Login Register Cart 0
Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

The Effects of Trifluoromethylated Derivatives on Prostaglandin E2 and Thromboxane A2 Production in Human Leukemic U937 Macrophages

Author(s): Ivana Beara*, Tatjana Majkić, Stefania Fioravanti, Laura Trulli, Neda Mimica-Dukić, Lucio Pellacani and "> Luciano Saso

Volume 16, Issue 1, 2020

Page: [63 - 68] Pages: 6

DOI: 10.2174/1573406415666190208150253

Price: $65

Abstract

Background: A convenient approach to modulation of the inflammation has an influence on the production of inflammatory mediators – icosanoids, generated in arachidonic acid (AA) metabolism. The common therapeutic activity of non-steroidal anti-inflammatory drugs (NSAID), such as aspirin, includes inhibition of two crucial enzymes of AA metabolism - cyclooxygenase- 1 and -2 (COX-1/2), with certain risk for gastrointestinal and renal intolerance. Ever since the enrolment of COX-2, particularly overabundance of its main products prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) in numerous pathological processes was recognized, it became a significant therapeutic target.

Objective: The aim of this study was to examine the effects of synthesized organo-fluorine compounds on PGE2 and TXA2 production in the inflammation process.

Methods: Trifluoromethyl compounds were synthesized from N-benzyl trifluoromethyl aldimine, commercially available 2-methyl or 2-phenyl α-bromo esters (β-lactams trans-1 and trans-2 and trifluoromethyl β-amino ester, respectively) and methyl 2-isocyanoacetate (2-imidazoline trans-4). The reactions proceeded with high geometric selectivity, furnishing the desired products in good yields. The influence of newly synthesized compounds on PGE2 and TXA2 production in human leukemic U937 macrophages on both enzyme activity and gene expression levels was observed.

Results: Among the tested trifluoromethyl compounds, methyl trans-1-benzyl-5-(trifluoromethyl)- 4,5-dihydro-1H-imidazole-4-carboxylate (trans-4) can be distinguished as the most powerful antiinflammatory agent, probably due to its trifluoromethyl-imidazoline moiety.

Conclusion: Some further structural modifications in tested compounds and particularly in the synthesis of different trifluoromethyl imidazolines could contribute to the development of new COX-2 inhibitors and potent anti-inflammatory agents.

Keywords: Inflammation, trifluoromethyl derivatives, cyclooxygenase, macrophage, lipoxygenases, enzymes.

