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

Xin Zhang, Sudhir Raghavan, Michael Ihnat, Jessica E. Thorpe, Bryan C. Disch, Anja Bastian, Lora C. Bailey-Downs, Nicholas F. Dybdal-Hargreaves, Cristina C. Rohena, Ernest Hamel, Susan L. Mooberry, Aleem Gangjee

Research output: Contribution to journalArticle

27 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3753-3772
Number of pages20
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number14
DOIs
StatePublished - Jul 15 2014

Keywords

  • Anticancer agents
  • Microtubule targeting agents
  • Single agent combination chemotherapy
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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    Zhang, X., Raghavan, S., Ihnat, M., Thorpe, J. E., Disch, B. C., Bastian, A., Bailey-Downs, L. C., Dybdal-Hargreaves, N. F., Rohena, C. C., Hamel, E., Mooberry, S. L., & Gangjee, A. (2014). 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. Bioorganic and Medicinal Chemistry, 22(14), 3753-3772. https://doi.org/10.1016/j.bmc.2014.04.049