruca, F.; et al. Tetrahedron 2004, 60 (10), 2393–2408. 8. Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60 (11), 2447– 2467. 9. Byun, J.-W.; Lee, Y.-S. Tetrahedron Lett. 2004, 45 (9), 1837–1840. 10. Aoyama, T.; et al. Tetrahedron Lett. 2004, 45 (9), 1873– 1876. 11. Henkel, B. Tetrahedron Lett. 2004, 45 (10), 2219–2221. 12. Elson, K. E.; et al. Tetrahedron Lett. 2004, 45 (12), 2491– 2493. 13. Kwok Wai Choi, M.; Toy, P. H. Tetrahedron 2004, 60 (12), 2875–2879. 14. Shintani, T.; et al. Tetrahedron Lett. 2004, 45 (9), 1849– 1851. 15. de Kort, M.; et al. Tetrahedron Lett. 2004, 45 (10), 2171– 2175. 16. Arseniyadis, S.; et al. Tetrahedron Lett. 2004, 45 (10), 2251–2253. 17. Kwok Wai Choi, M.; Toy, P. H. Tetrahedron 2004, 60 (12), 2903–2907. 18. Fazio, F.; et al. Tetrahedron Lett. 2004, 45 (12), 2689– 2692. 19. He, Y.; et al. Bioorg. Med. Chem. Lett. 2004, 14 (5), 1217– 1220. 20. Weber, C.; et al. Bioorg. Med. Chem. Lett. 2004, 14 (5), 1279–1281. 21. Li, T.; et al. Bioorg. Med. Chem. Lett. 2004, 14 (6), 1385– 1388. 22. Look, G. C.; et al. Bioorg. Med. Chem. Lett. 2004, 14 (6), 1423–1426. 23. Jennings, L. D.; et al. Bioorg. Med. Chem. Lett. 2004, 14 (6), 1427–1431. 24. Arnusch, C. J.; et al. Bioorg. Med. Chem. Lett. 2004, 14 (6), 1437–1440. 25. Peters, J.-U.; et al. Bioorg. Med. Chem. Lett. 2004, 14 (6), 1491–1493.
Further Reading Papers on combinatorial chemistry or solid-phase synthesis from other journals Ohno, H.; Tanaka, H.; Takahashi, T. Solid-phase synthesis of N-alkylated naltrindoles using a 3-nitrobenzyl safety-catch linker. Synlett 2004, (3), 508–511. Amaya, T.; Tanaka, H.; Takahashi, T. Solid-phase synthesis of carbohydrate cluster on tree-type linker with three types of orthogonally cleavable part. Synlett 2004, (3), 503–507. Amaya, T.; Tanaka, H.; Takahashi, T. Combinatorial synthesis of carbohydrate cluster on tree-type linker with orthogonally cleavable parts. Synlett 2004, (3), 497–502. Olsen, C. A.; Witt, M.; Jaroszewski, J. W.; Franzyk, H. Diols as building blocks in solid-phase synthesis of polyamine toxins by fukuyama-mitsunobu alkylation. Synlett 2004, (3), 473–476. Oliver, M.; Jorgensen, M. R.; Miller, A. D. Solid-phase assisted N-1 functionalization of azamacrocycles. Synlett 2004, (3), 453–456. Mei, Y.; Beers, K. L.; Byrd, H. C. M.; VanderHart, D. L.; Washburn, N. R. Solid-phase ATRP synthesis of peptidepolymer hybrids. Journal of the American Chemical Society 2004, 126 (11), 3472–3476. Lee, J. H.; Nandy, S. K.; Lawrence, D. S. A highly potent and selective PKCa inhibitor generated via combinatorial modification of a peptide scaffold. Journal of the American Chemical Society 2004, 126 (11), 3394–3395. de Koning, M. C.; Filippov, D. V.; van der Marel, G. A.; van Boom, J. H.; Overhand, M. Synthesis of peptide-PNApeptide conjugates by semi-solid-phase chemical ligation combined with deactivation/capture of excess reactants. European Journal of Organic Chemistry 2004, (4), 850–857. Parr, N. J.; McKeown, S. C.; Lindvall, M. K.; Lorthioir, O. E.; Congreve, M. S.; Watson, S. P. The application of quantitative analytical constructs for chemistry optimization, monomer rehearsal and reactivity prediction in solid phase library synthesis. Letters in Organic Chemistry 2004, 1 (1), 87–92. Juskowiak, G. L.; Stachel, S. J.; Tivitmahaisoon, P.; Van Vranken, D. L. Fluorogenic peptide sequences-transformation of short peptides into fluorophores under ambient photooxidative conditions. Journal of the American Chemical Society 2004, 126 (2), 550–556.