« Previous Next »
Graphical Abstract

[1]
Smith, W.L. The eicosanoids and their biochemical mechanisms of action. Biochem. J., 1989, 259(2), 315-324.
[http://dx.doi.org/10.1042/bj2590315] [PMID: 2655580]
[2]
Morita, I. Distinct functions of COX-1 and COX-2. Prostaglandins Other Lipid Mediat., 2002, 68-69, 165-175.
[http://dx.doi.org/10.1016/S0090-6980(02)00029-1] [PMID: 12432916]
[3]
Park, J.Y.; Pillinger, M.H.; Abramson, S.B.; Prostaglandin, E. Prostaglandin E2 synthesis and secretion: the role of PGE2 synthases. Clin. Immunol., 2006, 119(3), 229-240.
[http://dx.doi.org/10.1016/j.clim.2006.01.016] [PMID: 16540375]
[4]
Koeberle, A.; Laufer, S.A.; Werz, O. Design and development of microsomal prostaglandin E2 synthase-1 inhibitors: challenges and future directions. J. Med. Chem., 2016, 59(13), 5970-5986.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01750] [PMID: 26791385]
[5]
Penglis, P.S.; Cleland, L.G.; Demasi, M.; Caughey, G.E.; James, M.J. Differential regulation of prostaglandin E2 and thromboxane A2 production in human monocytes: implications for the use of cyclooxygenase inhibitors. J. Immunol., 2000, 165(3), 1605-1611.
[http://dx.doi.org/10.4049/jimmunol.165.3.1605] [PMID: 10903770]
[6]
Müller, K.; Faeh, C.; Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science, 2007, 317(5846), 1881-1886.
[http://dx.doi.org/10.1126/science.1131943] [PMID: 17901324]
[7]
Hagmann, W.K. The many roles for fluorine in medicinal chemistry. J. Med. Chem., 2008, 51(15), 4359-4369.
[http://dx.doi.org/10.1021/jm800219f] [PMID: 18570365]
[8]
Purser, S.; Moore, P.R.; Swallow, S.; Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev., 2008, 37(2), 320-330.
[http://dx.doi.org/10.1039/B610213C] [PMID: 18197348]
[9]
Böhm, H.J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M. Fluorine in medicinal chemistry. ChemBioChem, 2004, 5(5), 637-643.
[http://dx.doi.org/10.1002/cbic.200301023] [PMID: 15122635]
[10]
Jeschke, P. The unique role of fluorine in the design of active ingredients for modern crop protection. ChemBioChem, 2004, 5(5), 571-589.
[http://dx.doi.org/10.1002/cbic.200300833] [PMID: 15122630]
[11]
Maienfisch, P.; Hall, R.G. The importance of fluorine in the life science industry. Chimia (Aarau), 2004, 58(3), 93-99.
[http://dx.doi.org/10.2533/000942904777678091]
[12]
Berger, R.; Resnati, G.; Metrangolo, P.; Weber, E.; Hulliger, J. Organic fluorine compounds: a great opportunity for enhanced materials properties. Chem. Soc. Rev., 2011, 40(7), 3496-3508.
[http://dx.doi.org/10.1039/c0cs00221f] [PMID: 21448484]
[13]
O’Hagan, D. Fluorine in health care: Organofluorine containing blockbuster drugs. J. Fluor. Chem., 2010, 131(11), 1071-1081.
[http://dx.doi.org/10.1016/j.jfluchem.2010.03.003]
[14]
Xie, Z.; Zhang, Z.; Yu, S.; Cheng, D.; Zhang, H.; Han, C.; Lv, H.; Ye, F. Synthesis and evaluation of anti-inflammatory N-substituted 3,5-bis(2-(trifluoromethyl)benzylidene)piperidin-4-ones. ChemMedChem, 2017, 12(4), 327-336.
[http://dx.doi.org/10.1002/cmdc.201600606] [PMID: 28098433]
[15]
Sommer, H.; Braun, M.; Schröder, B.; Kirschning, A. 4-Ethoxy-1,1,1-trifluoro-3-buten-2-one (ETFBO), a versatile precursor for trifluoromethyl-substituted heteroarenes – a short synthesis of Celebrex® (Celecoxib). Synlett, 2018, 29(1), 121-125.
[http://dx.doi.org/10.1055/s-0036-1589097]
[16]
Kamath, A.; Ojima, I. Advances in the chemistry of β-lactam and its medicinal applications. Tetrahedron, 2012, 68(52), 10640-10664.
