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Design, synthesis, and structure-activity relationships of pyrimido[4,5-b]indole-4-amines as microtubule depolymerizing agents that are effective against multidrug resistant cells

  1. Author:
    Devambatla, Ravi Kumar Vyas
    Li, Wei
    Zaware, Nilesh
    Choudhary, Shruti
    Hamel, Ernest
    Mooberry, Susan L
    Gangjee, Aleem

  2. Author Address

    Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States., Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, MD 21702, United States., Department of Pharmacology, Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States. Electronic address: mooberry@uthscsa.edu., Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States. Electronic address: gangjee@duq.edu.,
    1. Year: 2017
    2. Date: Aug 01
    3. Epub Date: 2017 May 27
  2. Journal: Bioorganic & Medicinal Chemistry Letters
    1. 27
    2. 15
    3. Pages: 3423-3430
  4. Type of Article: Article
  1. Abstract:

    To identify the structural features of 9H-pyrimido[4,5-b]indoles as microtubule depolymerizers, pyrimido[4,5-b]indoles 2-8 with varied substituents at the 2-, 4- and 5-positions were designed and synthesized. Nucleophilic displacement of 2,5-substituted-4-chloro-pyrimido[4,5-b]indoles with appropriate arylamines was the final step employed in the synthesis of target compounds 2-8. Compounds 2 and 6 had two-digit nanomolar potency (IC50) against MDA-MB-435, SK-OV-3 and HeLa cancer cells in vitro. Compounds 2 and 6 also depolymerized microtubules comparable to the lead compound 1. Compounds 2, 3, 6 and 8 were effective in cells expressing P-glycoprotein or the ßIII isotype of tubulin, mechanisms that are associated with clinical drug resistance to microtubule targeting drugs. Proton NMR and molecular modeling studies were employed to identify the structural basis for the microtubule depolymerizing activity of pyrimido[4,5-b]indoles. Copyright © 2017 Elsevier Ltd. All rights reserved.

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External Sources

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  2. DOI: 10.1016/j.bmcl.2017.05.085
  3. PMID: 28610978
  4. View record in Web of Science®
  5. WOS: 000405106500041

Library Notes

  1. Fiscal Year: FY2016-2017
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