Design, synthesis, and biological evaluation of combretastatin nitrogen-containing derivatives as inhibitors of tubulin assembly and vascular disrupting agents
Design, synthesis, and biological evaluation of combretastatin nitrogen-containing derivatives as inhibitors of tubulin assembly and vascular disrupting agents
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DOI：
10.1016/j.bmc.2005.12.033
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发表时间：
2006-05-01
影响因子：
3.5
通讯作者：
Pinney, KG
中科院分区：
文献类型：
--
作者：
Monk, KA;Siles, R;Pinney, KG
合成了一系列在考布他汀 A-4 (CA4) B 环的 C-2'-、C-5'- 或 C-C-位置上具有硝基或丝氨酰胺取代基的类似物，并评估了其对心脏内皮瘤细胞的细胞毒性作用、SCID 小鼠肿瘤的血流量减少以及作为微管蛋白聚合抑制剂的作用。这些类似物的合成通常以适当官能化的芳醛和芳基鏻盐之间的 Wittig 反应为特征，然后分离所得的 F 和 Z-异构体。其中一些氮修饰的 CA4 衍生物（氨基和硝基）表现出对微管蛋白组装的显着抑制以及细胞毒性和体内血流量减少。 2'-氨基芪类7和2'-氨基-3'-羟基芪类29被证明是该系列中最活跃的。化合物 7 和 29 都具有进一步前药修饰和开发作为治疗实体瘤癌症和某些眼科疾病的血管破坏剂的潜力。 (c) 2006 Elsevier Ltd. 保留所有权利。
A series of analogs with nitro or serinamide substituents at the C-2'-, C-5'-, or C-C-position of the combretastatin A-4 (CA4) B-ring was synthesized and evaluated for cytotoxic effects against heart endothelioma cells, blood flow reduction to tumors in SCID mice, and as inhibitors of tubulin polymerization. The synthesis of these analogs typically featured a Wittig reaction between a suitably functionalized arylaldehyde and an arylphosphonium salt followed by separation of the resultant F and Z-isomers. several of these nitrogen-modified CA4 derivatives (both amino and nitro) demonstrate significant inhibition of tubulin assembly as well as cytotoxicity and in vivo blood flow reduction. 2'-Aminostilbenoid 7 and 2'-amino-3'-hydroxystilbenoid 29 proved to be the most active in this series. Both compounds, 7 and 29, have the potential for further pro-drug modification and development as vascular disrupting agents for treatment of solid tumor cancers and certain ophthalmological diseases. (c) 2006 Elsevier Ltd. All rights reserved.