- Email: [email protected]
Combinatorial Chemistry Online Volume 11, Issue 7, July 2009
Combinatorial Chemistry - An Online Journal 11 (2009) 25–27
Contents lists available at ScienceDirect
Combinatorial Chemistry - An Online Journal journal homepage: www.elsevier.com/locate/comche
Combinatorial Chemistry Online Volume 11, Issue 7, July 2009 N. K. Terrett Ensemble Discovery Corp., Cambridge, MA 02139, USA
1. Current literature highlights 1.1. An alpha-helix library targeting protein–protein interactions Protein–protein interactions are ubiquitous across all biological processes including cellular signalling. Modulation of such large surface interactions offers novel and effective ways of disrupting cell signalling and thus opportunities for therapeutic intervention. However, small molecules rarely make a sufficient number of binding interactions to give the level of potency required for a therapeutic, and thus the development of such molecules has been very slow. As many protein–protein interactions are mediated by the recognition of a protein a-helix structure, there has been an increasing focus on making mimics of this domain. A recent publication describes the design and synthesis of library of a-helix mimics based on a precedented triaryl template, and the screening of this library in the search for inhibitors of the MDM2/p53 binding interaction.1 The a-helix is a frequently occurring protein secondary structure, and interactions of this structure are often mediated by specific presentation of the side chains on the i, i + 4 and i + 7 amino acid residues. A number of synthetic mimics that present similarly spaced side chains have been investigated. For the 8000 compound library described in this publication, 400 mixtures each of 20 compounds were prepared in solution, to mimic all possible permutations of naturally occurring amino acid side chains. The structures (1) contained a non-natural aryl monomer in a central position flanked by natural amino acids at both ends. Screening the library mixtures against MDM2/p53 revealed a preference for the Trp side chain equivalent in the central position. Although this result represented an averaged affinity across the mixtures, and might have masked individual potent compounds with different central residues, further investigation of active structures was achieved by deconvolution of the other side chain positions. Individual compound synthesis identified H2N-Phe-[Trp]-Leu-OH (2) as the preferred inhibitor. 1.2. A fluorous-tagged ‘safety-catch’ linker for library synthesis Ring-closing metathesis, especially that using the ruthenium complex catalysts which are highly tolerant of other functional
E-mail: [email protected] doi:10.1016/j.comche.2009.05.002
R1
O
O
N H
COOH
H2N N H R3
OR2
1
O
O
N H
COOH
H2N N H O
2
N H
groups, has been widely used in chemistry in recent years. In particular, the mild conditions permit metathesis chemistry to be used in the synthesis of combinatorial libraries. A recent publication describes a novel fluorous-tagged linker that can be used for the synthesis of heterocycles prepared by ring-closing metathesis.2 The fluorous tag (RF) contains a perfluorinated alkyl chain that has a high affinity for other perfluorinated materials, such that this avidity can be used as a form of phase separation for tagged intermediates and products. The fluorous tags in this study allowed separation of wanted products from other excess reagents, by binding to a fluorous solid support in the process of fluorous solid-phase extraction (F-SPE). As the product would still be fluorous-tagged, further chemical manipulations can be undertaken and the same F-SPE process employed for purification. The fluorous ‘safety-catch’ linker in this study (3) was functionalised to generate a terminal alkene suitable as a metathesis substrate (4). A cascade of metathesis and cyclisation reactions was then undertaken, resulting in the generation of an acetal group.
26
N. K. Terrett / Combinatorial Chemistry - An Online Journal 11 (2009) 25–27
The ‘safety-catch’ design then allowed selective cleavage of the acetal 5 to release only the metathesis products from the fluorous linker. RF Ts N
zol-5-amine in the presence of p-toluenesulphonic acid as a catalyst, suitable for library synthesis has been developed. In this reaction, a new class of fully substituted pyrazolo[3,4-b]pyridine5-carboxamide derivatives was produced under mild reaction conditions and in good yields at ambient temperature.6 2.3. Scaffolds and synthons for combinatorial libraries
O
C8F17
3
No papers this month.
