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Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents

  1. Author:
    Islam, Farhana
    Doshi, Arpit
    Robles, Andrew J
    Quadery, Tasdique M
    Zhang, Xin
    Zhou, Xilin
    Hamel, Ernest
    Mooberry, Susan L [ORCID]
    Gangjee, Aleem

  2. Author Address

    Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA., Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA., Mays Cancer Center, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA., Molecular Pharmacology Branch, Developmental Therapeutics Program, Frederick National Laboratory for Cancer Research, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.,
    1. Year: 2022
    2. Date: Jan 05
  2. Journal: Molecules
    1. 27
    2. 1
  4. Type of Article: Article
  1. Abstract:

    A series of eleven 4-substituted 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines were designed and synthesized and their biological activities were evaluated. Synthesis involved the Gewald reaction to synthesize ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate ring, and SNAr reactions. Compound 4 was 1.6- and ~7-fold more potent than the lead compound 1 in cell proliferation and microtubule depolymerization assays, respectively. Compounds 4, 5 and 7 showed the most potent antiproliferative effects (IC50 values < 40 nM), while compounds 6, 8, 10, 12 and 13 had lower antiproliferative potencies (IC50 values of 53-125 nM). Additionally, compounds 4-8, 10 and 12-13 circumvented Pgp and ßIII-tubulin mediated drug resistance, mechanisms that diminish the clinical efficacy of paclitaxel (PTX). In the NCI-60 cell line panel, compound 4 exhibited an average GI50 of ~10 nM in the 40 most sensitive cell lines. Compound 4 demonstrated statistically significant antitumor effects in a murine MDA-MB-435 xenograft model.

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  1. Keywords:

External Sources

  1. View Full Text
  2. DOI: 10.3390/molecules27010321
  3. PMID: 35011550
  4. PMCID: PMC8747035
  5. PII : molecules27010321

Library Notes

  1. Open Access Publication
  2. Fiscal Year: FY2021-2022
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