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

来自 EBSCO

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摘要：

A drug of two halves: New artificial compounds composed of a macrosphelide core skeleton and an epothilone side chain were designed and synthesized. These compounds were more potent inducers of apoptosis than the parent natural-type macrosphelides.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 macrocyclization step. Biological evaluation of these new macrosphelide-based derivatives revealed that several epothilone hybrids, in which a thiazole-containing side chain was incorporated, exhibited potent apoptosis-inducing activity 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.

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关键词：

anticancer agents apoptosis epothilones macrosphelides metathesis

DOI：

10.1002/chem.200802661

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年份：

2010