HPLC-ESI-MS/MS analysis of oxidized di-caffeoylquinic acids generated by metalloporphyrin-catalyzed reactions

Santos, Michel David dos; Lopes, Norberto P.; Iamamoto, Yassuko

doi:10.1590/s0100-40422008000400011

Cited by 14 publications

(7 citation statements)

References 25 publications

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“…Oxidations using methaloporphyrins as catalysts can occur in very little reactive sites of the molecular structure, which are not possible using ordinal synthetic oxidations. 16) Examples of successful use of metalloporphyrins for the oxidation of drugs are given in the study of praziquantel, 20) caffeoilquinic acids 22) and primidone, 23) which lead to the formation of some major in vivo and in vitro metabolites, showing that these systems can be very useful to predict the CYP450 drug metabolism.…”

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confidence: 99%

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Biomimetic Oxidation of Piperine and Piplartine Catalyzed by Iron(III) and Manganese(III) Porphyrins

Schaab

Crotti

Iamamoto

et al. 2010

Biological & Pharmaceutical Bulletin

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Piperine and piplartine ( Fig. 1) are naturally occurring amides from Piper species (Piperaceae), which have been used in folk medicine of tropical and subtropical countries for treatment of asma, bronchitis, fever, hemorrhoidal afflictions, gastrointestinal diseases, rheumatism, and as food additive.1-3) The amide piperine is the pungent principle of black pepper (P. nigrum) and can be extracted from dried fruits with a yield of 3-7%.4) Several biological activities have been associated to piperine, including inhibition of liver metabolism, antioxidant, central nervous system depressant and antitumoral activities. [4][5][6][7][8][9] Piplartine is one of the major amide isolated from the roots of P. tuberculatum (popularly known as "long pepper"), which has been largely used in the folk medicine as a sedative and antidote for snake bite. Piplartine has shown significant cytotoxicity against cell tumor lines, as well as antifungal, antimitotic and anti-platelet aggregation compound.9-13) Piplartine anticancer potential has been highlighted by the undergoing preclinical evaluation. In vivo studies using murine tumors demonstrated that in spite of a moderate anticancer activity, piplartine has weak toxicological side effects. 3,14) Additionally, it increases 5-fluorouracil anticancer efficacy, while reduces chemotherapeutical side effects, as evidenced by the prevention of 5-FUinduced leucopenia.15) These data suggests that piplartine is a promising anticancer compound to be used in combination of already known antineoplastic agents.The study of the oxidative metabolism on promising natural products is of major importance before they become medicines, since their oxidations can affect the drug's safety and efficacy, due to the formation of therapeutically active or toxic metabolites. 16) Thus, efforts have been addressed to describe the metabolic pathways of drug candidate compounds.The cytochrome P450 (CYP) enzymes are catalytic hemoproteins known for their role in the metabolism of non-polar comounds, present in all forms of life (plants, bacteria, mammals). They have played a key role in the oxidative transformation of endogenous and exogenous molecules. 17,18) The cytochrome P450 enzymes catalyze the hydroxylation of saturated carbon-hydrogen bonds, epoxidation of double bounds, oxidation of heteroatoms, dealkylation reactions, and oxidations of aromatic carbons, etc.17) The oxidative metabolism of drugs by cytochrome P450 monooxygenases has been extensively studied through biological models, such as direct experiments on animals, the use of perfused organs or isolated cells. However, there are several ethical restrictions using animals and also experimental drawnbacks associated with the isolation of some hydrophilic and reactive metabolites that could bind to biological macromolecules, preparation of liver and cells (microsomes, hepatocytes) are of variable quality with low yields. [18][19][20] Thus, alternative model systems of cytocrome P450 have been employed in studies of P450 functions, as well as in syn...

