Combinatorial Chemistry Online

Combinatorial Chemistry - An Online Journal 15 (2013) 5–7

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Combinatorial Chemistry - An Online Journal journal homepage: www.elsevier.com/locate/comche

Combinatorial Chemistry Online Volume 15, Issue 2, February 2013 N.K. Terrett ⇑ Ensemble Therapeutics Corp., Cambridge, MA 02139, USA

1. Current literature highlights O

1.1. Mu selective opioid receptor ligands from a cyclic peptide library Cyclic peptides offer a number of advantages as potential therapeutic agents over their linear analogues. They can have enhanced binding affinity and selectivity, but of greater importance is their metabolic stability, as they are less vulnerable to proteases compared with the linear peptides. However, making cyclic peptides can be challenging, primarily because of the preference for Egeometry in the peptide bonds. A recent paper describes the synthesis of a positional scanning cyclic peptide library that uses a new imidazole-promoted cyclisation reaction.1 Positional scanning libraries are usually created in a number of sub-library mixtures in which an amino acid residue is held constant at a particular position within the peptide. The library is screened as individual mixtures, and the mixtures with the greatest potency are used as indicators for which residues are contributing most actively to binding. This particular library was synthesised with an anthraniloyl group on the R3 position, as this is a well characterised fluorescent probe with a relatively high quantum yield at 415 nm following excitation at 330 nm. A model cyclic peptide (1) was prepared using solid-phase synthesis on a mercaptomethylphenyl-functionalised silica support. Cleavage from the solid support was achieved by treating with anhydrous hydrogen fluoride and following removal of the HF under a nitrogen stream and lyophilisation, cyclisation of the peptide was achieved with a solution of acetonitrile and 1.5 M imidazole. The model cyclic peptide (1) was isolated in over 80% yield with less than 8% of the linear hydrolysis by-product and 7% of the linear precursor.

HOOC

NH

HN

NH

O Me

O

HN

O

O O

Me

N H

NH

1

H2N

The positional scanning library (2) was prepared using the same synthetic route. Position 1 was fixed as glycine, and position 3 was fixed as diaminopropionic acid with anthranilic acid attached to the 3-amino group. Positions 2 and 4 represented 36 different Land D-amino acids, and position 5 was represented by 19 different L-amino acids. The library was constructed in 91 individual mixtures – each mixture comprised 684 (19  36) cyclic peptides when position 2 or 4 was fixed, and 1296 (36  36) cyclic peptides when position 5 was fixed.

O

R5

NH

HN

O R2 NH

O HN R4

O O

N H

NH

2

O H2N

⇑ Tel.: +1 617 492 6977x225. E-mail address: [email protected] http://dx.doi.org/10.1016/j.comche.2012.12.001

Each mixture within the library was screened at a concentration of 1 mg/mL in a competitive radio receptor binding assay against the mu receptor. Several mixtures showed appreciable binding,

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N.K. Terrett / Combinatorial Chemistry - An Online Journal 15 (2013) 5–7

and key contributory amino acids were identified in each variable position of the cyclic peptide. Making the combinations of the preferred amino acids required the synthesis of 40 individual cyclic peptides and the most active combination (3) with a Ki value of 16 nM at the mu opioid receptor had L-tyrosine at R2, D-lysine at R4 and L-tyrosine at R5. As this compound provides the possibility of cyclisation onto the lysine side-chain, the side-chain to tail cyclised product was also prepared (4) and found to be a marginally more active fluorescent mu opioid receptor ligand.

O NH

HN

O

NH

O HN

O N H

O

H2N HO

NH

2.3. Scaffolds and synthons for combinatorial libraries

3

H2N

O H2N

O

NH

O

HN NH

O HN

4

2.2. Solution-phase synthesis A gold-catalysed regioselective heteroannulation strategy has been developed for the concise and efficient synthesis of imidazo[1,2-a]pyrazinones. The protocol allows the introduction of diversity via the application of substituted propargyl amines or via Suzuki coupling of the generated imidazo[1,2-a]pyrazinones with various (het)aryl boronic acids.4 An efficient protocol for the syntheses of diverse 2,6,7- and 2,6,9-trisubstituted purines has been reported starting from the guanine precursor, 2-amino-6-chloropurine nucleoside, through subsequent regioselective, high yielding Mitsunobu coupling and nucleophilic substitutions with versatile primary and secondary amines.5

