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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

La Regina, Giuseppe, Bai, Ruoli, Coluccia, Antonio, Famiglini, Valeria, Pelliccia, Sveva, Passacantilli, Sara, Mazzoccoli, Carmela, Ruggieri, Vitalba, Verrico, Annalisa, Miele, Andrea, Monti, Ludovica, Nalli, Marianna, Alfonsi, Romina, Di Marcotullio, Lucia, Gulino, Alberto, Ricci, Biancamaria, Soriani, Alessandra, Santoni, Angela, Caraglia, Michele, Porto, Stefania, Da Pozzo, Eleonora, Martini, Claudia, Brancale, Andrea, Marinelli, Luciana, Novellino, Ettore, Vultaggio, Stefania, Varasi, Mario, Mercurio, Ciro, Bigogno, Chiara, Dondio, Giulio, Hamel, Ernest, Lavia, Patrizia and Silvestri, Romano 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) , pp. 5789-5807. 10.1021/acs.jmedchem.5b00310

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
Publisher: American Chemical Society
ISSN: 0022-2623
Date of First Compliant Deposit: 30 March 2016
Last Modified: 10 Mar 2020 16:54
URI: http://orca-mwe.cf.ac.uk/id/eprint/75237

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