Synthesis of thiosemicarbazone derivatives as antiproliferating agents

We were interested in modification of the N-alkylated products of azanaphthoquinone annelated pyrrole (3) by condensation with thiosemicarbazide to improve the antiproliferative activity. Herein, we report the synthesis of two series of thiosemicarbazone derivatives as antiproliferation agents. In series one, N-alkylated products of azanaphthoquinone annelated pyrrole (3) and five thiosemicarbazone derivatives (62) were successfully synthesized in moderate to good yields. The different side chains at the nitrogen atom of pyrrole ring in the core structure were introduced by N-alkylation reaction under basic conditions and followed by condensation reaction of N-alkylated products (3) with thiosemicarbazide. We found that the N-alkylation of azanaphthoquinone annelated pyrrole (61) using two carbon side chains and its further condensation with thiosemicarbazide underwent smoothly to provide the desired products in good yields. On the other hand, longer side chain of alkylating agents (three carbon side chains) required the longer reaction time, and the products were obtained in morderate yields. In series two, N-alkylated products of 1-aminoanthraquinone (64) were successfully synthesized in moderate to good yields. The antiptoliferative activity of the synthezied compounds was evaluated against cervical carcinoma, HeLa cell line. N-Alkylated products (3) showed the most active compound, while thiosemicarbazone analogues (62) exhibited slightly higher activity than hydrazones 6. Incontrast, N-Alkylated products of 1-aminoanthraquinone (64) had to inhibitory against HeLa cell. This exploratory study provided interesting information of future designing and developing new core structures with more potent anticancer agents.