2. Academic Validation
  3. New 6- and 7-heterocyclyl-1H-indole derivatives as potent tubulin assembly and cancer cell growth inhibitors

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

  • Eur J Med Chem. 2018 May 25:152:283-297. doi: 10.1016/j.ejmech.2018.04.042.
Giuseppe La Regina 1,  Ruoli Bai 2,  Antonio Coluccia 1,  Valentina Naccarato 1,  Valeria Famiglini 1,  Marianna Nalli 1,  Domiziana Masci 1,  Annalisa Verrico 3,  Paola Rovella 3,  Carmela Mazzoccoli 4,  Eleonora Da Pozzo 5,  Chiara Cavallini 5,  Claudia Martini 5,  Stefania Vultaggio 6,  Giulio Dondio 7,  Mario Varasi 6,  Ciro Mercurio 6,  Ernest Hamel 2,  Patrizia Lavia 3,  Romano Silvestri 8
Affiliations

Affiliations

  • 1 Department of Drug Chemistry and Technologies, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
  • 2 Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States.
  • 3 Institute of Molecular Biology and Pathology (IBPM), CNR Consiglio Nazionale Delle Ricerche, C/o Sapienza University of Rome, Via Degli Apuli 4, I-00185 Roma, Italy.
  • 4 Laboratorio di Ricerca Pre-Clinica e Traslazionale, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Centro di Riferimento Oncologico Della Basilicata, Via Padre Pio 1, I-85028, Rionero in Vulture, Italy.
  • 5 Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, I-56126 Pisa, Italy.
  • 6 Experimental Therapeutics IFOM-the FIRC Institute of Molecular Oncology Foundation, Via Adamello 16, 20139 Milan, Italy.
  • 7 APHAD, Via Della Resistenza 65, 20090 Buccinasco MI, Italy.
  • 8 Department of Drug Chemistry and Technologies, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, I-00185 Roma, Italy. Electronic address: romano.silvestri@uniroma1.it.
PMID: 29730191 DOI: 10.1016/j.ejmech.2018.04.042
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.

Keywords

Cancer cell; Indole; Inhibitor; Microtubule; Tubulin.

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