Combinatorial Chemistry Online

Combinatorial Chemistry - An Online Journal 8 (2006) 31–34

Combinatorial Chemistry Online Volume 8, Issue 7, July 2006 N. K. Terrett Ensemble Discovery Corp., Cambridge, MA 02139 USA

1. Current literature highlights 1.1. Carbonic anhydrase inhibitors through dynamic combinatorial chemistry Dynamic combinatorial chemistry (DCC) uses reversible covalent reactions to synthesise libraries of molecules from a range of chemical precursors. Unlike conventional synthesis, the intention of DCC is not to generate high yielding pure compounds, but rather to provide access to a range of diverse products and enable amplification of the ‘best binder’ by interaction of library constituents with a biological target in a self-screening protocol. A DCC approach has been used to identify inhibitors of bovine carbonic anhydrase II (bCA II).1 The carbonic anhydrases are a family of Zn(II) metalloenzymes (EC 4.2.1.1) that catalyse the interconversion of CO2 and HCO 3 , a reaction that underpins many physiological processes associated with the control of pH, ion transport and fluid secretion. In terms of drug intervention, inhibitors of carbonic anhydrase have been explored clinically for the treatment of glaucoma, epilepsy and gastric ulcers. More recently, carbonic anhydrase inhibition has been implicated as playing an important role in cancer tumour progression.

mer CM products relative to the self-CM product. bCA II screening results demonstrated that the heterodimer CM products exhibited variable affinity for bCA II, with the most potent CM product identified as (iii) containing a terminal acetate group. When synthesised as a pure compound, this analogue revealed a Ki value of 4.9 nM.

O

R

O

+ (ii)

(i)

H2 NO 2S

O R

CM

O

H2 NO 2S

O OCOMe O

(iii) H2 NO 2S

This DCC approach to the discovery of bCA II inhibitors used DCC with alkene cross metathesis (CM) as the reversible reaction. Building block (i), an allyl ester benzene sulphonamide, was prepared specifically as a scaffold building block to facilitate this study, as the precursor contains both an aromatic sulphonamide moiety to interact with the carbonic anhydrase and an allyl substituent, to permit reaction through the CM reaction. The authors elected to use 10 equivalents of the allyl fragment (ii) as the CM partner of (i), in order to increase the proportion of the heterodi-

E-mail: [email protected] doi:10.1016/j.comche.2006.06.001

Overall, results for screening against bCA II, without prior isolation of the active constituent, were in full agreement with those obtained for equilibrium dissociation constants (Ki’s) of pure compounds. Some of these compounds discovered exhibited Ki values in the low nanomolar range. 1.2. Libraries from a new Ugi-palladium assisted N-aryl amidation strategy Combinatorial chemistry is always in need of more efficient synthetic strategies for the assembly of interesting and

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N. K. Terrett / Combinatorial Chemistry - An Online Journal 8 (2006) 31–34

diverse compound libraries. Multiple component reactions (MCR) are an effective way of rapidly generating compound libraries containing a variety of different and highly relevant heterocycles. Amongst the various available MCR processes, the Ugi reaction is one of the most explored approaches for rapidly assembling libraries of interesting chemical products. The area of palladium chemistry is diverse and a plethora of post-condensation modifications can be envisaged to the Ugi reaction. In a recent paper, a new strategy for the synthesis of highly substituted N-heterocyclic scaffolds based on the combination of the Ugi four-component reaction and a palladium-assisted intramolecular N-aryl amidation has been reported.2 The formation of the secondary amide (iv) was originally reported by Ugi et al via a four component condensation. The final ring-closing reaction was achieved by a classical intramolecular N-aryl amidation of secondary amides catalysed by palladium. Specifically, in the second step of the reaction sequence, the Ugi-product (iv) was dissolved in toluene and the N-amidation was performed at 100 °C by using the catalytic system tris(dibenzylideneacetone) di-palladium Pd2(dba)3, tri-o-tolylphosphine as ligand and a carbonate base. The expected N-heterocyclic compounds (for example (v)) were successfully isolated in moderate to good yields. In addition to substituted benzodiazepin-2,5-diones, appropriate choice of Ugi precursors also permitted the preparation of indol-2-ones, and quinoxalin-2-ones.

