Design, synthesis and preclinical evaluation of 5-methyl-N 4 -aryl-furo[2,3-d]pyrimidines as single agents with combination chemotherapy potential

• Published in: Bioorganic & medicinal chemistry letters 2018-10, Vol.28 (18), p.3085
• Main Authors: Devambatla, Ravi Kumar Vyas, Choudhary, Shruti, Ihnat, Michael, Hamel, Ernest, Mooberry, Susan L, Gangjee, Aleem
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; Humans; Mice; Molecular Docking Simulation; Molecular Structure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Receptor, Platelet-Derived Growth Factor beta - antagonists & inhibitors; Receptor, Platelet-Derived Growth Factor beta - metabolism; Structure-Activity Relationship; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 1464-3405

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.