期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 20, 期 14, 页码 4279-4289出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2012.05.059
关键词
Anticancer drug; Benzophenone; Diketopiperazine; Microtubule depolymerizing activity; Vascular disrupting agent
资金
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan [23790143, 23390029]
- MEXT
- Japan Health Science Foundation
- Grants-in-Aid for Scientific Research [23790143, 23390029] Funding Source: KAKEN
KPU-105 (4), a potent anti-microtubule agent that contains a benzophenone was derived from the dike-topiperazine-type vascular disrupting agent (VDA) plinabulin 3, which displays colchicine-like tubulin depolymerization activity. To develop derivatives with more potent anti-microtubule and cytotoxic activities, we further modified the benzophenone moiety of 4. Accordingly, we obtained a 4-fluorobenzophenone derivative 16j that inhibited tumor cell growth in vitro with a subnanomolar IC50 value against HT-29 cells (IC50 = 0.5 nM). Next, the effect of 16j on mitotic spindles was evaluated in HeLa cells. Treatment with 3 nM of 16j partially disrupted the interphase microtubule network. By contrast, treatment with the same concentration of CA-4 barely affected the microtubule network, indicating that 16j exhibited more potent anti-mitotic effects than did CA-4. (C) 2012 Elsevier Ltd. All rights reserved.
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