期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 22, 期 14, 页码 3753-3772出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.04.049
关键词
Tyrosine kinase inhibitors; Single agent combination chemotherapy; Anticancer agents; Microtubule targeting agents
资金
- National Cancer Institute [CA142868]
- Duquesne University Adrian Van Kaam Chair in Scholarly Excellence
- CTRC Cancer Center [P30 CA054174]
- NSF [NMR: CHE 0614785]
- COSTAR [DE014318]
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 beta (PDGFR-beta), 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-beta. Further, 11 binds at the colchicine site on tubulin, depolymerizes cellular microtubules and inhibits purified tubulin assembly and overcomes both beta III-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. (C) 2014 Elsevier Ltd. All rights reserved.
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