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

Author(s): Md Rahmat Ali, Suresh Kumar, Nishtha Shalmali, Obaid Afzal, Sabir Azim, Damini Chanana, Ozair Alam, Yam Nath Paudel, Manju Sharma, Sandhya Bawa*.

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 19 , Issue 5 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Introduction: 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.

Methodology: 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.

Conclusion: 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.

Keywords: Thiazole, 2-arachidonoylglycerol, Endocannabinoid, Monoacylglycerol lipase, NCI 60 cell line, Breast Cancer, endocannabinoid system (ECS).

[1]
Matuszak, N.; Es-Saadi, B.; Labar, G.; Marchand-Brynaert, J.; Lambert, D.M. Benzisothiazolinone as a useful template for the design of new monoacylglycerol lipase inhibitors: Investigation of the target residues and comparison with octhilinone. Bioorg. Med. Chem. Lett., 2011, 21, 7321-7324.
[2]
Aaltonen, N.; Savinainen, J.R.; Ribas, C.R.; Ronkko, J. Kuusisto.A.; Korhonen.J.; Navia-Paldanius, D.; Hayrinen, J.; Takabe, P.; Kasnanen, H.; Pantsar, T.; Laitinen, T.; Lehtonen, M.; Pasonen-Seppanen, S.; Poso, A.; Nevalainen, T.; Laitinen, J.T. Piperazine and piperidine triazole ureas as ultrapotent and highly selective inhibitors of monoacylglycerol lipase. Chem. Biol., 2013, 20, 379-390.
[3]
Tabrizi, M.A.; Baraldi, P.G.; Ruggiero, E.; Saponaro, G.; Baraldi, S.; Romagnoli, R.; Martinelli, A.; Tuccinardi, T. Pyrazole phenylcyclohexylcarbamates as inhibitors of human fatty acid amide hydrolases (FAAH). Eur. J. Med. Chem., 2015, 97, 289-305.
[4]
Labar, G.; Wouters, J.; Lambert, D.M. A Review on the monoacylglycerol lipase: At the interface between fat and endocannabinoid signalling. Curr. Med. Chem., 2010, 17, 2588-2607.
[5]
Kapanda, C.N.; Masquelier, J.; Labar, G.; Muccioli, G.G.; Poupaert, J.H.; Lambert, D.M. Synthesis and pharmacological evaluation of 2, 4-Dinitroaryldithiocarbamate derivatives as novel monoacylglycerol lipase inhibitors. J. Med. Chem., 2012, 55, 5774-5783.
[6]
Holtfrerich, A.; Hanekamp, W.; Lehr, M. (4-Phenoxyphenyl)-tetrazolecarboxamides and related compounds as dual inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Eur. J. Med. Chem., 2013, 63, 64-75.
[7]
Fowler, C.J. Monoacylglycerol lipase-a target for drug development? British. J. Pharmacol., 2012, 166, 1568-1585.
[8]
Magrioti, V.; Naxakis, G.; Hadjipavlou-Litina, D.; Makriyannis, A.; Kokotos, G. A novel monoacylglycerol lipase inhibitor with analgesic and anti-inflammatory activity. Bioorg. Med. Chem. Lett., 2008, 18, 5424-5427.
[9]
Mulvihill, M.M.; Nomura, D.K. Therapeutic Potential of Monoacylglycerol Lipase Inhibitors. Life Sci., 2013, 92, 492-497.
[10]
Afzal, O.; Akhtar, M.S.; Kumar, S.; Ali, M.R.; Jaggi, M.; Bawa, S. Hit to lead optimization of a series of N-[4-(1, 3-benzothiazol-2-yl)phenyl]acetamides as monoacylglycerol lipase inhibitors with potential anticancer activity. Eur. J. Med. Chem., 2016, 121, 318-330.
[11]
Hicks, J.W.; Parkes, J.; Tong, J.; Houle, S.; Vasdev, N.; Wilson, A.A. Radiosynthesis and ex vivo evaluation of [11C-carbonyl]-carbamate- and urea-based monoacylglycerol lipase inhibitors. Nuc. Med. Biol., 2014, 41, 688-694.
[12]
Wang, A.B. Synthesis of phenyl thioureas containing para substituted tertiary amino groups. Acta Chimica. Sinica.., 1954, 20, 73-76.
[13]
Mishra, P.K.; Dudhe, R.; Chaudhary, A.; Sharma, P.K. Synthesis and biological evaluation of N3-(4-substituted phenyl)-N5-phenyl-4H-1, 2, 4-triazole-3, 5-diamine derivatives. Orient. J. Chem., 2009, 25, 653-657.