R1

NH2

R2

CHO

R3

COOH

R4

NC

Br

Ugi

2. A summary of the papers in this month’s issue 2.1. Solid-phase synthesis Seventeen unsymmetrical curcumin derivatives have been synthesised in good yield and purity by a facile solid phase synthesis strategy.3 An efficient method for the reduction of aromatic azides in both solution and on solid-phase has been developed by employing BF3ÆOEt2/EtSH. This report also describes resin cleavage employing this reagent system, and the protocol has been used for the solid-phase synthesis of pyrrolo[2,1-c][1,4]benzodiazepines, including the naturally occurring antibiotic DC-81 and fused [2,1-b]quinazolinones.4 A stereoselective synthesis of dinucleoside boranophosphates by using nucleoside 3 0 -oxazaphospholidine derivatives has been described. (Rp)- and (Sp)-dithymidine boranophosphates were synthesised with excellent diastereoselectivity both in solution and on a solid-support.5 The preparation of three different 2-alkoxy-8-hydroxyadenylpeptide conjugates has been accomplished by solidphase synthesis combined with ‘on-resin’ Cu(I) catalyzed Huisgen cycloaddition.6 An efficient and straightforward methodology for the parallel solid-phase synthesis of a variety of new macrocyclic oligoheterocycles is described. Exhaustive reduction of resin-bound cyclic polyamides using borane generates polyamines, and treatment of separated pairs of amines with a variety of bifunctional reagents provides, following cleavage from the solid support, the desired macrocyclic oligoheterocyclic compounds in good yields and purities.7 2.2. Solution-phase synthesis

HN

R4

(iv)

O

O

[Pd]

e.g.

NR1 R2

N-amidation R3

N R4

O

(v)

In summary, a novel two-step solution phase procedure for the preparation of indol-2-ones, quinoxalin-2-ones and benzodiazepine-2,5-diones has been described. As the final products, accessed via a facile and rapid production protocol, contain four points of potential diversity, the combinatorial synthesis of thousands of compounds containing these important pharmacophoric scaffolds is now feasible.

A diversity-oriented synthetic approach toward skeletally diverse, cyclised peptidomimetics with diverse appendages has been reported. Starting from a-(N-acylamino)amides with various appendages, 12 to 16-membered lactams with defined olefin geometry were synthesised by a common synthetic sequence, directed toward a construction of a peptidomimetic library.8 A method for the preparation of oxybispyridines bearing several halogens has been described. These compounds, which could be further modified with other functional groups thus giving access to libraries with the bis-pyridyl ether moiety as the common structural feature, are of interest in cholinergic medicinal chemistry.9 2.3. Scaffolds for combinatorial libraries The first example of the synthesis of isocyanide derivatives of a-aminoalkylphosphonate diphenyl esters has been reported. This method permits the generation of an a-aminophosphonate-based library of biologically active phosphonopeptides.10

N. K. Terrett / Combinatorial Chemistry - An Online Journal 8 (2006) 31–34

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A novel one-pot two-step multi component reaction of acrylic aldehydes, bromoanilines, acids and isocyanides yielding polysubstituted indoles has been described, based on the combination of an Ugi four-component reaction followed by an intramolecular Heck-reaction. The simultaneous use of formic acid and cinnamaldehydes affords in situ generation of 1H-indoles suitable for a combinatorial approach.11

A library consisting of 60 arylpiperazines modified with N-acylated amino acids have been prepared on BAL linker SynPhaseTM Lanterns and evaluated in vitro for 5-HT1A receptor affinity. Biological screening, followed by a simple Fujita–Ban analysis, enabled the description of structure– activity relationships and allowed the selection of some potent, high-affinity ligands for in vivo pharmacological investigations.18