OH MeO
O
2.4. Solid-phase supported reagents No papers this month.
O RF
2.5. Novel resins, linkers and techniques
R X MeO
O
m
4
O
RF
H
Ts N
O
C8F17
R MeO
5
X
m
This approach has been used in the controlled functionalisation of a number of glucose-derived trialkenes to give an array of stereochemically controlled heterocyclic products. Overall the design of the fluorous ‘safety-catch’ linker permits easy purification of substrates, removal of the metathesis catalyst and the final clean release of metathesis products. 2. A summary of the papers in this month’s issue 2.1. Solid-phase synthesis Spiruchostatin A, a potent histone deacetylase inhibitor, has been efficiently synthesised from (3S,4R)-4-amino-3-hydroxy-5methylhexanoic acid utilising solid-phase peptide elongation with D-cysteine, D-alanine, and (E)-3-hydroxy-7-thio-4-heptenoic acid and solution-phase macrolactonisation, followed by intramolecular disulphide formation.3 The indole nucleus of Z-Trp-OBzl has been modified by acylation of the indole nitrogen using Boc-N-methyl butyric acid followed by catalytic hydrogenation and introduction of the Fmoc group. The resulting derivative, Fmoc-Trp(Boc-Nmbu)-OH, has been incorporated into peptide chains via solid-phase peptide synthesis (SPPS).4 Solid-phase synthesis has been used to obtain new linear and cyclic N,C-linked peptidocalixarenes. The synthetic strategy allows, for the first time, the condensation of a calix[4]arene amino acid during the stepwise elongation sequence of the peptide. An important role is played by the lower rim functionalisation of the calixarene since it modulates the flexibility of the calixarene scaffold and the conformational properties of the resulting non-natural peptide.5 2.2. Solution-phase synthesis A one-pot four-component reaction of an aliphatic or aromatic amine, diketene, an aromatic aldehyde and 1,3-diphenyl-1H-pyra-
A dynamic combinatorial library (DCL) based on the benzylidene exchange reactions between imidazolidin-1-ol, nitrone and oxadiazinane (INO) ring–chain–ring tautomers at room temperature has been created. The probable mechanism of the reaction is discussed based on Hammett type correlation analyses. The effect of Zn(II) and CF3SO3H on the DCL equilibria is also reported.7 The development of a highly efficient, insoluble, and non-swelling MPS-supported organocatalyst for the direct asymmetric Michael reaction of ketones and aldehydes to nitrostyrenes at room temperature in water has been described. Excellent yields (up to 100%) and high stereoselectivities (up to 94% dr and 93% ee) were achieved with 10 mol% of the catalyst. The resin-bound catalyst was separated and recovered by filtration, and reused for six consecutive trials without significant loss of activity or enantioselectivity.8 2.6. Library applications The preparation of a library of bis-imidazolium salts and corresponding palladium complexes has been reported. These complexes were screened as catalysts in the Suzuki reaction between 4-bromoanisole and phenylboronic acid. Each step was performed in parallel using a 24-position silicon carbide plate and microwave heating. The ease and speed of operation show the potential for microwave heating in conjunction with the silicon carbide plate as a tool for catalyst screening.9 A library of 1,4-benzodiazepin-3-one-based turn mimetics were synthesised and tested for their antithrombotic abilities. These mimetics were designed to incorporate amino acid side chains of the previously reported paratope of the inhibitory anti-von Willebrand Factor antibody 82D6A3. Modifications were performed on the scaffolds by alkylation of the N1-position and acylation of the reduced nitro group.10 A library of 3,5-disubstituted-1,2,4-oxadiazoles have been synthesised and evaluated for their in vitro anti-proliferative activities against various cancer cell lines. Formation of the 1,2,4-oxadiazole ring was accomplished by the reaction of amidoxime with carboxylic acids. The in vitro cytotoxic effects of 3,5-disubstituted-1,2,4oxadiazoles have been demonstrated across a wide array of tumour cell types and a few compounds exhibited specificity towards pancreatic and prostate cancer cells.11 Parallel synthesis of a series of N-benzylated isatin oximes have been developed as inhibitors of the mitogen-activated kinase, JNK3. X-ray crystallographic structures aided in the design and synthesis of novel, selective compounds, that inhibit JNK3, but not p38 MAP kinase and provided key insights into understanding the behavior of gatekeeper residue methionine-146 in determining target selectivity for this series.12 Direct anti-tuberculosis screening of commercially available compound libraries identified a novel piperidinol with interesting anti-tuberculosis activity and drug like characteristics. To gener-
