Abstract
Introduction: The signalling function of 2-arachidonoylglycerol (2-AG) in endocannabinoid system is delineated by Monoacylglycerol lipase (MAGL). MAUL readdresses the lipid stores in the direction of pro-tumorigenic signalling lipids in cancer cells. Selective as well as potent MAUL inhibitors are limited in number hence their continuous development may lead to a breakthrough invention in the field of MAUL inhibitors. In succession of the above, we have synthesised 2-amino-4-methylthiazole-5-carboxylate derivatives and characterised them by collective use of IR, H-1-NMR, C-13-NMR, Mass spectral data and elemental analysis.
Methodology: Thirteen compounds (3c-g, 4c, 4c, 4f and 6b-f) inhibited MAUL with IC50 value 0.037-9.60 mu M. Two compounds (3g and 4c) were found to be most potent with IC50 values 0.037 and 0.063 mu M, respectively. Thirty synthesised compounds were sent to NCI for anticancer screening, out of which nine compounds were selected for one dose anticancer assay. Compounds 3g (NSC:788170) and 4c (NSC:788176)were found to be the most potent during one dose anticancer screening and fulfilled the specified threshold for growth inhibition criteria of NCI and were further selected for full panel five dose assay at 10-fold dilutions of five different concentrations.
Conclusion: Compound 3g displayed GI(50) value 0.865 mu M against EKVX (Non-Small Cell Lung Cancer cell line), and 1.20 mu M against MDA-MB-468 (Breast Cancer cell Line), while (4c) showed GI(50) value 0.34 and 0.96 mu M against HOP-92 and EKVX (Non-Small Cell Lung Cancer cell line) and 1.08 mu M against MDA-MB-231/ATCC(Breast Cancer cell Line). In addition, molecular docking studies of the said MAUL inhibitors have also been presented in this article.