A small library of 2-oxo-5-(hetero)arylpyrroles has been prepared starting from 2,3-dioxo-5-(hetero)arylpyrrolidines. The 2-oxopyrroles offer a large number of possible derivatisations including reactions with electrophiles and are thus interesting and versatile synthetic building blocks.12

Using a scaleable, directed library approach based on orthogonally protected advanced intermediates, a series of potent keto-1,2,4-oxadiazoles have been prepared. This library was designed to explore the P2 binding pocket of human mast cell tryptase, while building in a high degree of selectivity over human trypsin and other serine proteases.19

2.4. Solid-phase supported reagents Amphiphilic polymer-supported N-heterocyclic carbene (NHC) precursor resins have been generated by loading polyethylene glycol (PEG) containing imidazolium groups on Merrifield resin. These PS–PEG–NHC–Pd catalysts showed better catalytic activity for Suzuki cross-coupling reactions of various aryl iodides and bromides with phenylboronic acid in water than the previously described polystyrene based catalysts.13 The synthesis of the major metabolite of a potent 3-aminopyrazole CDK2/cyclin A inhibitor has been presented. A stereoconservative approach starting from malic acid was employed to construct the hydroxy-substituted pyrrolidinone moiety. In the key step of the synthesis the use of cyanoborohydride immobilized on Amberlyst 26 in trifluoroethanol represented a valid alternative to conventional solution-phase reducing agents.14 2.5. Novel resins, linkers and techniques No papers this month.

New non-steroidal chemotypes are required for the development of drugs targeting the steroid hormone receptors. The parallel array synthesis of 3-aryl-1,2-diazepines employing solid-supported reagents has been described, and the resulting compounds demonstrated high affinity binding to the progesterone receptor.20 Potential inhibitors of the Trypanosoma cruzi dUTP nucleotidohydrolase have been docked into the enzyme using the program FlexX. Compounds that docked selectively were then synthesised using solid phase methodology, giving rise to a novel library of amino acid uracil acetamide compounds which were evaluated for enzyme inhibition and anti-parasitic activity.21 The synthesis and screening of a biased positional scanning library made up of peptoids (N-alkylglycines) and lysines has been described. A theoretical number of 390,625 compounds were synthesised and screened against the American Type Culture Collection (ATCC) Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922 bacterial strains, and the cytotoxic activities were assessed using a human blood hemolytic assay.22

2.6. Library applications A small library of squamocin analogues has been prepared and screened biologically (cytotoxicity, inhibition of mitochondrial complex I and complex III). To centre diversity on a crucial part of the molecule (i.e., the a,b-unsaturated lactone), an original and reliable lactone opening reaction has been discovered.15 Two small libraries of tripeptidic-based vinyl ester derivative proteasome inhibitors have been synthesised and tested, starting with the Hmb-Val-Gln-Leu-VE prototype. The P3 and P4 positions were investigated with a complete set of amino acid residues, some of which showed remarkable selective inhibition of the trypsin-like (b2) subunit.16 A recent study reports the generation of a focused library of Lisofylline (LSF) analogs that maintain the side chain (5-R-hydroxyhexyl) constant, while substituting a variety of nitrogen-containing heterocyclic substructures for the xanthine moiety of LSF. The LSF analogues were evaluated in a pancreatic b-cell line for the effects on apoptosis protection and insulin release.17

With the aim of developing small molecular non-peptide bsecretase (BACE) inhibitors, Leu-Ala hydroxyethylene (HE) has been investigated as a scaffold to design and synthesise a series of compounds. Taking advantage of efficient combinatorial synthesis approaches and molecular modelling, extensive structure–activity relationship (SAR) studies were carried out on the N- and C-terminal residues of the scaffold.23 Pyranocoumarin compounds have been identified to embody a novel and unique pharmacophore for anti-TB activity, and a systematic approach was taken to investigate the structural characteristics. Focused libraries of compounds were synthesised and evaluated for their anti-TB activity in primary screening assays.24 The condensation of a set of diversely substituted (S)-2amino-2-ferrocenyl ethanol derivatives with salicylaldehydes resulted in the generation of a small library of new chiral Schiff base-ligands, whose titanium isopropoxide complexes have been tested as catalysts in the asymmetric addition of trimethylsilyl cyanide to aldehydes.25

