Design, synthesis, and biological evaluation of artificial macrosphelides in the search for new apoptosis-inducing agents

Various artificial macrosphelides were designed and synthesized, including ring-enlarged analogues and epothilone-hybrid compounds. Syntheses were accomplished in an efficient manner by using a ring-closing metathesis (RCM) strategy in a key macro-cyclization step. Biological evaluation of these new macrosphelide-based de- rivatives revealed that several epothi-lone hybrids, in which a thiazole-con-taining side chain was incorporated, exhibited potent apoptosis-inducing activ- ity toward human lymphoma cells. These activities were considerably enhanced relative to those of natural macrosphelide compounds. Structure-activity relationship studies revealed that the "ene- dicarbonyl" substructure is apparently essential for bioactivity.