n-(4-methoxybenzyl)-n--(5-nitro-1-3-thiazol-2-yl)urea and Liver-Neoplasms

We have synthesized bioactive 1,4-disubstituted 1,2,3-triazole analogues containing 2H-1,4-benzoxazin-3-(4H)-one derivatives via 1,3-dipolar cycloaddition in the presence of CuI. All the reactions proceeded smoothly and afforded its desired products in excellent yields. Among these analogues, 3y exhibited a better cytotoxic effect on human hepatocellular carcinoma (HCC) Hep 3B cells and displayed less cytotoxicity on normal human umbilical vein endothelial cells, compared with Sorafenib, a targeted therapy for advanced HCC. 3y also induced stronger apoptosis and autophagy. Addition of curcumin enhanced 3y-induced cytotoxicity by further induction of autophagy. Using gene expression signatures of 3y to query Connectivity Map, a glycogen synthase kinase-3 inhibitor (AR-A014418) was predicted to display similar molecular action of 3y. Experiments further demonstrate that AR-A014418 acted like 3y, and vice versa. Overall, our data suggest the chemotherapeutic potential of 3y on HCC.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Carcinoma, Hepatocellular; Cell Line, Tumor; Copper; Curcumin; Databases, Genetic; Glycogen Synthase Kinase 3; Humans; Liver Neoplasms; Structure-Activity Relationship; Thiazoles; Triazoles; Urea