New 6- and 7-heterocyclyl-1H-indole derivatives as potent tubulin assembly and cancer cell growth inhibitors

Giuseppe La Regina; Ruoli Bai; Antonio Coluccia; Valentina Naccarato; Valeria Famiglini; Marianna Nalli; Domiziana Masci; Annalisa Verrico; Paola Rovella; Carmela Mazzoccoli; Eleonora Da Pozzo; Chiara Cavallini; Claudia Martini; Stefania Vultaggio; Giulio Dondio; Mario Varasi; Ciro Mercurio; Ernest Hamel; Patrizia Lavia; Romano Silvestri

doi:10.1016/j.ejmech.2018.04.042

New 6- and 7-heterocyclyl-1H-indole derivatives as potent tubulin assembly and cancer cell growth inhibitors

Giuseppe La Regina, Ruoli Bai, Antonio Coluccia, Valentina Naccarato, Valeria Famiglini, Marianna Nalli, Domiziana Masci, Annalisa Verrico, Paola Rovella, Carmela Mazzoccoli, Eleonora Da Pozzo, Chiara Cavallini, Claudia Martini, Stefania Vultaggio, Giulio Dondio, Mario Varasi, Ciro Mercurio, Ernest Hamel, Patrizia Lavia, Romano Silvestri

Research output: Contribution to journal › Article › peer-review

Abstract

We designed new 3-arylthio- and 3-aroyl-1H-indole derivatives 3–22 bearing a heterocyclic ring at position 5, 6 or 7 of the indole nucleus. The 6- and 7-heterocyclyl-1H-indoles showed potent inhibition of tubulin polymerization, binding of colchicine to tubulin and growth of MCF-7 cancer cells. Compounds 13 and 19 inhibited a panel of cancer cells and the NCI/ADR-RES multidrug resistant cell line at low nanomolar concentrations. Compound 13 at 50 nM induced 77% G2/M in HeLa cells, and at 20 nM caused 50% stable arrest of mitosis. As an inhibitor of HepG2 cells (IC₅₀ = 20 nM), 13 was 4-fold superior to 19. Compound 13 was a potent inhibitor of the human U87MG glioblastoma cells at nanomolar concentrations, being nearly one order of magnitude superior to previously reported arylthioindoles. The present results highlight 13 as a robust scaffold for the design of new anticancer agents.

Original language	English
Pages (from-to)	283-297
Number of pages	15
Journal	European Journal of Medicinal Chemistry
Volume	152
DOIs	https://doi.org/10.1016/j.ejmech.2018.04.042
Publication status	Published - May 25 2018

Keywords

Cancer cell
Indole
Inhibitor
Microtubule
Tubulin

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2018.04.042

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La Regina, G., Bai, R., Coluccia, A., Naccarato, V., Famiglini, V., Nalli, M., Masci, D., Verrico, A., Rovella, P., Mazzoccoli, C., Da Pozzo, E., Cavallini, C., Martini, C., Vultaggio, S., Dondio, G., Varasi, M., Mercurio, C., Hamel, E., Lavia, P., & Silvestri, R. (2018). New 6- and 7-heterocyclyl-1H-indole derivatives as potent tubulin assembly and cancer cell growth inhibitors. European Journal of Medicinal Chemistry, 152, 283-297. https://doi.org/10.1016/j.ejmech.2018.04.042

New 6- and 7-heterocyclyl-1H-indole derivatives as potent tubulin assembly and cancer cell growth inhibitors. / La Regina, Giuseppe; Bai, Ruoli; Coluccia, Antonio; Naccarato, Valentina; Famiglini, Valeria; Nalli, Marianna; Masci, Domiziana; Verrico, Annalisa; Rovella, Paola; Mazzoccoli, Carmela; Da Pozzo, Eleonora; Cavallini, Chiara; Martini, Claudia; Vultaggio, Stefania; Dondio, Giulio; Varasi, Mario; Mercurio, Ciro; Hamel, Ernest; Lavia, Patrizia; Silvestri, Romano.

In: European Journal of Medicinal Chemistry, Vol. 152, 25.05.2018, p. 283-297.