N. K. Terrett / Combinatorial Chemistry - An Online Journal 11 (2009) 25–27
ate a structure activity relationship around this hit, a 22 member optimisation library has been generated using parallel synthesis. Products of this library 1-((R)-3-(4-chlorophenoxy)-2-hydroxypropyl)-4-(4-chloro-3-(trifluoromethyl) phenyl)piperidin-4-ol and 1-((S)-3-(4-(trifluoromethyl) phenoxy)-2-hydroxypropyl)-4(4-chloro-3-(trifluoromethyl) phenyl) piperidin-4-ol demonstrated good anti-tuberculosis activity, although side effects were observed upon in vivo anti-tuberculosis testing of these compounds.13 Enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) is an important target for antimalarial agents that interfere with the FAS-II pathway of lipid synthesis, which is specific for the parasite. Recent studies showed that substituted analogues of triclosan (TCL) inhibit the purified PfENR enzyme with IC50 values below 200 nM when the suboptimal 5-chloro group was replaced by larger hydrophobic moieties. Computer-assisted combinatorial techniques have been used to design, focus and in silico screen a virtual library of TCL analogues substituted at positions 5, 40 and 20 .14 Combinatorial biocatalysis has been applied to generate a diverse set of dihydroxymethylzearalenone analogues with modified ring structure. In one representative chemoenzymatic reaction sequence, dihydroxymethylzearalenone was first subjected to a unique enzyme-catalyzed oxidative ring opening reaction that creates two new carboxylic groups on the molecule. These groups served as reaction sites for further derivatisation involving biocatalytic ring closure reactions with structurally diverse bifunctional reagents, including different diols and diamines. As a result, a library of cyclic bislactones and bislactams was created, with modified ring structures covering chemical space and structure activity relationships unattainable by conventional synthetic means.15 A combined solution and solid-phase method for the synthesis of benzodiazepinediones mimicking the lipid-modified C-terminus of the H-Ras protein has been developed. By means of this 14-step sequence, a collection of 42 peptidomimetics was synthesised.16 The identification of a lead compound for fructose 1,6-bisphosphatase (FBPase) is a critical step in the process of developing novel therapeutics against type-2 diabetes. A library of allosteric inhibitors against FBPase have been developed as potential antidiabetic drugs. A thiazole-based core structure was synthesised via the condensation of a-bromo-ketones with thioureas and substituents on the two aryl rings were varied.17 Factor VIIa (FVIIa), a serine protease, coupled with tissue factor (TF) plays an important role in a number of thrombosis-related disorders. Inhibition of TFFVIIa occurs early in the coagulation cascade and might provide some safety advantages over other related enzymes. A novel series of substituted biphenyl derivatives that are highly potent and selective TFFVIIa inhibitors have been investigated. Parallel synthesis coupled with structure-based drug design allowed the exploration of the S2 pocket of the enzyme active site, and a number of compounds with IC50 value of <10 nM were synthesised.18 References 1. Shaginian, A. et al.. J. Am. Chem. Soc. 2009, 131 (15), 5564–5572. 2. O’Leary-Steele, C. et al. Org. Lett. 2009, 11 (4), 915–918.
3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
27
Iijima, Y. et al. Tetrahedron Lett. 2009, 50 (24), 2970–2972. Wahlström, K.; Undén, A. Tetrahedron Lett. 2009, 50 (24), 2976–2978. Baldini, L. et al. Tetrahedron Lett. 2009, 50 (24), 3450–3453. Shaabani, A. et al. Tetrahedron Lett. 2009, 50 (24), 2911–2913. Cosßkun, N.; Aksoy, C. Tetrahedron Lett. 2009, 50 (25), 3008–3012. Chuan, Y. et al. Tetrahedron Lett. 2009, 50 (24), 3054–3058. Avery, K. B. et al. Tetrahedron Lett. 2009, 50 (24), 2851–2853. Deschrijver, T. et al. Tetrahedron 2009, 65 (23), 4521–4529. Kumar, D. et al. Bioorg. Med. Chem. Lett. 2009, 19 (10), 2739–2741. Cao, J. et al. Bioorg. Med. Chem. Lett. 2009, 19 (10), 2891–2895. Sun, D. et al. Bioorg. Med. Chem. 2009, 17 (10), 3588–3594. Frecer, V. et al. Eur. J. Med. Chem. 2008, 44 (7), 3009–3010. Rich, J. O. et al. Bioorg. Med. Chem. Lett. 2009, 19 (11), 3059–3062. Ludolph, B.; Waldmann, H. Tetrahedron Lett. 2009, 50 (26), 3148–3150. Heng, S. et al. Bioorg. Med. Chem. 2009, 17 (11), 3916–3922. Kotian, P. L. et al. Bioorg. Med. Chem. 2009, 17 (11), 3934–3958.
