Biomimetic Reduction of Nimesulide with NaBH4 Catalyzed by Metalloporphyrins.

Abstract

The biomimetic reduction of anti-inflammatory drug, nimesulide (1) with sodium borohydride catalyzed by 5,10,15,20-tetraarylporphyrinatoiron(III) chlorides [TAPFe(III)Cl] has been studied in organic solvents under anaerobic and aerobic conditions. Key words biomimetic reduction; nimesulide; metalloporhyrin; sodium borohydride; 4-aminonimesulide; 4Ј-hydroxynimesulide Nimesulide (4-nitro-2-phenoxymethanesulfonanilide) (1) is a potent nonsteroidal anti-inflammatory, analgesic and anti-pyretic agent. It inhibits cyclooxygenase-2 selectively 1,2) and reduces prostaglandin proinflammatory activity without interfering with the production of cytoprotective prostaglandins of gastric mucous membrane.3) 4-Aminonimesulide (2) (reductive metabolite) and 4Ј-hydroxynimesulide (3) (oxidative metabolite) have been reported as minor and major metabolites of 1, respectively, in urine and feces [4][5][6] of man (Chart 1).Further 1 is a protonophore and mitochondrial NAD(P)H oxidant agent whereas 2 has been reported as supressor of the above mitochondrial responses.7) It has also been shown that the reduced metabolite (2) partly protects against accumulation of reactive oxygen species (ROS) derived from the organelle under conditions of oxidative stress.7) The combination of sodium borohydride and metalloporphyrins have been shown to mimic the various redox transformations of organic substrates catalyzed by cytochrome P450 and NAD(P)H, in absence or presence of molecular oxygen. [8][9][10][11][12][13][14] Herein, we report the biomimetic reduction of 1 with sodium borohydride catalyzed by metalloporphyrins in organic solvents under anaerobic and aerobic conditions.In a typical run sodium borohydride (1200 mmol) was added to a mixture of 1 (100 mmol) and 5,10,15,20-tetraphenylporphyrinatoiron(III) chloride (TPPFe(III)Cl, 1 mmol) in methanol : dichloromethane (9 : 1, v/v) under nitrogen atmosphere. The reaction was stirred for 1 h at room temperature. The progress of the reaction was monitored by TLC and HPLC. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel to give 2 in 89% yield (Chart 2, Table 1). The formation of 2 was confirmed by comparison of HPLC retention time as well as other spectroscopic data 15) with that of authentic sample.The presence of molecular ion peak at 277 in electron impact (EI)-MS shows the complete reduction of 1 to 2. Further, the presence of a peak at 199 shows the loss of -SO 2 CH 3 group from the parent molecule. The appearance of broad singlet at 3.7 ppm in 1 H-NMR shows the presence of -NH 2 group in the compound. The upfield chemical shifts of aromatic protons show the complete reduction of nitro group to amino group. The presence of two peaks around 3394 and 3339 cm Ϫ1 in IR spectrum also confirms the formation of 2. The reduction of nimesulide is directly proportional to the substrate, NaBH 4 and iron(III) porphyrin ratio under N 2 atmosphere. As the ratio of iron(III) porphyrin and NaBH 4 is increased to 1 : 1200 mmol the reduction of nimesulide has c...

Biomimetic Chemical Catalysts in the Oxidative Activation of Drugs

“…[58] The combination of sodium borohydride and metalloporphyrins used in the absence or presence of molecular oxygen have been shown to mimic the various redox transformations of organic substrates by cytochrome P450 and NAD(P)H. As an example, the nonsteroidal anti-inflammatory, analgesic and antipyretic agent nimesulide (a selective inhibitor of cyclooxygenase-2) could give under aerobic conditions 4-aminonimesulide and 4'-hydroxynimesulide, which are the two reduced and oxidized metabolites found in the in vivo metabolic profile of this drug (Figure 19). [59] Figure 16. Biomimetic oxidation of aminopyrine.…”

“…Treatment of nimesulide with sodium borohydride and metalloporphyrins under anaerobic and aerobic conditions as a mimic of the in vivo cytochrome P450/NAD(P)H transformation. [59] REVIEWS Jean Bernadou, Bernard Meunier…”