Synthesis and Structure–Activity Relationship Study of Antimicrotubule Agents Phenylahistin Derivatives with a Didehydropiperazine-2,5-dione Structure
| Autor: | Akiko Oda, Gordafaried Deyanat-Yazdi, Brian R. Miller, Takayoshi Kitagawa, Yoshio Hayashi, Takeo Usui, Barbara C. M. Potts, Sumie Orikasa, Yoshiaki Kiso, Yuki Shinozaki, Takumi Chinen, Yuri Yamazaki, Fumika Yakushiji, Miki Akamatsu, Saskia T. C. Neuteboom, G. K. Lloyd, Kaneo Kanoh, Benjamin Nicholson, Hiroyuki Yasui, Koji Tanaka, Michael A. Palladino, Tomoko Yoshida |
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| Rok vydání: | 2012 |
| Předmět: |
Stereochemistry
Molecular Conformation Quantitative Structure-Activity Relationship Antineoplastic Agents Diketopiperazines Crystallography X-Ray chemistry.chemical_compound Derivative (finance) Drug Discovery Human Umbilical Vein Endothelial Cells Benzophenone Humans Cytotoxic T cell Phenyl group Structure–activity relationship biology Depolymerization Cell Cycle Imidazoles Stereoisomerism Tubulin Modulators Tubulin chemistry biology.protein Molecular Medicine Drug Screening Assays Antitumor HT29 Cells HeLa Cells Plinabulin |
| Zdroj: | Journal of Medicinal Chemistry. 55:1056-1071 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm2009088 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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