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Design, synthesis and preclinical evaluation of 5-methyl-N4-aryl-furo[2,3-d]pyrimidines as single agents with combination chemotherapy potential

  1. Author:
    Devambatla, Ravi Kumar Vyas
    Choudhary, Shruti
    Ihnat, Michael
    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., College of Pharmacy, University of Oklahoma Health Science Center, 1110 North Stonewall, Oklahoma City, OK 73117, United States., Screening Technologies 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 Pharmacology, Mays Cancer 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: 2018
    2. Date: Oct 1
    3. Epub Date: 2018 07 27
  2. Journal: Bioorganic & Medicinal Chemistry Letters
    1. 28
    2. 18
    3. Pages: 3085-3093
  4. Type of Article: Article
  1. Abstract:

    The design, synthesis and biological evaluation of 4-substituted 5-methyl-furo[2,3-d]pyrimidines is described. The Ullmann coupling of 5-methyl-furo[2,3-d]pyrimidine with aryl iodides was successfully optimized to synthesize these analogs. Compounds 6-10 showed single-digit nanomolar inhibition of EGFR kinase. Compounds 1 and 6-10 inhibited VEGFR-2 kinase better than or equal to sunitinib. Compounds 1 and 3-10 were more potent inhibitors of PDGFR-ß kinase than sunitinib. In addition, compounds 4-11 had higher potency in the CAM angiogenesis assay than sunitinib. Compound 1 showed in vivo efficacy in an A498 renal xenograft model in mice. Multiple RTK and tubulin inhibitory attributes of 1, 4, 6 and 8 indicates that these compounds may be valuable preclinical single agents targeting multiple intracellular targets. Copyright © 2018. Published by Elsevier Ltd.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.bmcl.2018.07.039
  3. PMID: 30098869
  4. View record in Web of Science®
  5. WOS: 000442761400014
  6. PII : S0960-894X(18)30620-6

Library Notes

  1. Fiscal Year: FY2017-2018
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