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

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

Journal Name: Medicinal Chemistry

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Background: Convenient approach to modulation of the inflammation is influence on production of inflammatory mediators – eicosanoids, generated in arachidonic acid (AA) metabolism. 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 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 significant therapeutic target.

Objective: The aim of this study was to examine effects of synthesized organo-fluorine compounds on PGE2 and TXA2 production in 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 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 anti-inflammatory agent, probably due to its trifluoromethyl-imidazoline moiety.

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

Keywords: inflammation, trifluoromethyl derivatives, cyclooxygenase, macrophage.

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(E-pub Ahead of Print)
DOI: 10.2174/1573406415666190208150253
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