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
Anticancer agents, Microtubule targeting agents, Single agent combination chemotherapy, Tyrosine kinase inhibitors
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. © 2014 Elsevier Ltd. All rights reserved.
Zhang, X., Raghavan, S., Ihnat, M., Thorpe, J., Disch, B., Bastian, A., Bailey-Downs, L., Dybdal-Hargreaves, N., Rohena, C., Hamel, E., Mooberry, S., & 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