2. Academic Validation
  3. New arylthioindoles and related bioisosteres at the sulfur bridging group. 4. Synthesis, tubulin polymerization, cell growth inhibition, and molecular modeling studies

New arylthioindoles and related bioisosteres at the sulfur bridging group. 4. Synthesis, tubulin polymerization, cell growth inhibition, and molecular modeling studies

  • J Med Chem. 2009 Dec 10;52(23):7512-27. doi: 10.1021/jm900016t.
Giuseppe La Regina 1,  Taradas Sarkar,  Ruoli Bai,  Michael C Edler,  Roberto Saletti,  Antonio Coluccia,  Francesco Piscitelli,  Lara Minelli,  Valerio Gatti,  Carmela Mazzoccoli,  Vanessa Palermo,  Cristina Mazzoni,  Claudio Falcone,  Anna Ivana Scovassi,  Vincenzo Giansanti,  Pietro Campiglia,  Amalia Porta,  Bruno Maresca,  Ernest Hamel,  Andrea Brancale,  Ettore Novellino,  Romano Silvestri
Affiliations

Affiliation

  • 1 Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
PMID: 19601594 DOI: 10.1021/jm900016t
Abstract

New arylthioindoles along with the corresponding ketone and methylene compounds were potent tubulin assembly inhibitors. As growth inhibitors of MCF-7 cells, sulfur derivatives were superior or sometimes equivalent to the ketones, while methylene derivatives were substantially less effective. Esters 24, 27-29, 36, 39, and 41 showed approximately 50% of inhibition on human HeLa and HCT116/chr3 cells at 0.5 microM, and these compounds inhibited the growth of HEK, M14, and U937 cells with IC(50)'s in the 78-220 nM range. While murine macrophage J744.1 cell growth was significantly less affected (20% at higher concentrations), four Other nontransformed cell lines remained sensitive to these esters. The effect of drug treatment on cell morphology was examined by time-lapse microscopy. In a protocol set up to evaluate toxicity on the Saccharomyces cerevisiae BY4741 wild type strain, compounds 24 and 54 strongly reduced cell growth, and 29, 36, and 39 also showed significant inhibition.

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