Design, Synthesis And Activity Study Of 1,3,4-oxadiazoles As KDR Kinase Inhibitor

Anti-angiogenic therapy arised as a new anti-cancer therapy for the treatment of cancer by inhibition of the angiogenesis.KDR(The Kinase insert Domain containing Receptor)is a receptor for VEGF(Vascular Endothelial Growth Factors)and acts as a key regulator of angiogenesis.KDR inhibitors are ATP competitive,which exert the inhibitory activity by binding in the ATP pocket of the kinase.It's crucial to find new potent KDR kinase inhibitors for anti-angiogenic therapy.Based on the previous work,with the help of computer-aided drug design,we have designed and synthesized a series of 2-Anilino-5-aryl 1,3,4-oxadiazoles,as a novel class of KDR kinase inhibitors.2-Anilino-5-aryl oxazole was chosed as a lead compound.We have replaced oxazole ring with 1,3,4-oxadiazole,and 5-sulfonyl-2-methoxyaniline in position 2 of oxazole moiety has been kept.In order to find more potent compounds,we have synthesized oxadiazole derivatives,by introducing of different substituents on the phenyl ring at position 5 of oxadiazole. Moreover,we have changed the phenyl ring for heteroaryl ones.By retrosynthetic analysis of the target compounds,we designed a rational synthetic way.19 new 1,3,4-oxadiazole compounds have been synthesized.All the target compounds were confirmed by ~1HNMR,IR and MS.All the target compounds have been tested against human umbilical vein endothelial cells(HUVEC)in vitro,and some of them possess modest HUVEC cell inhibitory activity on cell-based assay.The result will provide some useful informations for designing more potent KDR kinase inhibitors.