Design,Synthesis And Anti-Tumor Structure-Activity Relationships Of CDKs/HDACs Dual-Target Inhibitors

Tumor is a serious disease that endangers human life and health.The occurrence and development of tumor is associated with mutations and abnormal expression of multiple genes as well as the disorder of several signal transduction pathways.In recent years,protein kinase inhibitors have become one of the research focuses of anti-tumor drugs due to their superior effectiveness and safety.At present,a variety of protein kinase inhibitors were approved forcancer treatment.However,their application was limited by drug resistance and side effects.Several reports have shown that Flavopiridol combination with Vorinostatmight offer therapeutic effects in neuroblastoma and melanoma.In addition,it has been found that dual-target drugs have higher efficacy than single target drugs,and it also can avoid drug-drug interactions and circumvent pharmacokinetic problems.In this report,we designed and synthesized a series of CDKs/HDACs dual-target inhibitors based on the pharmacophore characteristics of CYC202 and SAHA.The structures of these compounds were confirmed by ¹H-NMR and ¹³C-NMR.According to the preliminary evaluation in vitro,compound T-17 has been shown to inhibit CDK2 kinase activities with an IC₅₀ of 18 nM,which was 10-fold higher than CYC202.And compound T-17 also with an IC₅₀ value of 6.6 nM against HDAC1 kinase.Our presented result demonstrated that compound T-17 can serve as a CDKs/HDACs dual-target inhibitor candidate for further pharmacological research,and it also lays a foundation for the research of dual-target and even multi-target inhibitors.Moreover,some studies indicated that the kinase inhibitory activities of SAHA can still maintained when the benzene ringwas replaced by 1,3,4-thiadiazole.Therefore,a new synthetic method of 1,3,4-thiadiazole was explored.KHSO₄ was employed as a dehydrating cyclization agentto catalyze the reaction of phenylsulfonyl hydrazide derivatives with amides to produce 1,3,4-thiadiazole under moderate conditions.Twenty-seven1,3,4-thiadiazole derivatives were synthesized with good yields under optimized reaction conditions.The structures of target compounds were confirmed by ¹H-NMR,¹³C-NMR and MS.The discovery of this method provides a new idea for the synthesis of related compounds.