Further reading Papers on combinatorial chemistry or solid-phase synthesis from other journals Rad-Moghadam, K.; Rouhi, S. Silica-bound benzoyl chloride mediated the solid-phase synthesis of 4H-3, 1-benzoxazin-4-ones. Beilstein Journal of Organic Chemistry 2009, 5 (13). Torr, J. E.; Large, J. M.; McDonald, E. Design and combinatorial synthesis of a library of methylenesulfonamides and related compounds as potential kinase inhibitors. Combinatorial Chemistry & High Throughput Screening 2009, 12 (3), 275–284. Kainkaryam, R. M.; Woolf, P. J. Pooling in high-throughput drug screening. Current Opinion in Drug Discovery & Development 2009, 12 (3), 339–350. Koppen, H. Virtual screening – what does it give us? Current Opinion in Drug Discovery & Development 2009, 12 (3), 397–407. Alvey, L.; Prado, S.; Saint-Joanis, B.; Michel, S.; Koch, M.; Cole, S. T.; Tillequin, F.; Janin, Y. L. Diversity-oriented synthesis of furo[3, 2-f]chromanes with antimycobacterial activity. European Journal of Medicinal Chemistry 2009, 44 (6), 2497–2505. Van der Plas, S. E.; Van Hoeck, E.; Lynen, F.; Sandra, P.; Madder, A. Towards a new SPE material for EDCs: fully automated synthesis of a library of tripodal receptors followed by fast screening by affinity LC. European Journal of Organic Chemistry 2009, 11, 1796–1805. Damm, M.; Kappe, C. O. High-throughput experimentation platform: parallel microwave chemistry in HPLC/GC vials. Journal of Combinatorial Chemistry 2009, 11 (3), 460–468. Pokhodylo, Nazariy T.; Matiychuk, Vasyl S.; Obushak, Mykola D. One-pot multicomponent synthesis of 1-aryl-5-methyl-N-R2–1H-1, 2, 3-triazole-4-carboxamides: an easy procedure for combinatorial chemistry. Journal of Combinatorial Chemistry 2009, 11 (3), 481–485. Baskovc, J.; Bevk, D.; Stanovnik, B.; Svete, J. Bis-enaminone based parallel solutionphase synthesis of 14-dihydropyridine Derivatives. Journal of Combinatorial Chemistry 2009, 11 (3), 500–507. Jagasia, R.; Holub, J. M.; Bollinger, M.; Kirshenbaum, K.; Finn, M. G. Peptide cyclization and cyclodimerization by CuI-mediated azide–alkyne cycloaddition. Journal of Organic Chemistry 2009, 74 (8), 2964–2974. Thompson, M. J.; Adams, H.; Chen, B. Development of a diversity-oriented approach to oxazole-5-amide libraries. Journal of Organic Chemistry 2009, 74 (10), 3856–3865. Duarte, M. O.; Stedele, G.; Pazinatto, M.; de Oliveira, E. R.; Eifler-Lima, V. L. New solidphase approach to synthesize a hyacinthacine core using the L-proline as a building block. Letters in Organic Chemistry 2009, 6 (1), 90–93. Dhanawat, M.; Shrivastava, S. K. Solid-phase synthesis of oligosaccharide drugs: a review. Mini-Reviews in Medicinal Chemistry 2009, 9 (2), 169–185. Beaumard, F.; Dauban, P.; Dodd, R. H. One-pot double Suzuki–Miyaura couplings: rapid access to nonsymmetrical tri(hetero)aryl derivatives. Organic Letters 2009, 11 (8), 1801–1804. Devarie-Baez, N. O.; Kim, W.-S.; Smith, A. B.; Xian, M. Multicomponent type II anion relay chemistry (ARC): one-pot syntheses of 2,3-disubstituted furans and thiophenes. Organic Letters 2009, 11 (8), 1861–1864. Harju, K.; Vesterinen, J.; Yli-Kauhaluoma, J. Solid-phase synthesis of amino acid derived N-unsubstituted pyrazoles via sydnones. Organic Letters 2009, 11 (10), 2219–2221.
