Formation of a defluorinated metabolite of a quinoxaline antiviral drug catalysed by human cytochrome P450 1A2

Abstract

The in-vitro metabolism of GW420867X ((S)-2-ethyl-7-fluoro-3-oxo-3, 4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester), a quinoxaline drug for the potential treatment of HIV, has been studied with singly expressed human cytochromes P450 (CYP 450). No biotransformation of [14C]GW420867X was evident in the presence of any of the CYP 450 isoforms, with the exception of CYP 450 1A2, where a single metabolite was observed in the HPLC radiochromatograms of enzyme incubations with the test compound. The structure of this metabolite was determined by nuclear magnetic resonance spectroscopy and mass spectrometry, and was shown to correspond to the replacement of the aromatic fluorine of GW420867X with a hydroxyl group. Thus, it appeared that CYP 450 1A2 catalysed the specific defluorination of GW420867X, presumably during formation of an arene oxide intermediate during aromatic hydroxylation.

Discovery of a P450-Catalyzed Oxidative Defluorination Mechanism toward Chiral Organofluorines: Uncovering a Hidden Pathway

“…Cytochrome P450 monooxygenases are ubiquitous and versatile biocatalysts found in nature, − which partake in the metabolism of various endogenous and exogenous compounds such as drugs, environmental pollutants, and carcinogens. − Relevant to our present study is the finding that P450s are capable of catalyzing the oxidative defluorination of certain fluoroalkanes, − fluoro-aromatics − and even fluorine-containing macromolecular drugs. − Although varieties of oxidative defluorination procedures catalyzed by P450 have been reported, mechanistic studies have focused mainly on the defluorination of fluorinated aromatic compounds, as reported in pioneering studies. ,− ,, P450-catalyzed oxidative defluorination of fluorinated aromatics involves an electrophilic attack of Fe IV O (Cpd I) on the substrate, the formation and rearrangement of a transient cationic intermediate, and the generation of quinone and fluoride ion release as final Fe–O bond cleavage occurs (Scheme a). In the presence of a reducing agent, the quinone can be further reduced to phenolic products such as hydroquinone.…”

Metabolism studies of 4′Cl‐CUMYL‐PINACA, 4′F‐CUMYL‐5F‐PINACA and 4′F‐CUMYL‐5F‐PICA using human hepatocytes and LC‐QTOF‐MS analysis

“…Oxidative defluorination at aromatic structures has been previously detected for GW420867X, an antiviral HIV drug withdrawn from clinical trials 30 ; famitinib, currently in Phase III trials in cancer treatment 31,32 ; and sunitinib and gefitinib, both currently used in cancer treatment 33,34 . From the listed pharmaceuticals, only famitinib and sunitinib share the same fluorinated ring structure.…”

Synthesis and antibacterial properties of new N4-acetylated hexahydro-2,7-dioxopyrido[2,3-f]quinoxaline-8-carboxylic acids

“…[1][2][3][4][5] Some derivatives such as 7-(4-arylpiperazin-1-yl)-6-fluoro-8-trifluoromethylquinolones, for example 1b, were reported to act as non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1 reverse transcriptase. [6][7][8][9] 1a (R 1 = c-C 3 H 5 ; R 2 On the other hand, simple or heterocyclic-fused quinoxalinones have become interesting compounds for study as antiviral agents [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] exemplified by the 3,4-dihydroquinoxalin-2-one core (2, Y=O), a second generation of NNRTIs, that is opaviraline (2a) [22][23][24][25][26][27] and the related 2-thione talveraline (2b), [14][15][16][17][18][19] are in clinical development. …”