title: Synthesis of epothilone analogues by antibody-catalyzed resolution of thiazole aldol synthons on a multigram scale. Biological consequences of C-13 alkylation of epothilones.
abstract: Three monoclonal aldolase antibodies (84G3, 85H6, and 93F3), generated against a beta-diketone hapten (II) by the reactive immunization technique, catalyzed highly enantioselective retro-aldol reactions of the racemic thiazole aldols 13-20. Antibody 84G3 (0.0004-0.005 mol%) was used to resolve (+/-)-13-(+/-)-18 to afford compounds 13-18 in multigram quantities. Multiple 13-alkyl analogues of epothilone (7-12) and their trans isomers ((E)-7-(E)-12) were synthesized starting from thiazole aldols 13-18. Construction of the trisubstituted olefin moiety in compounds 7-12 and (E)-7-(E)-12 was catalyzed by Grubbs' catalyst (X). Initial biological testing with compounds 7-10 and their trans isomers showed that compounds 9, 10, and (E)-10 have appreciable tubulin polymerization and antiproliferative activities that approached those of epothilone C. The most active compound, (E)-9, even displayed potencies comparable to those observed for epothilones A and D. Interestingly, all trans analogues were more potent than their corresponding cis isomers. While introduction of an alkyl group at C-13 in the cis series led to an overall reduction in biological activity (compared to epothilone C), appropriate modification of the thiazole moiety (replacement of the 2-methyl substituent by a 2-methylthio group) was able to compensate for this loss. These results are encouraging in view of the expectation that epoxidations of these compounds should further increase their cellular activities. Thus, compounds 9, 10, and (E)-9 and (E)-10 represent highly promising candidates for further studies.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. subhash@scripps.edu
authors.forename: S C
authors.initials: SC
authors.lastname: Sinha
authors.forename: J
authors.initials: J
authors.lastname: Sun
authors.forename: M
authors.initials: M
authors.lastname: Wartmann
authors.forename: R A
authors.initials: RA
authors.lastname: Lerner
mesh_terms: D000446:Aldehyde-Lyases / Q000737:chemistry / Q000276:immunology; D000478:Alkylation; D000818:Animals; D000906:Antibodies / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002384:Catalysis; D034261:Epothilones; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D013237:Stereoisomerism; D013552:Swine; D013844:Thiazoles / Q000737:chemistry*; D014404:Tubulin / Q000096:biosynthesis / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D034261:Epothilones; D007783:Lactones; D018942:Macrolides; D013844:Thiazoles; D014404:Tubulin; C426624:epothilone C; D000446:Aldehyde-Lyases