OH

HO

regioselective c-arylation. The cinnamylamine products are cleaved from the resin with trifluoroacetic acid under mild conditions and are converted into chromatographically separable acetamides. This solid-phase method offers a new alternative for the synthesis of cinnamylamine derivatives as biologically interesting compounds and useful synthetic intermediates.3

NH

O

N H

O OH

O H2N

This approach has rapidly prepared a library of cyclic peptides and identified useful fluorescent ligands to the mu opioid receptor, and holds promise for other libraries and pharmacological targets. 2. A summary of the papers in this month’s issue 2.1. Polymer supported synthesis An orthogonal protecting group strategy has been devised for the automated solid-phase synthesis of hydroxamic acid-containing peptides for biomimetic histone deacetylase (HDAC) inhibition. The basic building block was a protected aminosuberic acid derivative bearing a protected hydroxamate in the side-chain, related closely to HDAC inhibitors that are transition-state analogues of acetyllysine. This strategy was employed to synthesise a series of nonameric peptides related to actual HDAC substrates, and suggests a new class of HDAC inhibitors that may have enhanced selectivity for specific HDAC isoforms.2 The Heck reaction of Wang resin-bound allylamine with aryl iodides produces various, substituted cinnamylamines. The catalyst and additive system employed for this chemistry consisted of palladium(II) acetate, n-Bu4NOAc and potassium chloride, in addition to potassium carbonate in N,N-dimethylformamide, producing a

Synthesis of D-threo-hydroxyaspartic acid, orthogonally protected and compatible with an Fmoc solid-phase peptide synthesis strategy has been reported. This synthetic procedure started from (2R,3R)-dimethyltartrate and is adaptable to a multi-gram scale.6 A number of unique enantiopure polycyclic alkaloid-like scaffolds can be prepared on a multigram scale in only a few steps from a common, commercially available intermediate. The attached nitromethyl group can then be used as a handle for the construction of highly diverse functionalised libraries suitable for screening against biological targets of interest.7 2.4. Solid-phase supported reagents Palladium nanoparticles have been successfully immobilised on amine functionalised ionic liquid modified magnetic nanoparticles leading to a magnetically recoverable Pd catalyst. This catalyst exhibits high catalytic activity in the Suzuki coupling reaction at room temperature and can be separated from the reaction mixture by applying a permanent magnet externally and reused several times without significant loss of activity.8 An efficient synthesis of biaryls using a Hiyama reaction between aryl iodides and aryltrialkoxysilanes in the presence of a diphenylphosphinomethylpolystyrene-supported palladium catalyst has been described. The cross-coupling proceeds in the presence of only 0.1 mol% of supported palladium, and the catalyst can be used at least four times as the palladium leaching is extremely low.9 2.5. Novel resins, linkers and techniques No papers this month. 2.6. Library applications The discovery and SAR of a novel series of non-MPEP site metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) based on an aryl glycine sulphonamide scaffold has been reported. This series represents a rare non-MPEP site mGlu5 PAM chemotype. From this study, an unprecedented mGlu5 PAM chemotype with potent activity was discovered that is amenable to chemical optimisation via an iterative library approach.10

N.K. Terrett / Combinatorial Chemistry - An Online Journal 15 (2013) 5–7

As part of a research program aimed at discovering new antimalarial leads from Australian macrofungi, a unique fungi-derived prefractionated library was screened against a chloroquinesensitive Plasmodium falciparum line using a radiometric growth inhibition assay. A library fraction derived from a Cortinarius species displayed promising antimalarial activity and one isolated compound was used as a natural product scaffold in the parallel solution-phase synthesis of a small library of N-substituted tetrahydroanthraquinones.11 A lead compound, (E)-3-(4-chlorophenyl)-2-(1H-pyrrole-2carbonyl)acrylonitrile, that induced 50% growth inhibition of 11 cancer cell lines at 27–61 lM, was used as the starting point for the synthesis of a series of focused compound libraries. Six highly focused libraries (46 compounds in total) were synthesised and each allowed the identification of a new lead compound.12 Thiopeptide antibiotics exhibit a profound level of chemical diversity that is installed through cascades of posttranslational modifications on ribosomal peptides. A technique to rapidly explore the chemical space of the thiopeptide GE37468 through codon randomisation, yielding insights into thiopeptide maturation as well as structure and activity relationships has been reported. In this study, seven residues of the prepeptide-coding region were randomised, enabling the generation of 133 potential thiopeptide variants.13