Contents lists available at ScienceDirect
Combinatorial Chemistry - An Online Journal journal homepage: www.elsevier.com/locate/comche
Combinatorial Chemistry Online Volume 11, Issue 7, July 2009 N. K. Terrett Ensemble Discovery Corp., Cambridge, MA 02139, USA
1. Current literature highlights 1.1. An alpha-helix library targeting protein–protein interactions Protein–protein interactions are ubiquitous across all biological processes including cellular signalling. Modulation of such large surface interactions offers novel and effective ways of disrupting cell signalling and thus opportunities for therapeutic intervention. However, small molecules rarely make a sufficient number of binding interactions to give the level of potency required for a therapeutic, and thus the development of such molecules has been very slow. As many protein–protein interactions are mediated by the recognition of a protein a-helix structure, there has been an increasing focus on making mimics of this domain. A recent publication describes the design and synthesis of library of a-helix mimics based on a precedented triaryl template, and the screening of this library in the search for inhibitors of the MDM2/p53 binding interaction.1 The a-helix is a frequently occurring protein secondary structure, and interactions of this structure are often mediated by specific presentation of the side chains on the i, i + 4 and i + 7 amino acid residues. A number of synthetic mimics that present similarly spaced side chains have been investigated. For the 8000 compound library described in this publication, 400 mixtures each of 20 compounds were prepared in solution, to mimic all possible permutations of naturally occurring amino acid side chains. The structures (1) contained a non-natural aryl monomer in a central position flanked by natural amino acids at both ends. Screening the library mixtures against MDM2/p53 revealed a preference for the Trp side chain equivalent in the central position. Although this result represented an averaged affinity across the mixtures, and might have masked individual potent compounds with different central residues, further investigation of active structures was achieved by deconvolution of the other side chain positions. Individual compound synthesis identified H2N-Phe-[Trp]-Leu-OH (2) as the preferred inhibitor. 1.2. A fluorous-tagged ‘safety-catch’ linker for library synthesis Ring-closing metathesis, especially that using the ruthenium complex catalysts which are highly tolerant of other functional
E-mail: [email protected] doi:10.1016/j.comche.2009.05.002
R1
O
O
N H
COOH
H2N N H R3
OR2
1
O
O
N H
COOH
H2N N H O
2
N H
groups, has been widely used in chemistry in recent years. In particular, the mild conditions permit metathesis chemistry to be used in the synthesis of combinatorial libraries. A recent publication describes a novel fluorous-tagged linker that can be used for the synthesis of heterocycles prepared by ring-closing metathesis.2 The fluorous tag (RF) contains a perfluorinated alkyl chain that has a high affinity for other perfluorinated materials, such that this avidity can be used as a form of phase separation for tagged intermediates and products. The fluorous tags in this study allowed separation of wanted products from other excess reagents, by binding to a fluorous solid support in the process of fluorous solid-phase extraction (F-SPE). As the product would still be fluorous-tagged, further chemical manipulations can be undertaken and the same F-SPE process employed for purification. The fluorous ‘safety-catch’ linker in this study (3) was functionalised to generate a terminal alkene suitable as a metathesis substrate (4). A cascade of metathesis and cyclisation reactions was then undertaken, resulting in the generation of an acetal group.
26
N. K. Terrett / Combinatorial Chemistry - An Online Journal 11 (2009) 25–27
The ‘safety-catch’ design then allowed selective cleavage of the acetal 5 to release only the metathesis products from the fluorous linker. RF Ts N
zol-5-amine in the presence of p-toluenesulphonic acid as a catalyst, suitable for library synthesis has been developed. In this reaction, a new class of fully substituted pyrazolo[3,4-b]pyridine5-carboxamide derivatives was produced under mild reaction conditions and in good yields at ambient temperature.6 2.3. Scaffolds and synthons for combinatorial libraries
O
C8F17
3
No papers this month.
