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Structure Guided Design, Synthesis, and Biological Evaluation of Oxetane-Containing Indole Analogues

  1. Author:
    Ren, Wen
    Vairin, Rebecca
    Ward, Jacob D
    Francis, Ricardo
    VanNatta, Jenny
    Bai,Ruoli
    Tankoano, Pouguiniseli E
    Deng, Yuling
    Hamel,Ernest
    Trawick, Mary Lynn
    Pinney, Kevin G
  2. Author Address

    Department of Chemistry and Biochemistry, Baylor University, One Bear Place, No. 97348, Waco, TX 76798-7348, United States., Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, MD 21702, United States., Department of Chemistry and Biochemistry, Baylor University, One Bear Place, No. 97348, Waco, TX 76798-7348, United States. Electronic address: Kevin_Pinney@baylor.edu.,
    1. Year: 2023
    2. Date: Jun 29
    3. Epub Date: 2023 06 29
  1. Journal: Bioorganic & Medicinal Chemistry
    1. 92
    2. Pages: 117400
  2. Type of Article: Article
  3. Article Number: 117400
  1. Abstract:

    The oxetane functional group offers a variety of potential advantages when incorporated within appropriate therapeutic agents as a ketone surrogate. OXi8006, a 2-aryl-3-aroyl-indole analogue, functions as a small-molecule inhibitor of tubulin polymerization that has a dual mechanism of action as both an antiproliferative agent and a tumor-selective vascular disrupting agent. Replacement of the bridging ketone moiety in OXi8006 with an oxetane functional group has expanded structure activity relationship (SAR) knowledge and provided insights regarding oxetane incorporation within this class of molecules. A new synthetic method using an oxetane-containing tertiary alcohol subjected to Lewis acid catalyzed conditions led to successful Friedel-Crafts alkylation and yielded fourteen new oxetane-containing indole-based molecules. This synthetic approach represents the first method to successfully install an oxetane ring at the 3-position of a 2-aryl-indole system. Several analogues showed potent cytotoxicity (micromolar GI50 values) against human breast cancer cell lines (MCF-7 and MDA-MB-231) and a pancreatic cancer cell line (PANC-1), although they proved to be ineffective as inhibitors of tubulin polymerization. Molecular docking studies comparing colchicine with the OXi8006-oxetane analogue 5m provided a rationale for the differential interaction of these molecules with the colchicine site on the tubulin heterodimer. Copyright © 2023 Elsevier Ltd. All rights reserved.

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External Sources

  1. DOI: 10.1016/j.bmc.2023.117400
  2. PMID: 37556912
  3. PII : S0968-0896(23)00248-1

Library Notes

  1. Fiscal Year: FY2022-2023
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