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Small-molecule ‘diversity microarrays’ containing nearly 10,000 known bioactive small molecules, natural products, and small molecules originating from several diversity-oriented syntheses have been produced by using an isocyanate-mediated covalent capture strategy. The new surface of the diversity microarrays is highly compatible with approaches involving cellular lysates, and this has enabled a robust, optimized screening methodology, allowing the detection of specific interactions.26

References 1. Poulsen, S. A.; Bornaghi, L. F. Bioorg. Med. Chem. 2006, 14 (10), 3275–3284. 2. Kalinski, C. et al. Tetrahedron Lett. 2006, 47 (20), 3423–3426. 3. Shao, W. Y. et al. Tetrahedron Lett. 2006, 47 (24), 4085–4089. 4. Kamal, A. et al. Tetrahedron Lett. 2006, 47 (25), 4253–4257. 5. Wada, T.; Maizuru, Y. Bioorg. Med. Chem. Lett. 2006, 16 (12), 3111–3114. 6. Weterings, J. J. et al. Bioorg. Med. Chem. Lett. 2006, 16 (12), 3258–3261. 7. Nefzi, A.; Santos, R. T. Bioorg. Med. Chem. Lett. 2006, 16 (13), 3358–3361. 8. Oikawa, M. et al. Tetrahedron Lett. 2006, 47 (27), 4763–4767. 9. Voisin, A. S. et al. Tetrahedron 2006, 62 (25), 6000–6005. 10. Sien´czyk, M. et al. Tetrahedron Lett. 2006, 47 (25), 4209–4211. 11. Kalinski, C. et al. Tetrahedron Lett. 2006, 47 (27), 4683–4686. 12. Metten, B. et al. Tetrahedron 2006, 62 (25), 6018–6028. 13. Kim, J.-W. et al. Tetrahedron Lett. 2006, 47 (27), 4745–4748. 14. Nesi, M. et al. Bioorg. Med. Chem. Lett. 2006, 16 (12), 3205–3208. 15. Duval, R. A. et al. Tetrahedron 2006, 62 (26), 6248–6257. 16. Marastoni, M. et al. Bioorg. Med. Chem. Lett. 2006, 16 (12), 3125–3130. 17. Cui, P. et al. Bioorg. Med. Chem. Lett. 2006, 16 (13), 3401–3405. 18. Zajdel, P. et al. Bioorg. Med. Chem. Lett. 2006, 16 (13), 3406–3410. 19. Palmer, J. T. et al. Bioorg. Med. Chem. Lett. 2006, 16 (13), 3434–3439. 20. Wiethe, R. W. et al. Bioorg. Med. Chem. Lett. 2006, 16 (14), 3777–3779. 21. McCarthy, O. K. et al. Bioorg. Med. Chem. Lett. 2006, 16 (14), 3809–3812. 22. Ryge, T. S.; Hansen, P. R. Bioorg. Med. Chem. 2006, 14 (13), 4444–4451. 23. Xiao, K. et al. Bioorg. Med. Chem. 2006, 14 (13), 4535– 4551. 24. Xu, Z.-Q. et al. Bioorg. Med. Chem. 2006, 14 (13), 4610–4626. 25. Moreno, R. M. et al. Tetrahedron: Asymmetry 2006, 17 (7), 1089–1103. 26. Bradner, J. E. et al. Chem. Biol. 2006, 13 (5), 493–504.

