2. Academic Validation
  3. The design and discovery of water soluble 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as multitargeted receptor tyrosine kinase inhibitors and microtubule targeting antitumor agents

The design and discovery of water soluble 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as multitargeted receptor tyrosine kinase inhibitors and microtubule targeting antitumor agents

  • Bioorg Med Chem. 2014 Jul 15;22(14):3753-72. doi: 10.1016/j.bmc.2014.04.049.
Xin Zhang 1,  Sudhir Raghavan 1,  Michael Ihnat 2,  Jessica E Thorpe 2,  Bryan C Disch 2,  Anja Bastian 2,  Lora C Bailey-Downs 2,  Nicholas F Dybdal-Hargreaves 3,  Cristina C Rohena 3,  Ernest Hamel 4,  Susan L Mooberry 3,  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 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.
  • 4 Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Institutes of Health, 1050 Boyles Street, Frederick, MD 21702, United States.
  • 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: 24890652 DOI: 10.1016/j.bmc.2014.04.049
Abstract

The design, synthesis and biological evaluations of fourteen 4-substituted 2,6-dimethylfuro[2,3-d]pyrimidines are reported. Four compounds (11-13, 15) inhibit vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor β (PDGFR-β), and target tubulin leading to cytotoxicity. Compound 11 has nanomolar potency, comparable to sunitinib and semaxinib, against tumor cell lines overexpressing VEGFR-2 and PDGFR-β. Further, 11 binds at the colchicine site on tubulin, depolymerizes cellular microtubules and inhibits purified tubulin assembly and overcomes both βIII-tubulin and P-glycoprotein-mediated drug resistance, and initiates mitotic arrest leading to Apoptosis. In vivo, its HCl salt, 21, reduced tumor size and vascularity in xenograft and allograft murine models and was superior to docetaxel and sunitinib, without overt toxicity. Thus 21 affords potential combination chemotherapy in a single agent.

Keywords

Anticancer agents; Microtubule targeting agents; Single agent combination chemotherapy; Tyrosine kinase inhibitors.

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