[http://dx.doi.org/10.1016/j.tet.2012.07.090] [PMID: 23264702]
[17]
Sarnpitak, P.; Mujumdar, P.; Morisseau, C.; Hwang, S.H.; Hammock, B.; Iurchenko, V.; Zozulya, S.; Gavalas, A.; Geronikaki, A.; Ivanenkov, Y.; Krasavin, M. Potent, orally available, selective COX-2 inhibitors based on 2-imidazoline core. Eur. J. Med. Chem., 2014, 84, 160-172.
[http://dx.doi.org/10.1016/j.ejmech.2014.07.023] [PMID: 25016374]
[18]
Trulli, L.; Sciubba, F.; Fioravanti, S. Chiral trans-carboxylic trifluoromethyl 2-imidazolines by a Ag2O-catalyzed Mannich-type reaction. Tetrahedron, 2017, 74(5), 572-577.
[http://dx.doi.org/10.1016/j.tet.2017.12.029]
[19]
Carroccia, L.; Fioravanti, S.; Pellacani, L.; Tardella, P.A. Solvent-free stereoselective synthesis of (E)-trifluoromethyl imines and hydrazones. Synthesis, 2010, 23, 4096-4100.
[20]
Dos Santos, M.; Crousse, B.; Bonnet-Delpon, D. Barbier conditions for Reformatsky and alkylation reactions on trifluoromethyl aldimines. Synlett, 2008, 3, 399-401.
[21]
Fioravanti, S. Trifluoromethyl aldimines: an overview in the last ten years. Tetrahedron, 2016, 72(30), 4449-4489.
[http://dx.doi.org/10.1016/j.tet.2016.06.015]
[22]
Trulli, L.; Raglione, V.; Fioravanti, S. Selective synthesis of trifluoromethyl β-lactams by a Zn-promoted 2-bromo ester addition on C-CF3-substituted aldimines. Eur. J. Org. Chem., 2018, 3743-3749.
[http://dx.doi.org/10.1002/ejoc.201800168]
[23]
Wong, E.; DeLuca, C.; Boily, C.; Charleson, S.; Cromlish, W.; Denis, D.; Kargman, S.; Kennedy, B.P.; Ouellet, M.; Skorey, K.; O’Neill, G.P.; Vickers, P.J.; Riendeau, D. Characterization of autocrine inducible prostaglandin H synthase-2 (PGHS-2) in human osteosarcoma cells. Inflamm. Res., 1997, 46(2), 51-59.
[http://dx.doi.org/10.1007/s000110050063] [PMID: 9085144]
[24]
Beara, I.N.; Orcić, D.Z.; Lesjak, M.M.; Mimica-Dukić, N.M.; Peković, B.A.; Popović, M.R. Liquid chromatography/tandem mass spectrometry study of anti-inflammatory activity of plantain (Plantago L.) species. J. Pharm. Biomed. Anal., 2010, 52(5), 701-706.
[http://dx.doi.org/10.1016/j.jpba.2010.02.014] [PMID: 20219312]
[25]
Lesjak, M.; Beara, I.; Orčić, D.; Ristić, J.; Anačkov, G.; Božin, B.; Mimica-Dukić, N. Chemical characterisation and biological effects of Juniperus foetidissima Willd. 1806. Lebensm. Wiss. Technol., 2013, 53(2), 530-539.
[http://dx.doi.org/10.1016/j.lwt.2013.03.010]
[26]
Jiang, Y.J.; Lu, B.; Choy, P.C.; Hatch, G.M. Regulation of cytosolic phospholipase A2, cyclooxygenase-1 and -2 expression by PMA, TNFalpha, LPS and M-CSF in human monocytes and macrophages. Mol. Cell. Biochem., 2003, 246(1-2), 31-38.
[http://dx.doi.org/10.1023/A:1023495626568] [PMID: 12841340]
[27]
Chomczynski, P.; Sacchi, N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem., 1987, 162(1), 156-159.
[http://dx.doi.org/10.1016/0003-2697(87)90021-2] [PMID: 2440339]
[28]
Grosser, T.; Fries, S.; FitzGerald, G.A. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J. Clin. Invest., 2006, 116(1), 4-15.
[http://dx.doi.org/10.1172/JCI27291] [PMID: 16395396]
[29]
Petracca, R.; Ponzano, S.; Bertozzi, S.M.; Sasso, O.; Piomelli, D.; Bandiera, T.; Bertozzi, F. Progress in the development of β-lactams as N-Acylethanolamine Acid Amidase (NAAA) inhibitors: Synthesis and SAR study of new, potent N-O-substituted derivatives. Eur. J. Med. Chem., 2017, 126, 561-575.
[http://dx.doi.org/10.1016/j.ejmech.2016.11.039] [PMID: 27915171]

Rights & Permissions Print Cite
Article Metrics
26
1
© 2024 Bentham Science Publishers | Privacy Policy