Design,Synthesis And Preliminary Activity Studies Of C-Met Inhibitors

Cancer,characterized by the uncontrolled growth of malignant cells,is a complex disease caused by a variety of factors,also known as malignant tumors.According to the WHO,the global trend is increasing alarmingly by millions every year,and it is estimated to reach 22.0 million by 2030,which has severely affected the health and life quality of people.Consistent with this,molecular targeted therapy,which is anticipated to selectively target to tumor sites with high efficacy and safety,remains an effective regimen in the treatment of various types of tumors.The mesenchymal epithelial cell transforming factor c-Met,a high-affinity receptor for Hepatocyte Growth Factor(HGF),is one of members of the receptor tyrosine kinases(RTKs).The HGF/c-Met signaling pathway,which has a cross-talk relationship with many other cellular signaling pathways,has close correlation with tumor growth,invasion,and metastasis.Thus,c-Met represents a prominent therapeutic biotarget for developing potent anticancer drugs for effective tumor prevention and therapy.At present,the identified small molecular c-Met inhibitors can be classified into three different types according to their structural features and binding modes with biotarget.Type ? inhibitors are ATP competitive inhibitors and competitively bind to c-Met with a 'U-shape' spatial topology.Type ? inhibitors are usually ATP-competitive and multitargeted c-Met kinase inhibitors with more stretched conformations.Type ?inhibitors are non-ATP competitive and atypical c-Met kinase inhibitors.As an important nitrogen-containing heterocyclic ring,the pyrimidine ring has been widely existed in a wide range of molecules with multiple biological activities.In particularly,the privileged aminopyrimidine skeleton has attracted more attention due to its excellent antineoplastic activity.Herein,we report our newly synthesized aminopyrimidine-based type I c-Met inhibitors(series A and B)by using receptor-based drug design coupled with molecular hybridization strategy.In addition,series C compounds were further exploited through utilizing the structural features of the currently available type ?c-Met inhibitors(a nitrogen-containing heterocycle as the basic nucleus connected with a chain of 5 atoms),together with a ligand-based drug design and molecular hybridization strategy.As a result,a total of 37 compounds,including 8 of series A,19 of series B,and 10 of series C,have been obtained.The preliminary bioevaluation results showed that most of compounds presented low c-Met inhibition at a concentration of 1 ?M,except two compounds(BH-19 and C-10)which gave 15.3%and 24.4%inhibition,respectively.At a cellular level,some compounds gave decent anti-proliferative activities against tumor cells MCF-7 and A549.Specifically,for MCF-7,BH-2 and BH-5 gave IC50 values of 2.84 and 2.59 ?M,respectively.As to the A549,BH-17 and BH-19 gave IC50 values of 1.20 and 1.56 ?M,which are comparable with the positive control Crizotinib(MCF-7 IC50 0.92 ?M;A549 IC50=2.02 ?M)In brief,we have designed and synthesized 37 compounds based on receptor structure,ligand-based structure and molecular hybridization strategies.The preliminary bioevaluation showed compounds BH-17 and BH-19 gave comparable antiproliferative activities with the positive control Crizotinib,which are virtually worth researching.