Synthesis and Characterization of Sorafenib Analogues and Evaluation of Their Potential for the Treatment of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma is one of the deadly type of cancer across the world. The initiation starts from cirrhosis which finally transforms to full nodular hepatocellular carcinoma. The disease has poor prognosis and treatment options though available but they are not much effective. The diagnosis usually takes place at late stages where surgery and transplant cannot be considered. The only drug having FDA approval is Sorafenib, which is considered to be multikinase inhibitor, marketed by the name of Nexavar. The drug is angiogenic inhibitor but has major associated side effects like cardiac toxicity, hand-foot syndrome and development of resistance. Moreover, the median survival rate with Sorafenib is only three months which is far below the expectation based on clinical trials. Keeping this in mind, analogues of Sorafenib are always in interest of researchers. In this study, out of 10 proposed analogues, analogues 3- (SRB) (N-benzyl-4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)picolinamide) and analo-gue 7 (SRE) (N-ethyl-4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)pheno- xy)picolinamide) were selected on the basis of results obtained through molecular docking and ADME analysis. The study revealed that analogues were showing effect on the RAS/MAPK pathways similar to Sorafenib but, interestingly, they were affecting additional pathways mainly c-Jun, Tert-pathway having major role in cancer. Further, Edge Betweeness study revealed major receptor nodes for regulating the mechanism of synthesised SRB and SRE. Thus, efficacy of synthesised analogues were established successfully in Hepatocellular carcinoma. newline