Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi-110062, India.
Department of Pharmacology, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi-110062, India.
Mini Rev Med Chem. 2019;19(5):410-423. 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.
内源性大麻素系统中的 2-花生四烯酸甘油（2-AG）的信号功能由单酰基甘油脂肪酶（MAGL）来描绘。MAGL 将脂质库重新定向到癌细胞中的促肿瘤信号脂质。选择性和有效的 MAGL 抑制剂数量有限，因此它们的持续开发可能会在 MAGL 抑制剂领域取得突破发明。基于上述内容，我们合成了 2-氨基-4-甲基噻唑-5-羧酸酯衍生物，并通过红外光谱（IR）、1H-NMR、13C-NMR、质谱数据和元素分析对其进行了综合表征。
13 种化合物（3c-g、4c、4e、4f 和 6b-f）对 MAGL 的抑制作用具有 IC50 值，范围为 0.037-9.60µM。两种化合物（3g 和 4c）被发现具有最强的抑制作用，IC50 值分别为 0.037µM 和 0.063µM。我们将 30 种合成的化合物送到 NCI 进行抗癌筛选，其中 9 种化合物被选为单剂量抗癌测定。化合物 3g（NSC：788170）和 4c（NSC：788176）在单剂量抗癌筛选中表现出最强的活性，并且满足 NCI 生长抑制标准的特定阈值，因此进一步被选为在五种不同浓度的 10 倍稀释下进行全谱五剂量测定。
化合物 3g 对 EKVX（非小细胞肺癌细胞系）的 GI50 值为 0.865µM，对 MDA-MB-468（乳腺癌细胞系）的 GI50 值为 1.20µM，而（4c）对 HOP-92 和 EKVX（非小细胞肺癌细胞系）的 GI50 值分别为 0.34µM 和 0.96µM，对 MDA-MB-231/ATCC（乳腺癌细胞系）的 GI50 值为 1.08µM。此外，本文还介绍了所述 MAGL 抑制剂的分子对接研究。
