Development of Thiazole-5-carboxylate Derivatives as Selective Inhibitors of Monoacylglycerol Lipase as Target in Cancer

• Published in: Mini reviews in medicinal chemistry Vol. 19; no. 5; p. 410
• Main Authors: Ali, Md Rahmat, Kumar, Suresh, Shalmali, Nishtha, Afzal, Obaid, Azim, Sabir, Chanana, Damini, Alam, Ozair, Paudel, Yam Nath, Sharma, Manju, Bawa, Sandhya
• Format: Journal Article
• Language: English
• Published: Netherlands 01-01-2019
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Arachidonic Acids - metabolism; Breast Neoplasms - drug therapy; Breast Neoplasms - enzymology; Breast Neoplasms - metabolism; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - enzymology; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Line, Tumor; Endocannabinoids - metabolism; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Female; Glycerides - metabolism; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Lung Neoplasms - metabolism; Molecular Docking Simulation; Monoacylglycerol Lipases - antagonists & inhibitors; Monoacylglycerol Lipases - chemistry; Monoacylglycerol Lipases - metabolism; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - metabolism; Structure-Activity Relationship; Thiazoles - chemistry; Thiazoles - pharmacology; endocannabinoid system (ECS); Monoacylglycerol lipase; Endocannabinoid; Breast Cancer; NCI 60 cell line; Thiazole; 2-arachidonoylglycerol
• ISSN: 1875-5607
• DOI: 10.2174/1389557518666180702103542

The signalling function of 2-arachidonoylglycerol (2-AG) in endocannabinoid system is delineated by Monoacylglycerol lipase (MAGL). MAGL readdresses the lipid stores in the direction of pro-tumorigenic signalling lipids in cancer cells. Selective as well as potent MAGL inhibitors are limited in number hence their continuous development may lead to a breakthrough invention in the field of MAGL inhibitors. In succession of the above, we have synthesised 2-amino-4- methylthiazole-5-carboxylate derivatives and characterised them by collective use of IR, 1H-NMR, 13C-NMR, Mass spectral data and elemental analysis.
Thirteen compounds (3c-g, 4c, 4e, 4f and 6b-f) inhibited MAGL with IC50 value 0.037- 9.60 µM. Two compounds (3g and 4c) were found to be most potent with IC50 values 0.037 and 0.063µM, 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.
Compound 3g displayed GI50 value 0.865 μM against EKVX (Non-Small Cell Lung Cancer cell line), and 1.20 µM against MDA-MB-468 (Breast Cancer cell Line), while (4c) showed GI50 value 0.34 and 0.96 µM against HOP-92 and EKVX (Non-Small Cell Lung Cancer cell line) and 1.08 µM against MDA-MB-231/ATCC(Breast Cancer cell Line). In addition, molecular docking studies of the said MAGL inhibitors have also been presented in this article.