Synthesis and structure-activity relationships of benzophenone-bearing diketopiperazine-type anti-microtubule agents.
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.
Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
Yuri
Y
Yamazaki
Makiko
M
Sumikura
Yurika
Y
Masuda
Yoshiki
Y
Hayashi
Hiroyuki
H
Yasui
Yoshiaki
Y
Kiso
Takumi
T
Chinen
Takeo
T
Usui
Fumika
F
Yakushiji
Barbara
B
Potts
Saskia
S
Neuteboom
Michael
M
Palladino
George Kenneth
GK
Lloyd
Yoshio
Y
Hayashi
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001577:Benzophenones / Q000138:chemical synthesis / Q000737:chemistry*; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000737:chemistry; D018360:Crystallography, X-Ray; D054659:Diketopiperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D008870:Microtubules / Q000737:chemistry* / Q000378:metabolism; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity
D000970:Antineoplastic Agents; D001577:Benzophenones; D054659:Diketopiperazines; D050257:Tubulin Modulators; C047723:benzophenone; D003078:Colchicine