Abstract
This dissertation is concerned with the development of furano[2,3-d]pyrimidine compounds as Aurora kinases inhibitors. Start from compound 1, we utilize rational drug design to synthesize two particular hits, compound 20 and 48. We analyze the co-crystal structures of two hits with Aurora-A, and observe the protein structures belong to DFG-out and DFG-out-like conformation. At the same time, we apply high-throughput parallel synthesis (HTPS) to accelerate the synthesis of analogues. Fortunately, we discover the lead compound 183 which was modified from compound 145 by forming the urea functionality and terminal phenyl group. We analyze the co-crystal structure of compound 183, and find the protein structure is DFG-in conformation. The variety does not only display in protein conformation but also improve the bioactivity. After lead optimization, we confirm the ethyl-phenyl-urea was the best side chain structure, and find compound 252 which successfully improve the cell bioactivity and reduce the molecular weight and lipophilicity.