Chemical synthesis and biological evaluation of novel epothilone B and trans-12,13-cyclopropyl epothilone B analogues

In addition to the total synthesis of the thiomethyl thiazole side chain analogue of epothilone B (3), a series of related trans-12,13-cyclopropyl epothilone B analogues (6, 8, 10, 12-14) was accomplished. While the synthesis of the epothilone B analogue (3) proceeded through a Stille coupling of a vinyl iodide substrate containing the epothilone macrocycle with the appropriate side chain stannane, that of the cyclopropyl analogues (6, 8, 10, 12-14) involved a convergent strategy in which a Nozaki-Hiyama-Kishi coupling as a means of introducing the side chains prior to Yamaguchi macrolactonization and final elaboration to the target molecules. The synthesized analogues were subjected to biological evaluation involving in vitro tubulin polymerization, affinity for the microtubule Taxol(R) binding site and cell cytotoxicity assays. The results identified the methylthio thiazole side chain as a potency enhancing moiety for the epothilones and shed further light on the structure-activity relationships within this important class of chemotherapeutic agents. (C) 2002 Elsevier Science Ltd. All rights reserved.