Further reading Papers on combinatorial chemistry or solid-phase synthesis from other journals

Mitchell, J. M.; Shaw, J. T. A structurally diverse library of polycyclic lactams resulting from systematic placement of proximal functional groups. Angewandte Chemie, International Edition 2006, 45 (11), 1722–1726. de Bruin, B.; Hauwert, P.; Reek, J. N. H. Dynamic combinatorial chemistry: the unexpected choice of receptors by guest molecules. Angewandte Chemie, International Edition 2006, 45 (17), 2660–2663. Gross, G. A.; Mayer, G.; Albert, J.; Riester, D.; Osterodt, J.; Wurziger, H.; Schober, A. Spatially encoded single-bead biginelli synthesis in a microstructured silicon array. Angewandte Chemie, International Edition 2006, 45 (19), 3102–3106. Senaiar, R. S.; Young, D. D.; Deiters, A. Pyridines via solidsupported [2+2+2] cyclotrimerization. Chemical Communications (Cambridge, United Kingdom) 2006, 12, 1313–1315. Gonzalez-Alvarez, A.; Alfonso, I.; Gotor, V. Highly diastereoselective amplification from a dynamic combinatorial library of macrocyclic oligoimines. Chemical Communications (Cambridge, United Kingdom) 2006, 21, 2224–2226. Namuswe, F.; Goldberg, D. P. A combinatorial approach to minimal peptide models of a metalloprotein active site. Chemical Communications (Cambridge, United Kingdom) 2006, 22, 2326–2328. Zhang, W.; Lu, Y.; Chen, C. H.-T.; Curran, D. P.; Geib, S. Fluorous synthesis of hydantoin-, piperazinedione-, and benzodiazepinedione-fused tricyclic and tetracyclic ring systems. European Journal of Organic Chemistry 2006, 9, 2055–2059. Roettger, S.; Waldmann, H. Solid-phase synthesis of decalin scaffolds by robinson annulation with immobilised nazarov reagents. European Journal of Organic Chemistry 2006, 9, 2093–2099. Rivera, D. G.; Wessjohann, L. A. Supramolecular compounds from multiple Ugi multicomponent macrocyclizations: peptoid-based cryptands, cages, and cryptophanes. Journal of the American Chemical Society 2006, 128 (22), 7122–7123. Liu, X.-L.; Sheng, S.-R.; Wang, Q.-Y.; Sun, W.-K.; Xin, Q.; Ao, H.-Y. A facile solid-phase synthesis of vinyl ethers using a selenium traceless linker. Journal of Chemical Research 2006, 2, 118–120. Hwang, J. Y.; Gong, Y.-D. Solid-phase synthesis of the 2aminobenzoxazole library using thioether linkage as the safetycatch linker. Journal of Combinatorial Chemistry 2006, 8 (3), 297–303. Paulick, M. G.; Hart, K. M.; Brinner, K. M.; Tjandra, M.; Charych, D. H.; Zuckermann, R. N. Cleavable hydrophilic linker for one-bead-one-compound sequencing of oligomer libraries by tandem mass spectrometry. Journal of Combinatorial Chemistry 2006, 8 (3), 417–426. Montanari, V.; Kumar, K. Enabling routine fluorous capping in solid phase peptide synthesis. Journal of Fluorine Chemistry 2006, 127 (4–5), 565–570. Raghuraman, A.; Mosier, P. D.; Desai, U. R. Finding a needle in a haystack: development of a combinatorial virtual screening approach for identifying high specificity heparin/heparan sulfate sequence(s). Journal of Medicinal Chemistry 2006, 49 (12), 3553–3562. Bowman, M. D.; Jacobson, M. M.; Blackwell, H. E. Discovery of fluorescent cyanopyridine and deazalumazine dyes using small molecule macroarrays. Organic Letters 2006, 8 (8), 1645–1648. Leeuwenburgh, M. A.; Geurink, P. P.; Klein, T.; Kauffman, H. F.; Van der Marel, G. A.; Bischoff, R.; Overkleeft, H. S. Solidphase synthesis of succinylhydroxamate peptides: functionalized matrix metalloproteinase inhibitors. Organic Letters 2006, 8 (8), 1705–1708. D’Onofrio, J.; De Napoli, L.; Di Fabio, G.; Montesarchio, D. 2-(Phenylthio)ethyl as a novel two-stage base protecting group for thymidine analogues. Synlett 2006, 6, 845–848.