References 1. Li Y, Dooley CT, Misler JA, Debevec G, Giulianotti MA, Cazares ME, et al. Fluorescent mu selective opioid ligands from a mixture based cyclic peptide library. ACS Comb Sci 2012;14(12):673–9. 2. Wilson DM, Silverman LN, Bergauer M, Keshari KR. Solid phase synthesis of hydroxamate peptides for histone deacetylase inhibition. Tetrahedron Lett 2013;54(2):151–3. 3. Leikoski T, Wrigstedt P, Helminen J, Matikainen J, Sipilä J, Yli-Kauhaluoma J. The Heck reaction of polymer-supported allylamine with aryl iodides. Tetrahedron 2013;69(2):839–43. 4. Vachhani DD, Modha SG, Sharma A, Van der Eycken EV. A facile diversity-oriented synthesis of imidazo1,2-apyrazinones via gold-catalyzed regioselective heteroannulation of propynylaminopyrazinones. Tetrahedron 2013;69(1):359–65. 5. Manvar A, Shah A. Diversity oriented efficient access of trisubstituted purines via sequential regioselective Mitsunobu coupling and SNAr based C6 functionalizations. Tetrahedron 2013;69(2):680–91. 6. Boyaud F, Viguier B, Inguimbert N. Synthesis of a protected derivative of (2R,3R)b-hydroxyaspartic acid suitable for Fmoc-based solid phase synthesis. Tetrahedron Lett 2013;54(2):158–61. 7. Go DA. Diverse alkaloid-like structures from a common building block. Tetrahedron 2013;69(1):242–56. 8. Wang J, Xu B, Sun H, Song G. Palladium nanoparticles supported on functional ionic liquid modified magnetic nanoparticles as recyclable catalyst for room temperature Suzuki reaction. Tetrahedron Lett 2013;54(3):238–41. 9. Diebold C, Derible A, Becht J-M, Le Drian C. A simple and efficient reusable polystyrene-supported palladium catalyst for Hiyama cross-coupling. Tetrahedron 2013;69(1):264–7. 10. Rodriguez AL, Zhou Y, Williams R, Weaver CD, Vinson PN, Dawson ES, et al. Discovery and SAR of a novel series of non-MPEP site mGlu5 PAMs based on an aryl glycine sulfonamide scaold. Bioorg Med Chem Lett 2012;22(24):7388–92. 11. Choomuenwai V, Andrews KT, Davis RA. Synthesis and antimalarial evaluation of a screening library based on a tetrahydroanthraquinone natural product scaold. Bioorg Med Chem 2012;20(24):7167–74. 12. Tarleton M, Dyson L, Gilbert J, Sako JA, McCluskey A. Focused library development of 2-phenylacrylamides as broad spectrum cytotoxic agents. Bioorg Med Chem 2013;21(1):333–47. 13. Young TS, Dorrestein PC, Walsh CT. Codon randomization for rapid exploration of chemical space in thiopeptide antibiotic variants. Chem Biol 2012;19(12):1600–10.

