Design, Synthesis And Study Of Antitumor Activity Of Novel 1H-indazole Derivatives

Cancer is a multifactorial disease and causes significant mortalicy in the world. Cyclin Dependent Kinases(CDKs) are the key targets for antitumor drug discovery,and several drug candidates are under clinical trails.CDK7,an important member of the CDKs super-family,plays essential roles in regulating both the cell-division cycle and transcription,making it an attractive target for cancer therapy.In this dissertation,based on the structure of the lead compound,one of 3-(1H-indol-2-yl)-1H-indazole derivatives,a series of heteroaromatic ring-indazole derivatives were designed and synthesized according to bioisosteric principle. Structurally,these new compounds are 4-aza-indol-indazoles and imidazole-indazoles which have hydrophobic substituents on 4-aza-indole or imidazole ring.Docking researches showed that the compounds form three hydrogen bonds with Met94,Asp92 and interact with the hydrophobic pocket of CDK7 through the hydrophobic substituent. 34 novel compounds were synthesized,confirmed by ¹H NMR and MS.All compounds were tested for their in vitro cytotoxic activities against five human tumor cell lines. Most compounds showed potent cytotoxic activities,among them,4 compounds displayed potent cytotoxic activities against all tested cell lines(IC₅₀ from 0.0013 to 8μM).Furthermore,one compound showed a significant effect in in vivo animal model with an inhibition rate reaching to 24.9%.These results suggest that these compounds have excellent antitumor activity,further pharmacological tests are in progress.Another part of the dissertation is the building of the docking model for CDK7 inhibitors.A novel and reliable docking model was developed by Discovery Studio (version 2.1)/LigandFit,based on the crystal structure of CDK7.Enrichment Factor(EF) and Receiver Operating Characteristic Curves(ROC) were applied as validation methods to evaluate the accuracy of the established model.LigScore2 was selected as the best score function(EF at 4%,8%and 12%are 20.0,11.7 and 7.8;AUC,0.95).15 compounds with preferable scores were obtained by screening through the in-house database,further pharmacological tests are in progress.