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Design, Synthesis, and Biological Evaluation of Artificial Macrosphelides in the Search for New Apoptosis‐Inducing Agents
Author(s) -
Matsuya Yuji,
Kobayashi Yuta,
Kawaguchi Takanori,
Hori Ayana,
Watanabe Yuka,
Ishihara Kentaro,
Ahmed Kanwal,
Wei ZhengLi,
Yu DaYong,
Zhao QingLi,
Kondo Takashi,
Nemoto Hideo
Publication year - 2009
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200802661
Subject(s) - thiazole , epothilone , stereochemistry , chemistry , apoptosis , combinatorial chemistry , ring closing metathesis , biological activity , natural product , metathesis , biochemistry , organic chemistry , in vitro , polymerization , polymer
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.