Research output: Contribution to journal › Article › peer-review

La Regina, G, Bai, R, Coluccia, A, Naccarato, V, Famiglini, V, Nalli, M, Masci, D, Verrico, A, Rovella, P, Mazzoccoli, C, Da Pozzo, E, Cavallini, C, Martini, C, Vultaggio, S, Dondio, G, Varasi, M, Mercurio, C, Hamel, E, Lavia, P & Silvestri, R 2018, 'New 6- and 7-heterocyclyl-1H-indole derivatives as potent tubulin assembly and cancer cell growth inhibitors', European Journal of Medicinal Chemistry, vol. 152, pp. 283-297. https://doi.org/10.1016/j.ejmech.2018.04.042

La Regina, Giuseppe ; Bai, Ruoli ; Coluccia, Antonio ; Naccarato, Valentina ; Famiglini, Valeria ; Nalli, Marianna ; Masci, Domiziana ; Verrico, Annalisa ; Rovella, Paola ; Mazzoccoli, Carmela ; Da Pozzo, Eleonora ; Cavallini, Chiara ; Martini, Claudia ; Vultaggio, Stefania ; Dondio, Giulio ; Varasi, Mario ; Mercurio, Ciro ; Hamel, Ernest ; Lavia, Patrizia ; Silvestri, Romano. / New 6- and 7-heterocyclyl-1H-indole derivatives as potent tubulin assembly and cancer cell growth inhibitors. In: European Journal of Medicinal Chemistry. 2018 ; Vol. 152. pp. 283-297.

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abstract = "We designed new 3-arylthio- and 3-aroyl-1H-indole derivatives 3–22 bearing a heterocyclic ring at position 5, 6 or 7 of the indole nucleus. The 6- and 7-heterocyclyl-1H-indoles showed potent inhibition of tubulin polymerization, binding of colchicine to tubulin and growth of MCF-7 cancer cells. Compounds 13 and 19 inhibited a panel of cancer cells and the NCI/ADR-RES multidrug resistant cell line at low nanomolar concentrations. Compound 13 at 50 nM induced 77% G2/M in HeLa cells, and at 20 nM caused 50% stable arrest of mitosis. As an inhibitor of HepG2 cells (IC50 = 20 nM), 13 was 4-fold superior to 19. Compound 13 was a potent inhibitor of the human U87MG glioblastoma cells at nanomolar concentrations, being nearly one order of magnitude superior to previously reported arylthioindoles. The present results highlight 13 as a robust scaffold for the design of new anticancer agents.",

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AU - Naccarato, Valentina

AU - Famiglini, Valeria

AU - Nalli, Marianna

AU - Masci, Domiziana

AU - Verrico, Annalisa

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AU - Mazzoccoli, Carmela

AU - Da Pozzo, Eleonora

AU - Cavallini, Chiara

AU - Martini, Claudia

AU - Vultaggio, Stefania

AU - Dondio, Giulio

AU - Varasi, Mario

AU - Mercurio, Ciro

AU - Hamel, Ernest

AU - Lavia, Patrizia

AU - Silvestri, Romano

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N2 - We designed new 3-arylthio- and 3-aroyl-1H-indole derivatives 3–22 bearing a heterocyclic ring at position 5, 6 or 7 of the indole nucleus. The 6- and 7-heterocyclyl-1H-indoles showed potent inhibition of tubulin polymerization, binding of colchicine to tubulin and growth of MCF-7 cancer cells. Compounds 13 and 19 inhibited a panel of cancer cells and the NCI/ADR-RES multidrug resistant cell line at low nanomolar concentrations. Compound 13 at 50 nM induced 77% G2/M in HeLa cells, and at 20 nM caused 50% stable arrest of mitosis. As an inhibitor of HepG2 cells (IC50 = 20 nM), 13 was 4-fold superior to 19. Compound 13 was a potent inhibitor of the human U87MG glioblastoma cells at nanomolar concentrations, being nearly one order of magnitude superior to previously reported arylthioindoles. The present results highlight 13 as a robust scaffold for the design of new anticancer agents.

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New 6- and 7-heterocyclyl-1H-indole derivatives as potent tubulin assembly and cancer cell growth inhibitors

Abstract

Keywords

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