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

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

  • Bioorg Med Chem Lett. 2018 Oct 1;28(18):3085-3093. doi: 10.1016/j.bmcl.2018.07.039.
Ravi Kumar Vyas Devambatla 1,  Shruti Choudhary 1,  Michael Ihnat 2,  Ernest Hamel 3,  Susan L Mooberry 4,  Aleem Gangjee 5
Affiliations

Affiliations

  • 1 Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States.
  • 2 College of Pharmacy, University of Oklahoma Health Science Center, 1110 North Stonewall, Oklahoma City, OK 73117, United States.
  • 3 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.
  • 4 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.
  • 5 Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States. Electronic address: gangjee@duq.edu.
PMID: 30098869 DOI: 10.1016/j.bmcl.2018.07.039
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-β 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.

Keywords

Angiogenesis; Combination chemotherapy; Furo[2,3-d]pyrimidines; Structure-activity relationships; Tubulin inhibitors.

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