OH MeO
O
2.4. Solid-phase supported reagents No papers this month.
O RF
2.5. Novel resins, linkers and techniques
R X MeO
O
m
4
O
RF
H
Ts N
O
C8F17
R MeO
5
X
m
This approach has been used in the controlled functionalisation of a number of glucose-derived trialkenes to give an array of stereochemically controlled heterocyclic products. Overall the design of the fluorous ‘safety-catch’ linker permits easy purification of substrates, removal of the metathesis catalyst and the final clean release of metathesis products. 2. A summary of the papers in this month’s issue 2.1. Solid-phase synthesis Spiruchostatin A, a potent histone deacetylase inhibitor, has been efficiently synthesised from (3S,4R)-4-amino-3-hydroxy-5methylhexanoic acid utilising solid-phase peptide elongation with D-cysteine, D-alanine, and (E)-3-hydroxy-7-thio-4-heptenoic acid and solution-phase macrolactonisation, followed by intramolecular disulphide formation.3 The indole nucleus of Z-Trp-OBzl has been modified by acylation of the indole nitrogen using Boc-N-methyl butyric acid followed by catalytic hydrogenation and introduction of the Fmoc group. The resulting derivative, Fmoc-Trp(Boc-Nmbu)-OH, has been incorporated into peptide chains via solid-phase peptide synthesis (SPPS).4 Solid-phase synthesis has been used to obtain new linear and cyclic N,C-linked peptidocalixarenes. The synthetic strategy allows, for the first time, the condensation of a calix[4]arene amino acid during the stepwise elongation sequence of the peptide. An important role is played by the lower rim functionalisation of the calixarene since it modulates the flexibility of the calixarene scaffold and the conformational properties of the resulting non-natural peptide.5 2.2. Solution-phase synthesis A one-pot four-component reaction of an aliphatic or aromatic amine, diketene, an aromatic aldehyde and 1,3-diphenyl-1H-pyra-
A dynamic combinatorial library (DCL) based on the benzylidene exchange reactions between imidazolidin-1-ol, nitrone and oxadiazinane (INO) ring–chain–ring tautomers at room temperature has been created. The probable mechanism of the reaction is discussed based on Hammett type correlation analyses. The effect of Zn(II) and CF3SO3H on the DCL equilibria is also reported.7 The development of a highly efficient, insoluble, and non-swelling MPS-supported organocatalyst for the direct asymmetric Michael reaction of ketones and aldehydes to nitrostyrenes at room temperature in water has been described. Excellent yields (up to 100%) and high stereoselectivities (up to 94% dr and 93% ee) were achieved with 10 mol% of the catalyst. The resin-bound catalyst was separated and recovered by filtration, and reused for six consecutive trials without significant loss of activity or enantioselectivity.8 2.6. Library applications The preparation of a library of bis-imidazolium salts and corresponding palladium complexes has been reported. These complexes were screened as catalysts in the Suzuki reaction between 4-bromoanisole and phenylboronic acid. Each step was performed in parallel using a 24-position silicon carbide plate and microwave heating. The ease and speed of operation show the potential for microwave heating in conjunction with the silicon carbide plate as a tool for catalyst screening.9 A library of 1,4-benzodiazepin-3-one-based turn mimetics were synthesised and tested for their antithrombotic abilities. These mimetics were designed to incorporate amino acid side chains of the previously reported paratope of the inhibitory anti-von Willebrand Factor antibody 82D6A3. Modifications were performed on the scaffolds by alkylation of the N1-position and acylation of the reduced nitro group.10 A library of 3,5-disubstituted-1,2,4-oxadiazoles have been synthesised and evaluated for their in vitro anti-proliferative activities against various cancer cell lines. Formation of the 1,2,4-oxadiazole ring was accomplished by the reaction of amidoxime with carboxylic acids. The in vitro cytotoxic effects of 3,5-disubstituted-1,2,4oxadiazoles have been demonstrated across a wide array of tumour cell types and a few compounds exhibited specificity towards pancreatic and prostate cancer cells.11 Parallel synthesis of a series of N-benzylated isatin oximes have been developed as inhibitors of the mitogen-activated kinase, JNK3. X-ray crystallographic structures aided in the design and synthesis of novel, selective compounds, that inhibit JNK3, but not p38 MAP kinase and provided key insights into understanding the behavior of gatekeeper residue methionine-146 in determining target selectivity for this series.12 Direct anti-tuberculosis screening of commercially available compound libraries identified a novel piperidinol with interesting anti-tuberculosis activity and drug like characteristics. To gener-
