TY - JOUR
T1 - 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
AU - Zhang, Xin
AU - Raghavan, Sudhir
AU - Ihnat, Michael
AU - Thorpe, Jessica E.
AU - Disch, Bryan C.
AU - Bastian, Anja
AU - Bailey-Downs, Lora C.
AU - Dybdal-Hargreaves, Nicholas F.
AU - Rohena, Cristina C.
AU - Hamel, Ernest
AU - Mooberry, Susan L.
AU - Gangjee, Aleem
N1 - Funding Information:
The support of the National Cancer Institute for performing the in vitro antitumor evaluation in their 60 tumor preclinical screening program is gratefully acknowledged. Grant support from the National Cancer Institute , CA142868 (A.G., S.L.M.) is acknowledged as is support by the Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (A.G.), the CTRC Cancer Center Support Grant, P30 CA054174 and an NSF equipment Grant for NMR instrumentation (NMR: CHE 0614785 ), COSTAR grant DE014318 (NF, DH).
PY - 2014/7/15
Y1 - 2014/7/15
N2 - 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.
AB - 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.
KW - Anticancer agents
KW - Microtubule targeting agents
KW - Single agent combination chemotherapy
KW - Tyrosine kinase inhibitors
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U2 - 10.1016/j.bmc.2014.04.049
DO - 10.1016/j.bmc.2014.04.049
M3 - Article
C2 - 24890652
AN - SCOPUS:84902536299
VL - 22
SP - 3753
EP - 3772
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 14
ER -