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 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.
Matsuya
Yuji
Y
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. matsuya@pha.u-toyama.ac.jp
Kobayashi
Yuta
Y
Kawaguchi
Takanori
T
Hori
Ayana
A
Watanabe
Yuka
Y
Ishihara
Kentaro
K
Ahmed
Kanwal
K
Wei
Zheng-Li
ZL
Yu
Da-Yong
DY
Zhao
Qing-Li
QL
Kondo
Takashi
T
Nemoto
Hideo
H
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D003500:Cyclization; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D034261:Epothilones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry
D000970:Antineoplastic Agents; D034261:Epothilones; D013844:Thiazoles