glyceryl-2-arachidonate and Lung-Neoplasms

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.

Topics: Antineoplastic Agents; Arachidonic Acids; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Endocannabinoids; Enzyme Inhibitors; Female; Glycerides; Humans; Lung Neoplasms; Molecular Docking Simulation; Monoacylglycerol Lipases; Neoplasms; Structure-Activity Relationship; Thiazoles

The endocannabinoid system has been considered as a target for pharmacological intervention. Accordingly, inhibition of fatty acid amide hydrolase (FAAH), a degrading enzyme of the endocannabinoids N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG) as well as of the endocannabinoid-like substances N-oleoylethanolamine (OEA) and N-palmitoylethanolamine (PEA), can cause augmented endogenous cannabinoid tone. Using liquid chromatography coupled with positive electrospray ionisation mass spectrometry, we herein describe a method to simultaneously quantify levels of AEA, OEA, PEA and 2-AG in cultured cells. The procedure was developed according to the FDA guidelines for bioanalytical methods validation. The limits of quantification (LOQs) were 0.05 pmol for AEA, 0.09 pmol for OEA, 0.10 pmol for PEA and 0.80 pmol for 2-AG when molecular ion monitoring was used. In H460 human lung carcinoma cells, basal levels of all four analytes ranged between 2 and 17 pmol mg(-1) protein with PEA showing the lowest and OEA the highest concentrations. Endocannabinoid levels observed in mesenchymal stem cells were of the same order of magnitude when compared to those in H460 human lung carcinoma cells.

Topics: Amides; Arachidonic Acids; Cell Line, Tumor; Chromatography, Liquid; Endocannabinoids; Ethanolamines; Glycerides; Humans; Limit of Detection; Lung Neoplasms; Mass Spectrometry; Mesenchymal Stem Cells; Oleic Acids; Palmitic Acids; Polyunsaturated Alkamides; Reproducibility of Results