[14]
Process for the preparation of febuxostat and salts thereof, US Patent No-WO2011/073617 A1,
[15]
Mhaske, P.C.; Vadgaonkar, K.S.; Jadhav, R.P.; Bobade, V.D. Synthesis and Biological Screening of Thiazole-5-Carboxamide Derivatives. J. Kor. Chem. Soc., 2011, 55, 882-886.
[16]
An Improved process for preparation of febuxostat and its polymorphic crystalline form thereof,, US Patent No-WO2012/131590 A1.,
[17]
Christian, A.G.N.; Montalbetti, C.A.G.N.; Falque, V. Amide bond formation and peptide coupling. Tetrahedron, 2005, 61, 10827-10852.
[18]
Muccioli, G.; Labar, G.; Lambert, D. CAY10499, a novel monoglyceride lipase inhibitor evidenced by an expeditious MGL assay. ChemBioChem, 2008, 9, 2704-2710.
[19]
Grever, M.R.; Schepartz, S.A.; Chabner, B.A. The National Cancer Institute: Cancer drug discovery and development program. Semin. Oncol., 1992, 19, 622-638.
[20]
Shoemaker, R.H. The NCI60 human tumour cell line anticancer drug screen. Natl. Rev., 2006, 6, 813-823.
[21]
Corona, P.; Carta, A.; Loriga, M.; Vitale, G.; Paglietti, G. Synthesis and in vitro antitumor activity of new quinoxaline derivatives. Eur. J. Med. Chem., 2009, 44, 1579-1591.
[22]
Holbeck, S.L.; Collins, J.M.; Doroshow, J.H. Analysis of Food and Drug Administration-approved anticancer agents in the NCI60 panel of human tumor cell lines. Mol. Cancer Ther., 2010, 9, 1451-1460.
[23]
Boyd, M.R.; Paull, K.D. Some practical considerations and applications of the National Cancer Institute in vitro anticancer drug discovery screen. Drug Dev. Res., 1995, 34, 91-109.
[24]
Schrodinger, M. Maestro, Version 10.1, LLC, New York, NY, 2015.
[25]
Schalk-Hihi, C.; Schubert, C.; Alexander, R.; Bayoumy, S.; Clemente, J.C.; Deckman, I.; Jarlais, D.R.L.; Dzordzorme, K.C.; Flores, C.M.; Grasberger, B.; Kranz, J.K.; Lewandowski, F.; Liu, L.; Ma, H.; Maguire, D.; Macielag, M.J.; Mc-Donnell, M.E.; Mezzasalma, H.T.; Miller, R.; Milligan, C.; Reynolds, C.; Kuo, L.C. Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 Å resolution. Protein Sci., 2011, 20, 670.
[26]
Loving, K.; Salam, N.K.; Sherman, W.J. Energetic analysis of fragment docking and application to structure-based pharmacophore hypothesis generation. J. Comput. Aided Mol. Des., 2009, 23, 541.
[27]
Ali, M.R.; Kumar, S.; Afzal, O.; Shalmali, N.; Sharma, M.; Bawa, S. Development of 2-(Substituted Benzylamino)-4-Methyl-1, 3-Thiazole-5-Carboxylic acid derivatives as xanthine oxidase inhibitors and free radical scavengers. Chem. Biol. Drug Des., 2016, 87, 508-516.
[28]
Hopkins, A.L.; Keserü, G.M.; Leeson, P.D.; Rees, D.C.; Reynolds, C.H. The role of ligand efficiency metrics in drug discovery. Nat. Rev. Drug Discov., 2014, 13, 105-121.
[29]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. J. Adv. Drug Deliv. Rev., 2001, 46, 3.
[30]
Hou, T. Wang, J.; Zhang, W.; Xu, X. ADME evaluation in drug discovery. Can oral bioavailability in humans be effectively predicted by simple molecular property-based rules? J. Chem. Inf. Model., 2007, 47, 460-463.
[31]
Meanwell, N.A. Improving drug candidates by design: a focus on physicochemical properties as a means of improving compound disposition and safety. Chem. Res. Toxicol., 2001, 24-, 1420-1456. I.
[32]
Tarcsay, A.; Nyíri, K.; Keseru, G.M. Impact of lipophilic efficiency on compound quality. J. Med. Chem., 201(55), 1252-1260.


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 19
ISSUE: 5
Year: 2019
Page: [410 - 423]
Pages: 14
DOI: 10.2174/1389557518666180702103542
Price: $58

Article Metrics

PDF: 17
HTML: 3
EPUB: 1