N. K. Terrett / Combinatorial Chemistry - An Online Journal 11 (2009) 25–27
ate a structure activity relationship around this hit, a 22 member optimisation library has been generated using parallel synthesis. Products of this library 1-((R)-3-(4-chlorophenoxy)-2-hydroxypropyl)-4-(4-chloro-3-(trifluoromethyl) phenyl)piperidin-4-ol and 1-((S)-3-(4-(trifluoromethyl) phenoxy)-2-hydroxypropyl)-4(4-chloro-3-(trifluoromethyl) phenyl) piperidin-4-ol demonstrated good anti-tuberculosis activity, although side effects were observed upon in vivo anti-tuberculosis testing of these compounds.13 Enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) is an important target for antimalarial agents that interfere with the FAS-II pathway of lipid synthesis, which is specific for the parasite. Recent studies showed that substituted analogues of triclosan (TCL) inhibit the purified PfENR enzyme with IC50 values below 200 nM when the suboptimal 5-chloro group was replaced by larger hydrophobic moieties. Computer-assisted combinatorial techniques have been used to design, focus and in silico screen a virtual library of TCL analogues substituted at positions 5, 40 and 20 .14 Combinatorial biocatalysis has been applied to generate a diverse set of dihydroxymethylzearalenone analogues with modified ring structure. In one representative chemoenzymatic reaction sequence, dihydroxymethylzearalenone was first subjected to a unique enzyme-catalyzed oxidative ring opening reaction that creates two new carboxylic groups on the molecule. These groups served as reaction sites for further derivatisation involving biocatalytic ring closure reactions with structurally diverse bifunctional reagents, including different diols and diamines. As a result, a library of cyclic bislactones and bislactams was created, with modified ring structures covering chemical space and structure activity relationships unattainable by conventional synthetic means.15 A combined solution and solid-phase method for the synthesis of benzodiazepinediones mimicking the lipid-modified C-terminus of the H-Ras protein has been developed. By means of this 14-step sequence, a collection of 42 peptidomimetics was synthesised.16 The identification of a lead compound for fructose 1,6-bisphosphatase (FBPase) is a critical step in the process of developing novel therapeutics against type-2 diabetes. A library of allosteric inhibitors against FBPase have been developed as potential antidiabetic drugs. A thiazole-based core structure was synthesised via the condensation of a-bromo-ketones with thioureas and substituents on the two aryl rings were varied.17 Factor VIIa (FVIIa), a serine protease, coupled with tissue factor (TF) plays an important role in a number of thrombosis-related disorders. Inhibition of TFFVIIa occurs early in the coagulation cascade and might provide some safety advantages over other related enzymes. A novel series of substituted biphenyl derivatives that are highly potent and selective TFFVIIa inhibitors have been investigated. Parallel synthesis coupled with structure-based drug design allowed the exploration of the S2 pocket of the enzyme active site, and a number of compounds with IC50 value of <10 nM were synthesised.18 References 1. Shaginian, A. et al.. J. Am. Chem. Soc. 2009, 131 (15), 5564–5572. 2. O’Leary-Steele, C. et al. Org. Lett. 2009, 11 (4), 915–918.
3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
27
Iijima, Y. et al. Tetrahedron Lett. 2009, 50 (24), 2970–2972. Wahlström, K.; Undén, A. Tetrahedron Lett. 2009, 50 (24), 2976–2978. Baldini, L. et al. Tetrahedron Lett. 2009, 50 (24), 3450–3453. Shaabani, A. et al. Tetrahedron Lett. 2009, 50 (24), 2911–2913. Cosßkun, N.; Aksoy, C. Tetrahedron Lett. 2009, 50 (25), 3008–3012. Chuan, Y. et al. Tetrahedron Lett. 2009, 50 (24), 3054–3058. Avery, K. B. et al. Tetrahedron Lett. 2009, 50 (24), 2851–2853. Deschrijver, T. et al. Tetrahedron 2009, 65 (23), 4521–4529. Kumar, D. et al. Bioorg. Med. Chem. Lett. 2009, 19 (10), 2739–2741. Cao, J. et al. Bioorg. Med. Chem. Lett. 2009, 19 (10), 2891–2895. Sun, D. et al. Bioorg. Med. Chem. 2009, 17 (10), 3588–3594. Frecer, V. et al. Eur. J. Med. Chem. 2008, 44 (7), 3009–3010. Rich, J. O. et al. Bioorg. Med. Chem. Lett. 2009, 19 (11), 3059–3062. Ludolph, B.; Waldmann, H. Tetrahedron Lett. 2009, 50 (26), 3148–3150. Heng, S. et al. Bioorg. Med. Chem. 2009, 17 (11), 3916–3922. Kotian, P. L. et al. Bioorg. Med. Chem. 2009, 17 (11), 3934–3958.
