A new class of antimetabolites: Pyridine thioglycosides as potential anticancer agents

Abstract

The present study was designed for highlighting and focusing on the cytotoxic activity of a new class of antimetabolites both on human cell lines, namely liver carcinoma cell line (Hepg2), lung carcinoma cell line (H460), breast carcinoma cell line (MCF7), brain carcinoma cell line (U251), and animal cell line EAC (Ehrlich ascites carcinoma cells). The results revealed that some of these modifi ed deazapyrimidine thioglycosides have signifi cant cytotoxic activity against EAC cells with growth inhibition percentage ranged between 80% to 90%. The possible inhibitory mechanism of the pyridine thioglycosides was explored by studying the cell cycle perturbation of thioglycosides against human cell lines (in vitro) as well as the most suitable time for maximum compound cytotoxic activity after 6, 18, and 24 h of incubation. To confi rm the cytotoxic activity of these compounds, they have been tested for their apoptotic and antiproliferative activity in vivo against solid Ehrlich tumours using fi ve groups of Swiss albino mice for 37 days from inoculation and three treatments, 250, 500 and 1,000 μg/kg body weight. There was signifi cant reduction in Ehrlich tumour size in case of the 500 and 1,000 μg/kg body weight group but mild signifi cant tumour reduction in the 250 μg/kg body weight group. Histograms of DNA per cell for each treatment group indicated that there was a dose-dependent increase in the preG1 phase with a corresponding complete arrest of cells from entering the G2/M phase compared to the untreated EAC group. In conclusion, pyridine thioglycosides have proven good cytotoxic effects against EAC cells and also signifi cant cytotoxic activity against the four tested human cell lines. Flow cytometric DNA ploidy analysis of pyridine thioglcyosides against the Hepg2 and U251 cell lines revealed that the postulated mechanism of action of pyridine thioglcyosides is cell cycle arrest in the S phase. This is similar to antimetabolites and cell cycle arrest in the G2/M phase (M phase) in the same way as microtubule inhibitors like pyridine thioglycosides are cell-cycle-specifi c in the S phase and the M phase (in case of human cell lines) and have apoptotic effects (in case of animal cell line). © 2010 Verlag der Zeitschrift für Naturforschung. Tübingen.