Design,Synthesis And Biological Evaluation Of Novel Macrocylic Compounds As Potent Kinase Inhibitors

The hunting for anticancer drugs has always been a central task in the Drug R&D. Protein kinases constitutes one of the most important protein families in humans. As kinases play important physiological and pathological roles in diverse biological events, the human kinome represents one of the most important drug discovery opportunities in oncology and other therapeutic areas such as metabolic disorders and inflammation. Compounds that inhibit the kinase activity of tyrosine kinases are potential candidates of new therapeutic antitumor agents. To date,9 kinase inhibitors have received approvals from US Food and Drug Administration as cancer treatments, and there are considerable efforts to develop selective small molecule inhibitors for a host of other kinases that are implicated in cancer and other diseases.Most known kinase inhibitors target the adenosine triphosphate (ATP) binding pocket with the kinase activation loop in the active (typeâ… ) or inactive (typeâ…¡) conformation. The typeâ…¡inhibitors have revealed a new binding mode that exploits an additional binding site immediately adjacent to the region occupied by ATP. Based on the study of new binding mode, a series of novel trazine macrocycle compounds were designed and synthesized and most of them showed potential biological activities. We successfully established a novel general procedure for the synthesis of macrocylic compounds of interesting. An efficient synthesis methodology for macrocyclic compounds was developed with Grubbs metathesis macrocyclization as the key step. The novel general procedure will enable us to explore much bigger chemical spaces based on a novel macrocycle template.