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

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 PortoEleonora 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

Research output: Contribution to journalArticle

Abstract

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 4-7. 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 20-50 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.

Original languageEnglish
Pages (from-to)5789-5807
Number of pages19
JournalJournal of Medicinal Chemistry
Volume58
Issue number15
DOIs
Publication statusPublished - Jul 1 2015

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

La Regina, G., Bai, R., Coluccia, A., Famiglini, V., Pelliccia, S., Passacantilli, S., Mazzoccoli, C., Ruggieri, V., Verrico, A., Miele, A., Monti, L., Nalli, M., Alfonsi, R., Di Marcotullio, L., Gulino, A., Ricci, B., Soriani, A., Santoni, A., Caraglia, M., ... Silvestri, R. (2015). 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. Journal of Medicinal Chemistry, 58(15), 5789-5807. https://doi.org/10.1021/acs.jmedchem.5b00310