Synthesis and structure-activity relationships of benzophenone-bearing diketopiperazine-type anti-microtubule agents.

Abstract

KPU-105 (4), a potent anti-microtubule agent that contains a benzophenone was derived from the diketopiperazine-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 IC(50) value against HT-29 cells (IC(50)=0.5 nM). Next, the effect of 16j on mitotic spindles was evaluated in HeLa cells. Treatment with 3nM 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.

• Authors: Yuri Yamazaki, Makiko Sumikura, Yurika Masuda, Yoshiki Hayashi, Hiroyuki Yasui, Yoshiaki Kiso, Takumi Chinen, Takeo Usui, Fumika Yakushiji, Barbara Potts, Saskia Neuteboom, Michael Palladino, George Kenneth Lloyd, Yoshio Hayashi
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 20 Issue 14 Pg. 4279-89 (Jul 15 2012) ISSN: 1464-3391 [Electronic] England
• PMID: 22727370 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Benzophenones
• Diketopiperazines
• Tubulin Modulators
• benzophenone
• Colchicine

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, toxicity)
• Benzophenones (chemical synthesis, chemistry)
• Cell Proliferation (drug effects)
• Colchicine (chemistry)
• Crystallography, X-Ray
• Diketopiperazines (chemical synthesis, chemistry, toxicity)
• HT29 Cells
• HeLa Cells
• Humans
• Microtubules (chemistry, metabolism)
• Molecular Conformation
• Structure-Activity Relationship
• Tubulin Modulators (chemical synthesis, chemistry, toxicity)