Synthesis and biological evaluation of a novel class of isatin analogs as dual inhibitors of tubulin polymerization and Akt pathway.
Synthesis and biological evaluation of a novel class of isatin analogs as dual inhibitors of tubulin polymerization and Akt pathway.
复制标题
DOI：
10.1016/j.bmc.2011.08.044
复制
发表时间：
2011-10-15
影响因子：
3.5
通讯作者：
Amin, Shantu
中科院分区：
文献类型：
--
作者：
Krishnegowda, Gowdahalli;Gowda, A. S. Prakasha;Tagaram, Hephzibah Rani S.;Carroll, Kevin F. Staveley-O';Irby, Rosalyn B.;Sharma, Arun K.;Amin, Shantu
合成了一系列新的5，7-二溴吲哚类似物，并评价了它们对结肠癌HT29、乳腺MCF-7、肺A549和黑色素瘤UACC903等四种人癌细胞的细胞毒作用。化合物6、11和13在1µM范围内对HT29人结肠癌细胞株表现出良好的体外抗癌活性。类似物5、9和12在烷基上含有一个硒氰酸酯基团，是对乳腺癌MCF-7细胞株最有希望的化合物。通过与细胞凋亡相关的生物学检测来了解这些类似物的作用机制。化合物5和6对微管蛋白聚合的抑制作用与抗癌药物硫酸长春花碱相同，但化合物11和13的抑制作用明显强于长春花碱。进一步的蛋白质印迹分析表明，化合物6在2µM时降低了Akt的水平和磷酸化状态。化合物11和13在1µM时引起Akt蛋白水平降低，并强烈抑制Akt的磷酸化。因此，11和13被证明是微管蛋白聚合和Akt途径的有效双重抑制剂，是进一步研究的良好候选者。更重要的是，微管和Akt双重抑制剂的策略可能是开发抗癌新药的一个有前途的方向。
A novel series of 5,7-dibromoisatin analogs were synthesized and evaluated for their cytotoxicities against four human cancer cell lines including colon HT29, breast MCF-7, lung A549 and melanoma UACC903. Analogs 6, 11 and 13 displayed good in vitro anticancer activity on the HT29 human colon cancer cell line in the 1 µM range. Analogs 5, 9 and 12, containing a selenocyanate group in the alkyl chain were the most promising compounds on the breast cancer MCF-7 cell line. Biological assays relating to apoptosis were performed to understand the mechanism of action of these analogs. Compounds 5 and 6 were found to inhibit tubulin polymerization to the same extent as the anticancer drug vinblastine sulfate, but compounds 11 and 13 inhibited significantly better than vinblastine. Further western blot analysis suggested that compound 6 at 2 µM reduced both levels and phosphorylation state of Akt. Compounds 11 and 13 at 1 µM caused reduced Akt protein levels and strongly suppressed the phosphorylation of Akt. Therefore, 11 and 13 were demonstrated as efficient dual inhibitors of both tubulin polymerization and the Akt pathway and good candidates for further study. More importantly, the strategy of microtubule and Akt dual inhibitors might be a promising direction for developing novel drugs for cancer.
登录
查看更多内容
影响因子：
5.7
作者：
Madhunapantula, SubbaRao V.;Desai, Dhimant;Robertson, Gavin P.
通讯作者：
Robertson, Gavin P.
影响因子：
4.7
作者：
Hu, HB;Jiang, C;Lü, JX
通讯作者：
Lü, JX
DOI：
10.2174/1568011023354290
发表时间：
2002-01-01
期刊：
Current Medicinal Chemistry - Anti-Cancer Agents
影响因子：
--
作者：
Jordan, M. A.
通讯作者：
Jordan, M. A.
影响因子：
4.8
作者：
Chen, YR;Wang, WF;Tan, TH
通讯作者：
Tan, TH
DOI：
10.1139/o04-130
发表时间：
2005-04-01
期刊：
BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE
影响因子：
--
作者：
Bandura, L;Drukala, J;Korohoda, W
通讯作者：
Korohoda, W