New Indole Tubulin Assembly Inhibitors Cause Stable Arrest of Mitotic Progression, Enhanced Stimulation of Natural Killer Cell Cytotoxic Activity, and Repression of Hedgehog-Dependent Cancer
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- 作者：Giuseppe La Regina ; Ruoli Bai ; Antonio Coluccia ; Valeria Famiglini ; Sveva Pelliccia ; Sara Passacantilli ; Carmela Mazzoccoli ; Vitalba Ruggieri ; Annalisa Verrico ; Andrea Miele ; Ludovica Monti ; Marianna Nalli ; Romina Alfonsi ; Lucia Di Marcotullio ; Alberto Gulino ; Biancamaria Ricci ; Alessandra Soriani ; Angela Santoni ; Michele Caraglia ; Stefania Porto ; Eleonora Da Pozzo ; Claudia Martini ; Andrea Brancale ; Luciana Marinelli ; Ettore Novellino ; Stefania Vultaggio ; Mario Varasi ; Ciro Mercurio ; Chiara Bigogno ; Giulio Dondio ; Ernest Hamel ; Patrizia Lavia ; Romano Silvestri
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：August 13, 2015
- 年：2015
- 卷：58
- 期：15
- 页码：5789-5807
- 全文大小：782K
- ISSN：1520-4804
文摘
We designed 39 new 2-phenylindole derivatives as potential anticancer agents bearing the 3,4,5-trimethoxyphenyl moiety with a sulfur, ketone, or methylene bridging group at position 3 of the indole and with halogen or methoxy substituent(s) at positions 4鈥?. Compounds 33 and 44 strongly inhibited the growth of the P-glycoprotein-overexpressing multi-drug-resistant cell lines NCI/ADR-RES and Messa/Dx5. At 10 nM, 33 and 44 stimulated the cytotoxic activity of NK cells. At 20鈥?0 nM, 33 and 44 arrested >80% of HeLa cells in the G2/M phase of the cell cycle, with stable arrest of mitotic progression. Cell cycle arrest was followed by cell death. Indoles 33, 44, and 81 showed strong inhibition of the SAG-induced Hedgehog signaling activation in NIH3T3 Shh-Light II cells with IC50 values of 19, 72, and 38 nM, respectively. Compounds of this class potently inhibited tubulin polymerization and cancer cell growth, including stimulation of natural killer cell cytotoxic activity and repression of Hedgehog-dependent cancer.