Apigenin-7-O-glucoside oxidation catalyzed by P450-bioinspired systems.

Apigenin-7-O-glucoside (A7G) is the main flavonoid of Bidens gardneri Bak., a Brazilian plant with wide application in folk medicine. Despite the popular use of this plant, its biological effects are not completely known. This work tested the 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin iron(III) and manganese(III) chloride (Fe(TFPP)Cl and Mn(TFPP)Cl), and Jacobsen's catalyst as P450-bioinspired catalysts for A7G oxidation by different oxidants (PhIO, H2O2, m-CPBA, and t-BuOOH). Up to nine different products were detected by HPLC analysis; Reactions with metalloporphyrin/PhIO systems afforded high catalytic conversions (58-89%). In spite of providing smaller product yields, the metalloporphyrin/H2O2 systems led to superior product distribution. Fe(TFPP)Cl yielded the highest A7G conversion rates (79-93%) with the four different oxidants tested herein. In the presence of PhIO, the oxidative profile of the manganese catalysts was very close to the oxidative profile of Fe(TFPP)Cl. However, in medium containing peroxide, the reactivity of the manganese catalysts was lower as compared to the reactivity of Fe(TFPP)Cl. Reactions with Fe(TFPP)Cl/oxidant systems were analyzed by UPLC-MS; up to thirteen compounds were detected. A7G oxidation catalyzed by Fe(TFPP)Cl yielded seven compounds. Three other compounds had m/z profile compatible with the profile of the A7G metabolites. The A7G oxidation assays performed in the presence of P450-bioinspired catalysts demonstrated their great catalytic potential toward A7G. The present results may be useful to many areas of knowledge and to the research and development of numerous chemical and phamarcological processes, especially in terms of drug design, biological assays, and applications in medicinal chemistry.

In vitro metabolism of monensin A: microbial and human liver microsomes models.

1. Monensin A, an important antibiotic ionophore that is primarily employed to treat coccidiosis, selectively complexes and transports sodium cations across lipid membranes and displays a variety of biological properties. 2. In this study, we evaluated the fungi Cunninghamella echinulata var. elegans ATCC 8688A, Cunninghamella elegans NRRL 1393 ATCC 10028B and human hepatic microsomes as CYP-P450 models to investigate the in vitro metabolism of monensin A and compare the products with the metabolites produced in vivo. 3. Mass spectrometry analysis of the products from these model systems revealed the formation of three metabolites: 3-O-demethyl monensin A, 12-hydroxy monensin A and 12-hydroxy-3-O-demethyl monensin A. We identified these products by tandem mass spectrometry and through comparison with the in vivo metabolites. 4. This analysis demonstrated that the model systems produce the same metabolites found in in vivo studies, thus they could be used to predict the metabolism of monensin A. Furthermore, we verified that liquid chromatography coupled to mass spectrometry is a powerful tool to study the in vitro metabolism of drugs, because it allows the successful identifications of several derivatives from different metabolic models.

Biomimetic oxidation studies of monensin A catalyzed by metalloporphyrins: identification of hydroxyl derivative product by electrospray tandem mass spectrometry

Monensin A is an important commercially available natural product isolated from Streptomyces cinnamonensins that shows antibiotic and anti-parasitic activities. This molecule has a significant influence in the antibiotic market, but until now there are no studies on putative metabolite formations. Bioorganic catalysts applying metalloporphyrins and mono-oxygen donors are able to mimic the cytochrome P450 reactions. This model has been employed for natural product metabolism studies affording several new putative metabolites and in vivo experiments confirming the relevance of this procedure. In this work we evaluated the potential of 10,15,20-tetrakis (pentafluorophenyl) porphyrin metal(III) chloride [Fe(TFPP)Cl] catalyst models to afford a putative monensin A metabolite. Oxidation agents such as meta-chloroperoxy benzoic acid, iodosylbenzene, hydrogen peroxide 30 wt.% and tert-butyl hydroperoxide 70 wt.%, were used to investigate different reaction conditions, in addition to the analysis of the influence of the solvent. The quantification of total monensin A conversion and the structure of the new hydroxylated putative metabolite were proposed based on electrospray ionization tandem mass spectrometry analysis. The porphyrin tested, afforded moderate conversions of monensin A in all reaction conditions and the selectivity was found to be dependent on the oxidation/medium employed.

Metalloporphyrins as biomimetic models for cytochrome p-450 in the oxidation of atrazine.

The aim of this work was to evaluate whether metalloporphyrin models could mimic the action of cytochrome P-450 in the oxidation of atrazine, a herbicide. The commercially available second-generation metalloporphyrins 5,10,15,20-tetrakis(2,6-dichlorophenyl)porphyrin metal(III) chloride [M(TDCPP)Cl] and 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin metal(III) chloride [M(TFPP)Cl] (metal = Fe or Mn) and the oxidants iodosylbenzene and metachloroperbenzoic acid were employed in this study. Results showed that the metalloporphyrins used here can oxidize atrazine. Yields as high as 32% were obtained for the Mn(TFPP)Cl/PhIO system, which shows that these catalysts can mimic both the in vivo and the in vitro action of cytochrome P-450, with formation of the metabolites DEA and DIA. The formation of five other unknown products was also detected, but only one of them could be identified, since the other four were present in very low concentrations. The compound COA, identified by mass spectrometry, was the main product in most of the oxidation reactions.

Photophysical properties of crowned porphyrins.

In this study, we evaluated the photophysical properties of 5,10,15,20-tetrakis[4-(1,4,7,10,13-pentaoxacyclopentadecane-2-aminomethyl)2,3,5,6-(tetrafluoro)-phenyl]-porphyrin (H2C4P) and Zn(II)5,10,15,20-tetrakis[4-(1,4,7,10,13-pentaoxacyclopenta-decane-2-aminomethyl)2,3,5,6-(tetrafluoro)-phenyl]-porphyrinate (ZnC4P). We observed that these porphyrins have unique properties when compared with classical porphyrins. The porphyrins H2C4P and ZnC4P showed efficient transfer energy S1 to T1 by intersystem crossing with high and reasonable yields of triplet excited state and singlet oxygen production. These amphiphilic structures of these porphyrins could improve its localization in the tumor cells due to the presence of the crown ether in its framework. We also believed that the crown ether could modulate the change in ion homeostase (Ca(+2), K+, Na+) as already described by some new phthalocyanine dye. This fact makes us believe that it could be reasonably used as a photosensitizer for PDT purposes.