Synthesis and structure-activity relationship study of antimicrotubule agents phenylahistin derivatives with a didehydropiperazine-2,5-dione structure

J Med Chem. 2012 Feb 9;55(3):1056-71. doi: 10.1021/jm2009088.

Yuri Yamazaki ¹, Koji Tanaka, Benjamin Nicholson, Gordafaried Deyanat-Yazdi, Barbara Potts, Tomoko Yoshida, Akiko Oda, Takayoshi Kitagawa, Sumie Orikasa, Yoshiaki Kiso, Hiroyuki Yasui, Miki Akamatsu, Takumi Chinen, Takeo Usui, Yuki Shinozaki, Fumika Yakushiji, Brian R Miller, Saskia Neuteboom, Michael Palladino, Kaneo Kanoh, George Kenneth Lloyd, Yoshio Hayashi

Affiliations

Affiliation

1 Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.

PMID: 22185476 DOI: 10.1021/jm2009088

Abstract

Plinabulin (11, NPI-2358) is a potent microtubule-targeting agent derived from the natural diketopiperazine "phenylahistin" (1) with a colchicine-like tubulin depolymerization activity. Compound 11 was recently developed as VDA and is now under phase II clinical trials as an Anticancer drug. To develop more potent antimicrotubule and cytotoxic derivatives based on the didehydro-DKP skeleton, we performed further modification on the tert-butyl or phenyl groups of 11, and evaluated their cytotoxic and tubulin-binding activities. In the SAR study, we developed more potent derivatives 33 with 2,5-difluorophenyl and 50 with a benzophenone in place of the phenyl group. The anti-HuVEC activity of 33 and 50 exhibited a lowest effective concentration of 2 and 1 nM for microtubule depolymerization, respectively. The values of 33 and 50 were 5 and 10 times more potent than that of CA-4, respectively. These derivatives could be a valuable second-generation derivative with both vascular disrupting and cytotoxic activities.

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