Synthesis and Structure-Activity Relationship Study of Antimicrotubule Agents Phenylahistin Derivatives with a Didehydropiperazine-2,5-dione Structure
Synthesis and Structure-Activity Relationship Study of Antimicrotubule Agents Phenylahistin Derivatives with a Didehydropiperazine-2,5-dione Structure
复制标题
DOI：
10.1021/jm2009088
复制
发表时间：
2012-02-09
影响因子：
7.3
通讯作者：
Hayashi, Yoshio
中科院分区：
文献类型：
--
作者：
Yamazaki, Yuri;Tanaka, Koji;Hayashi, Yoshio
普那布林（11，NPI-2358）是一种有效的微管靶向药物，来源于天然二酮哌嗪“苯基组氨酸”（1），具有秋水仙碱样微管蛋白解聚活性。化合物11最近被开发为VDA，目前正作为抗癌药物进行II期临床试验。为了开发更有效的基于二脱氢DKP骨架的抗微管和细胞毒性衍生物，我们对11的叔丁基或苯基基团进行了进一步的修饰，并评估了它们的细胞毒性和微管蛋白结合活性。在SAR研究中，我们开发了具有2，5-二氟苯基的更有效的衍生物33和具有活性的50，33和50表现出最低的有效浓度。33和50的值比具有血管破坏和二苯甲酮代替苯基的第二代衍生物的效力高5倍和10倍。2和1 nM的抗HuVEC分别用于微管解聚。分别是CA-4。这些衍生物可能具有很好的细胞毒活性。
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 activity of 33 and 50 exhibited a lowest effective concentration The values of 33 and 50 were 5 and 10 times more potent than second-generation derivative with both vascular disrupting and a benzophenone in place of the phenyl group. The anti-HuVEC of 2 and 1 nM for microtubule depolymerization, respectively. that of CA-4, respectively. These derivatives could be a valuable cytotoxic activities.