Design, synthesis and preclinical evaluation of 5-methyl-N4-aryl-furo[2,3-d]pyrimidines as single agents with combination chemotherapy potential

Abstract 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.