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
DOI
10.1016/j.bmc.2014.04.049
Document Type
Journal Article
Publication Date
7-15-2014
Publication Title
Bioorganic and Medicinal Chemistry
Volume
22
Issue
14
First Page
3753
Last Page
3772
ISSN
9680896
Keywords
Anticancer agents, Microtubule targeting agents, Single agent combination chemotherapy, Tyrosine kinase inhibitors
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. © 2014 Elsevier Ltd. All rights reserved.
Open Access
Green Accepted
Preprint
Repository Citation
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