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 journalArticlepeer-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 languageEnglish
Pages (from-to)283-297
Number of pages15
JournalEuropean Journal of Medicinal Chemistry
Volume152
DOIs
Publication statusPublished - May 25 2018

Keywords

  • Cancer cell
  • Indole
  • Inhibitor
  • Microtubule
  • Tubulin

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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