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Further Reading Papers on combinatorial chemistry or solid-phase synthesis from other journals van der Wer LC, Robinson AJ, Kyratzis IL. Combinatorial approach for the rapid determination of thermochromic behavior of binary and ternary cholesteric liquid crystalline mixtures. ACS Comb Sci 2012;14(11):605–12. Rentsch D, Staehelin C, Obkircher M, Hany R, Simeunovic M, Samson D, et al. Quantitative assessment of preloaded 4-alkoxybenzyl alcohol resins for solid phase peptide syntheses by 1D and 2D HR-MAS NMR. ACS Comb Sci 2012;14(11):613–20. Ryabukhin SV, Panov DM, Plaskon AS, Grygorenko OO. Approach to the library of 3hydroxy-1,5-dihydro-2H-pyrrol-2-ones through a three-component condensation. ACS Comb Sci 2012;14(12):631–5. Lemrova B, Soural M. Solid-phase synthesis of 4,7,8-trisubstituted 1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ones. ACS Comb Sci 2012;14(12):645–50. Fulopova V, Gucky T, Grepl M, Soural M. Solid-phase synthesis of trisubstituted benzo[1,4]-diazepin-5-one derivatives. ACS Comb Sci 2012;14(12):651–6. Sanders AM, Dawidczyk TJ, Katz HE, Tovar JD. Peptide-based supramolecular semiconductor nanomaterials via Pd-catalyzed solid-phase ‘‘dimerizations’’. ACS Macro Lett 2012;1(11):1326–9. Khoury K, Sinha MK, Nagashima T, Herdtweck E, Doemling A. Efficient assembly of iminodicarboxamides by a ‘‘truly’’ four-component reaction. Angew Chem Int Ed 2012;51(41):10280–3. Pan X, Yi F, Zhang X, Chen S. Synthesis of amino chalcones in presence of ionic liquid as soluble support. Asian J Chem 2012;24(9):3809–13. Devpura A, Singh JP, Jaitawat N, Rathore R, Kumawat M, Dulawat SS. Microwave assisted synthesis, spectral studies and antibacterial activity of 1,5-benzodiazepines derivatives on a solid surface. Asian J Chem 2012;24(12):5914–6. Gupta N, Singh M. Microwave assisted high speed chemistry, a new technology for pharmaceutical industry. Asian J Chem 2012;24(12):5937–8. Knepper K, Vanderheiden S, Braese S. Synthesis of diverse indole libraries on polystyrene resin – scope and limitations of an organometallic reaction on solid supports. Beilstein J Org Chem 2012;8:1191–9. Fenster E, Hill D, Reiser O, Aube J. Automated three-component synthesis of a library of c-lactams. Beilstein J Org Chem 2012;8:1804–13. Yin J, Eller S, Collot M, Seeberger PH. Acylsulfonamide safety-catch linker: promise and limitations for solid-phase oligosaccharide synthesis. Beilstein J Org Chem 2012;8:2067–71. Nagata S, Takagaki K, Wada T. Improved method for the solid-phase synthesis of oligoribonucleotide 50 -triphosphates. Chem Pharm Bull 2012;60(9):1212–5. Kolesinska B, Kasperowicz-Frankowska K, Fraczyk J, Kaminski ZJ. Enantioselective solid-phase peptide synthesis using traceless chiral coupling reagents and racemic amino acids. Helv Chim Acta 2012;95(11):2084–98. Cardenal C, Vollrath SBL, Schepers U, Braese S. Synthesis of functionalized glutamineand asparagine-type peptoids – scope and limitations. Helv Chim Acta 2012;95(11):2237–48. Sandhya K, Ravindranath B. Comparative efficacy of polyamine-based scavenger resins. Int J Org Chem 2012;2(1):71–4. Cavallaro CL, Briceno S, Chen J, Cvijic ME, Davies P, Hynes Jr J, et al. Discovery and lead optimization of a novel series of CC chemokine receptor 1 (CCR1)-selective piperidine antagonists via parallel synthesis. J Med Chem 2012;55(22):9643–53. van de Langemheen H, Brouwer AJ, Kemmink J, Kruijtzer JAW, Liskamp RMJ. Synthesis of cyclic peptides containing a thioester handle for native chemical ligation. J Org Chem 2012;77(22):10058–64. Pinczewska A, Sosna M, Bloodworth S, Kilburn JD, Bartlett PN. High-throughput synthesis and electrochemical screening of a library of modified electrodes for NADH oxidation. J Am Chem Soc 2012;134(43):18022–33. Cougnon FBL, Ponnuswamy N, Jenkins NA, Pantos GD, Sanders JKM. Structural parameters governing the dynamic combinatorial synthesis of catenanes in water. J Am Chem Soc 2012;134(46):19129–35. Ryabukhin SV, Panov DM, Plaskon AS, Chuprina A, Pipko SE, Tolmachev AA, et al. Combinatorial synthesis of chemical building blocks: 1. Azomethines. Mol Divers 2012;16(4):625–37. Cortes E, Mendez L, Mata EG, Abonia R, Quiroga J, Insuasty B. Synthesis of 3-aryl-1,2,4benzotriazines via intramolecular cyclization of solid-supported o-hydrazidoanilines. Mol Divers 2012;16(4):839–46. Diaz-Rodriguez V, Mullen DG, Ganusova E, Becker JM, Distefano MD. Synthesis of peptides containing C-terminal methyl esters using trityl side-chain anchoring: application to the synthesis of a-factor and a-factor analogs. Org Lett 2012;14(22):5648–51. Xiao Y-C, Zhou Q-Q, Dong L, Liu T-Y, Chen Y-C. Asymmetric Diels–Alder reaction of 2methyl-3-indolylmethanols via in situ generation of o-quinodimethanes. Org Lett 2012;14(23):5940–3.