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confidence: 99%

“…As part of our ongoing project on the metalloporphyrincatalyzed oxidation reactions of drugs 20) and natural products, 22) we report herein the biomimetic oxidation of piperine and piplartine catalyzed by iron(III) and manganese(III) porphyrins using iodosylbenzene (PhIO) as oxygen donor.…”

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confidence: 99%

Biomimetic Oxidation of Piperine and Piplartine Catalyzed by Iron(III) and Manganese(III) Porphyrins

Schaab

Crotti

Iamamoto

et al. 2010

Biological & Pharmaceutical Bulletin

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“…On-line coupling of HPLC with ESI mass spectrometry has been used to analyze reaction mechanisms [29,30]. After stirring starting material 2 (4 mg/mL) in MeOH for 72 h, the, separation was achieved on ODS analytical column (Phenomenex Prodigy ODS3 100A, 5 μm, 250 × 4.6 mm i.d) using a gradient elution of acetonitrile and 0.04 mM NH 4 OH/H 2 O (pH = 9) in the following ratios 95% of water at 0 min, 88% of water at 5 min, 80% of water at 25 min, 54% of water at 30 min, 34% of water at 35−50 min, 1% of water at 55−65 min, 95% of water at 66−76 min.…”

Section: Methodsmentioning

confidence: 99%

Mechanistic Studies on Regioselective Dephosphorylation of Phosphate Prodrugs during a Facile Synthesis of Antitumor Phosphorylated 2-Phenyl-6,7-methylenedioxy-1H-quinolin-4-one

et al. 2013

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Phosphorylation of 2-(3-hydroxy-5-methoxyphenyl)-6,7-methylenedioxy-1H-quinolin-4-one (1) afforded diphosphate 2. We found that, upon treatment with methanol under mild conditions, 2 can undergo facile and highly regioselective dephosphorylation to give the monophosphate 3, with a phosphate group remaining on the phenyl ring. The details of the dephosphorylation process were postulated and then probed by LC-MS and HPLC analyses. Furthermore, as a preliminary study, the water soluble monophosphate prodrug 4 was tested for antitumor activity against a MCF-7 xenograft nude mice model.

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“…Rat liver microsomes were obtained after sequential centrifugation of male Wistar rat livers as described in Santos et al (2008). Animals were housed and euthanized in accordance with the guidelines set by the Animal Care Committee (CEUA) of the Universidade de São Paulo, Brazil (Protocol Number: 10.1.408.53.2).…”

Section: Microsome Oxidationsmentioning

confidence: 99%

Biomimetic Metabolism of Kaurenoic Acid Validated by Microsomal Reactions

Fernandes¹,

Oliveira²,

Barros³

et al. 2020

Rev. Bras. Farmacogn.

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The cytochrome P450 is a remarkable family of enzymes with widespread occurrence in animals and plants. In humans, they catalyze phase I metabolism reactions, such as oxidations and hydroxylations, playing a significant role in xenobiotics detoxification. Although mechanistic details of the catalytic cycle of cytochrome P450 are known, and human isoforms have their crystal structure solved, mimicking cytochrome P450 reactions using in vitro systems is still challenging. For this reason, biological assays using isolated enzymes or microsomal fractions are typically required to study the oxidative metabolism of new drugs before approval by regulatory agencies. Here we demonstrate that a series of metalloporphyrin catalysts generate the same oxidative product in vitro as a liver microsomal assay. The bioactive diterpene kaurenoic acid was chosen as a substrate model because it is a component of widely used phytomedicines in Brazil, such as guaco syrups and copaiba waxes. We evaluated the influence of reaction parameters such as catalyst type, oxygen donor type, solvent, and catalyst concentration on substrate consumption. Three products had their structures proposed by mass spectrometry, and among them, a dihydroxylated oxidation product was detected as a major metabolite after liver microsomal biotransformation and using porphyrin catalysts. We envision that the use of metalloporphyrins could be a useful strategy for biomimetic oxidation of kaurenic terpenes.

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HPLC-ESI-MS/MS analysis of oxidized di-caffeoylquinic acids generated by metalloporphyrin-catalyzed reactions

Cited by 14 publications

References 25 publications

Biomimetic Oxidation of Piperine and Piplartine Catalyzed by Iron(III) and Manganese(III) Porphyrins

Biomimetic Oxidation of Piperine and Piplartine Catalyzed by Iron(III) and Manganese(III) Porphyrins

Mechanistic Studies on Regioselective Dephosphorylation of Phosphate Prodrugs during a Facile Synthesis of Antitumor Phosphorylated 2-Phenyl-6,7-methylenedioxy-1H-quinolin-4-one

Biomimetic Metabolism of Kaurenoic Acid Validated by Microsomal Reactions

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