Toward highly potent cancer agents by modulating the C-2 group of the arylthioindole class of tubulin polymerization inhibitors

Giuseppe La Regina, Ruoli Bai, Whilelmina Maria Rensen, Erica Di Cesare, Antonio Coluccia, Francesco Piscitelli, Valeria Famiglini, Alessia Reggio, Marianna Nalli, Sveva Pelliccia, Eleonora Da Pozzo, Barbara Costa, Ilaria Granata, Amalia Porta, Bruno Maresca, Alessandra Soriani, Maria Luisa Iannitto, Angela Santoni, Junjie Li, Marlein Miranda ConaFeng Chen, Yicheng Ni, Andrea Brancale, Giulio Dondio, Stefania Vultaggio, Mario Varasi, Ciro Mercurio, Claudia Martini, Ernest Hamel, Patrizia Lavia, Ettore Novellino, Romano Silvestri

Research output: Contribution to journalArticlepeer-review

Abstract

New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC50 = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes.

Original languageEnglish
Pages (from-to)123-149
Number of pages27
JournalJournal of Medicinal Chemistry
Volume56
Issue number1
DOIs
Publication statusPublished - Jan 10 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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