Design, synthesis and preclinical evaluation of 5-methyl-N4-aryl-furo[2, 3-d]pyrimidines as single agents with combination chemotherapy potential. Issue 18 (1st October 2018)

• Record Type: Journal Article
• Authors: Devambatla, Ravi Kumar Vyas; Choudhary, Shruti; Ihnat, Michael; Hamel, Ernest; Mooberry, Susan L.; Gangjee, Aleem
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 18(2018)
• Page Start: 3085
• Page End: 3093
• Publication Date: 2018-10-01
• Subjects: RTKs Receptor tyrosine kinases -- VEGF vascular endothelial growth factor -- VEGFR-2 vascular endothelial growth factor receptor-2 -- PDGFR-β platelet-derived growth factor receptor-β -- EGFR epidermal growth factor receptor -- ATP adenosine triphosphate -- NCI National Cancer Institute -- CA-1 combretastatin A-1 -- CA-4 combretastatin A-4 -- PDB Protein Data Bank -- CAM chorioallantoic membrane -- Pgp P-glycoprotein; Angiogenesis -- Combination chemotherapy -- Furo[2, 3-d]pyrimidines -- Structure-activity relationships -- Tubulin inhibitors; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.07.039
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Discovered a new class of single agents for cancer chemotherapy. Compounds are highly potent inhibitors of tubulin and angiogenesis pathway. Optimized Ullmann coupling, a key step in the synthesis of target compounds. Compound1 showed efficacy in human renal (A498) xenograft model in mice. 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. Compounds6 –10 showed single-digit nanomolar inhibition of EGFR kinase. Compounds1 and6 –10 inhibited VEGFR-2 kinase better than or equal to sunitinib. Compounds1 and3 –10 were more potent inhibitors of PDGFR-β kinase than sunitinib. In addition, compounds4 –11 had higher potency in the CAM angiogenesis assay than sunitinib. Compound1 showed in vivo efficacy in an A498 renal xenograft model in mice. Multiple RTK and tubulin inhibitory attributes of1, 4, 6 and8 indicates that these compounds may be valuable preclinical single agents targeting multiple intracellular targets.