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Design and Synthesis of 2-Heterocyclyl-3-arylthio-1H-indoles as Potent Tubulin Polymerization and Cell Growth Inhibitors with Improved Metabolic Stability

  1. Author:
    La Regina, G.
    Bai, R.
    Rensen, W.
    Coluccia, A.
    Piscitelli, F.
    Gatti, V.
    Bolognesi, A.
    Lavecchia, A.
    Granata, I.
    Porta, A.
    Maresca, B.
    Soriani, A.
    Iannitto, M. L.
    Mariani, M.
    Santoni, A.
    Brancale, A.
    Ferlini, C.
    Dondio, G.
    Varasi, M.
    Mercurio, C.
    Hamel, E.
    Lavia, P.
    Novellino, E.
    Silvestri, R.

  2. Author Address

    [La Regina, Giuseppe; Coluccia, Antonio; Piscitelli, Francesco; Gatti, Valerio; Silvestri, Romano] Sapienza Univ Roma, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur, Fdn Cenci Bolognetti, I-00185 Rome, Italy. [Bai, Ruoli; Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Rensen, Willeke; Bolognesi, Alessio; Santoni, Angela; Lavia, Patrizia] Sapienza Univ Roma, Inst Mol Biol & Pathol, Natl Res Council, CNR, I-00185 Rome, Italy. [Granata, Ilaria; Porta, Amalia; Maresca, Bruno] Univ Salerno, Sez Biomed, Dipartimento Sci Farmaceut, I-84084 Salerno, Italy. [Brancale, Andrea] Cardiff Univ, Welsh Sch Pharm, Cardiff CF10 3NB, S Glam, Wales. [Lavecchia, Antonio; Novellino, Ettore] Univ Naples Federico 2, Dipartirnento Chim Farmaceut & Tossicol, I-80131 Naples, Italy. [Soriani, Alessandra; Iannitto, Maria Luisa; Santoni, Angela] Sapienza Univ Roma, Dipartimento Med Sperimentale & Patol, I-00161 Rome, Italy. [Mariani, Marisa; Ferlini, Cristiano] Danbury Hosp Res Inst, Tumor Reprod Biol Res Lab, Danbury, CT 06810 USA. [Dondio, Giulio] NiKem Res Srl, I-20021 Milan, Italy. [Varasi, Mario] European Inst Oncol, I-20139 Milan, Italy. [Mercurio, Ciro] DAC SRL, Genextra Grp, I-20139 Milan, Italy.;Silvestri, R (reprint author), Sapienza Univ Roma, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur, Fdn Cenci Bolognetti, Piazza Aldo Moro 5, I-00185 Rome, Italy;romano.silvestri@uniroma1.it
    1. Year: 2011
    2. Date: Dec
  2. Journal: Journal of Medicinal Chemistry
    1. 54
    2. 24
    3. Pages: 8394-8406
  4. Type of Article: Article
  5. ISSN: 0022-2623
  1. Abstract:

    New arylthioindoles (ATIs) were obtained by replacing the 2-alkoxycarbonyl group with a bioisosteric 5-membered heterocycle nucleus. The new ATIs 5, 8, and 10 inhibited tubulin polymerization, reduced cell growth of a panel of human transformed cell lines, and showed higher metabolic stability than the reference ester 3. These compounds induced mitotic arrest and apoptosis at a similar level as combretastatin A-4 and vinblastine and triggered caspase-3 expression in a significant fraction of cells in both p53-proficient and p53-defective cell lines. Importantly, ATIs 5, 8, and 10 were more effective than vinorelbine, vinblastine, and paclitaxel as growth inhibitors of the P-glycoprotein-overexpressing cell line NCI/ADR-RES. Compound 5 was shown to have medium metabolic stability in both human and mouse liver microsomes, in contrast to the rapidly degraded reference ester 3, and a pharmacokinetic profile in the mouse characterized by a low systemic clearance and excellent oral bioavailability.

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External Sources

  1. View Full Text
  2. DOI: 10.1021/jm2012886
  3. View record in Web of Science®
  4. WOS: 000297946300016

Library Notes

  1. Fiscal Year: FY2011-2012
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