Synthesis and Structure–Activity Relationship Study of Antimicrotubule Agents Phenylahistin Derivatives with a Didehydropiperazine-2,5-dione Structure
| العنوان: | Synthesis and Structure–Activity Relationship Study of Antimicrotubule Agents Phenylahistin Derivatives with a Didehydropiperazine-2,5-dione Structure |
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| المؤلفون: | 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 |
| المصدر: | Journal of Medicinal Chemistry. 55:1056-1071 |
| بيانات النشر: | American Chemical Society (ACS), 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| تدمد: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm2009088 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e08db2de8e15dab780cbc1ea466ba863 https://doi.org/10.1021/jm2009088 |
| رقم الانضمام: | edsair.doi.dedup.....e08db2de8e15dab780cbc1ea466ba863 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
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| DOI: | 10.1021/jm2009088 |