Further reading Papers on combinatorial chemistry or solid-phase synthesis from other journals Rad-Moghadam, K.; Rouhi, S. Silica-bound benzoyl chloride mediated the solid-phase synthesis of 4H-3, 1-benzoxazin-4-ones. Beilstein Journal of Organic Chemistry 2009, 5 (13). Torr, J. E.; Large, J. M.; McDonald, E. Design and combinatorial synthesis of a library of methylenesulfonamides and related compounds as potential kinase inhibitors. Combinatorial Chemistry & High Throughput Screening 2009, 12 (3), 275–284. Kainkaryam, R. M.; Woolf, P. J. Pooling in high-throughput drug screening. Current Opinion in Drug Discovery & Development 2009, 12 (3), 339–350. Koppen, H. Virtual screening – what does it give us? Current Opinion in Drug Discovery & Development 2009, 12 (3), 397–407. Alvey, L.; Prado, S.; Saint-Joanis, B.; Michel, S.; Koch, M.; Cole, S. T.; Tillequin, F.; Janin, Y. L. Diversity-oriented synthesis of furo[3, 2-f]chromanes with antimycobacterial activity. European Journal of Medicinal Chemistry 2009, 44 (6), 2497–2505. Van der Plas, S. E.; Van Hoeck, E.; Lynen, F.; Sandra, P.; Madder, A. Towards a new SPE material for EDCs: fully automated synthesis of a library of tripodal receptors followed by fast screening by affinity LC. European Journal of Organic Chemistry 2009, 11, 1796–1805. Damm, M.; Kappe, C. O. High-throughput experimentation platform: parallel microwave chemistry in HPLC/GC vials. Journal of Combinatorial Chemistry 2009, 11 (3), 460–468. Pokhodylo, Nazariy T.; Matiychuk, Vasyl S.; Obushak, Mykola D. One-pot multicomponent synthesis of 1-aryl-5-methyl-N-R2–1H-1, 2, 3-triazole-4-carboxamides: an easy procedure for combinatorial chemistry. Journal of Combinatorial Chemistry 2009, 11 (3), 481–485. Baskovc, J.; Bevk, D.; Stanovnik, B.; Svete, J. Bis-enaminone based parallel solutionphase synthesis of 14-dihydropyridine Derivatives. Journal of Combinatorial Chemistry 2009, 11 (3), 500–507. Jagasia, R.; Holub, J. M.; Bollinger, M.; Kirshenbaum, K.; Finn, M. G. Peptide cyclization and cyclodimerization by CuI-mediated azide–alkyne cycloaddition. Journal of Organic Chemistry 2009, 74 (8), 2964–2974. Thompson, M. J.; Adams, H.; Chen, B. Development of a diversity-oriented approach to oxazole-5-amide libraries. Journal of Organic Chemistry 2009, 74 (10), 3856–3865. Duarte, M. O.; Stedele, G.; Pazinatto, M.; de Oliveira, E. R.; Eifler-Lima, V. L. New solidphase approach to synthesize a hyacinthacine core using the L-proline as a building block. Letters in Organic Chemistry 2009, 6 (1), 90–93. Dhanawat, M.; Shrivastava, S. K. Solid-phase synthesis of oligosaccharide drugs: a review. Mini-Reviews in Medicinal Chemistry 2009, 9 (2), 169–185. Beaumard, F.; Dauban, P.; Dodd, R. H. One-pot double Suzuki–Miyaura couplings: rapid access to nonsymmetrical tri(hetero)aryl derivatives. Organic Letters 2009, 11 (8), 1801–1804. Devarie-Baez, N. O.; Kim, W.-S.; Smith, A. B.; Xian, M. Multicomponent type II anion relay chemistry (ARC): one-pot syntheses of 2,3-disubstituted furans and thiophenes. Organic Letters 2009, 11 (8), 1861–1864. Harju, K.; Vesterinen, J.; Yli-Kauhaluoma, J. Solid-phase synthesis of amino acid derived N-unsubstituted pyrazoles via sydnones. Organic Letters 2009, 11 (10), 2219–2221.