TY - JOUR
T1 - Design, synthesis and preclinical evaluation of 5-methyl-N4-aryl-furo[2,3-d]pyrimidines as single agents with combination chemotherapy potential
AU - Devambatla, Ravi Kumar Vyas
AU - Choudhary, Shruti
AU - Ihnat, Michael
AU - Hamel, Ernest
AU - Mooberry, Susan L.
AU - Gangjee, Aleem
N1 - Funding Information:
This work was supported, in part, by a grant from the National Institutes of Health , National Cancer Institute (CA142868 (AG, SLM)); by the Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (AG); and by an NSF equipment grant for NMR instrumentation (NMR: CHE 0614785).
PY - 2018/10/1
Y1 - 2018/10/1
N2 - The design, synthesis and biological evaluation of 4-substituted 5-methyl-furo[2,3-d]pyrimidines is described. The Ullmann coupling of 5-methyl-furo[2,3-d]pyrimidine with aryl iodides was successfully optimized to synthesize these analogs. Compounds 6–10 showed single-digit nanomolar inhibition of EGFR kinase. Compounds 1 and 6–10 inhibited VEGFR-2 kinase better than or equal to sunitinib. Compounds 1 and 3–10 were more potent inhibitors of PDGFR-β kinase than sunitinib. In addition, compounds 4–11 had higher potency in the CAM angiogenesis assay than sunitinib. Compound 1 showed in vivo efficacy in an A498 renal xenograft model in mice. Multiple RTK and tubulin inhibitory attributes of 1, 4, 6 and 8 indicates that these compounds may be valuable preclinical single agents targeting multiple intracellular targets.
AB - The design, synthesis and biological evaluation of 4-substituted 5-methyl-furo[2,3-d]pyrimidines is described. The Ullmann coupling of 5-methyl-furo[2,3-d]pyrimidine with aryl iodides was successfully optimized to synthesize these analogs. Compounds 6–10 showed single-digit nanomolar inhibition of EGFR kinase. Compounds 1 and 6–10 inhibited VEGFR-2 kinase better than or equal to sunitinib. Compounds 1 and 3–10 were more potent inhibitors of PDGFR-β kinase than sunitinib. In addition, compounds 4–11 had higher potency in the CAM angiogenesis assay than sunitinib. Compound 1 showed in vivo efficacy in an A498 renal xenograft model in mice. Multiple RTK and tubulin inhibitory attributes of 1, 4, 6 and 8 indicates that these compounds may be valuable preclinical single agents targeting multiple intracellular targets.
KW - Angiogenesis
KW - Combination chemotherapy
KW - Furo[2,3-d]pyrimidines
KW - Structure-activity relationships
KW - Tubulin inhibitors
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U2 - 10.1016/j.bmcl.2018.07.039
DO - 10.1016/j.bmcl.2018.07.039
M3 - Article
C2 - 30098869
AN - SCOPUS:85051078342
VL - 28
SP - 3085
EP - 3093
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 18
ER -