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.

Prodrugs of dynemicin analogs for selective chemotherapy mediated by an aldolase catalytic Ab

“…The highly promiscuous binding sites of 38C2 allowed production of a wide variety of aldol compounds. (19) Reactions were amenable to large-scale production of the aldol compounds (20,21), which allowed multistep synthesis of natural products and their analogs (22)(23)(24). In general, 38C2-catalyzed aldol and retro-aldol reactions provided compounds with very high enantiomeric purity.…”

Catalytic Antibody Route to the Naturally Occurring Epothilones: Total Synthesis of Epothilones A-F

“…Following the reported procedure by Grubbs,32a catalyst VII was synthesized which was proven to be fairly stable to air and moisture. Recently, we have used VII as a RCM catalyst for the synthesis of 13‐alkyl epothilones 33. Using the catalyst VII , metathesis of 32 and 34 in refluxing CH 2 Cl 2 was successfully achieved to afford the mixture of cyclized olefins 36 and 38 , and their respective trans isomers in a ratio of 1.1:1 in favor of 36 and 38 .…”

The Epothilones: An Outstanding Family of Anti-Tumor Agents

“…In addition, several other fragment syntheses have been reported (119)(120)(121)(122)(123)(124)(125), which are not discussed in detail. Epothilones E and F (1c,1d) and Their 12,2d) …”

“…However, the data by Sinha on C13-modified Epo C analogs (120) clearly demonstrate that increased steric bulk at C13 is associated with reduced potency and this may be a major reason for the strongly diminished potency of analogs such as VI-31-VI-33. In light of these findings Altmann and co-workers have continued to explore the potential utility of nitrogen incorporation at position 12 of the macrocycle, as a functional handle for further substitution, without concomitant modification of C13.…”