Metabolism evaluation of the anticancer candidate AC04 by biomimetic oxidative model and rat liver microsomes

Pigatto, Maiara Cássia; Lima, Maria do Carmo Alves de; Galdino, Suely Lins; Pitta, Ivan da Rocha; Vessecchi, Ricardo; Assis, Marilda das Dores; Santos, Joicy Santamalvina dos; Costa, Teresa Dalla; Lopes, Norberto Peporine

doi:10.1016/j.ejmech.2011.06.029

Cited by 19 publications

(15 citation statements)

References 31 publications

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“…Our group recently applied Jacobsen catalyst ([Mn (salen)]) to produce similar metabolites of CYP450 enzymes yielding the product in good scale [21,22]. Comparative analysis confirmed the presence of the same putative metabolite in biomimetic oxidative model, microsomal fractions and in vivo experiments, reinforcing the importance of this methodology for pre-clinical trials [20,23,24]. In this context, the aim of this work was to investigate the metabolism of erythraline in the pig cecum model and through biomimetic reactions, in order to improve information on its pre-clinical pharmacokinetic and also on the biological activity of the putative metabolite.…”

Section: Introductionmentioning

confidence: 98%

In vitro metabolism studies of erythraline, the major spiroalkaloid from Erythrina verna

Guaratini

Silva

Bizaro

et al. 2014

BMC Complement Altern Med

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BackgroundErythrina verna, popularly known as “mulungu”, is a Brazilian medicinal plant used to treat anxiety. Erythrina alkaloids have been described in several species of Erythrina, which have biological and therapeutic properties well known that include anxiolytic and sedative effects.MethodsIn this work, in vitro metabolism of erythraline (1), the major spirocyclic alkaloid of Erythrina verna, was studied in the pig cecum model and by biomimetic phase I reactions. The biomimetic reactions were performed with Jacobsen catalyst to produce oxidative metabolites and one metabolite was isolated and evaluated against cancer cells, as HL-60 (promyelocytic leukemia), SF-295 (Glioblastoma) and OVCAR-8 (ovarian carcinoma).ResultsErythraline exhibited no metabolization by the pig microbiota and a main putative metabolite was formed in a biomimetic model using Jacobsen catalyst. This metabolite was isolated and identified as 8-oxo-erythraline (2). Finally, erythraline and the putative metabolite were tested in MTT model and both compounds showed no important cytotoxic activity against tumor cells.ConclusionsThe alkaloid erythraline was not metabolized by intestinal microbiota, but it was possible to identify its oxidative metabolite from biomimetic reactions. So these data are interesting and stimulate other studies involving this alkaloid, since it is present in phytomedicine products and there are not reported data about the metabolism of erythrina alkaloids.

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Section: Introductionmentioning

confidence: 98%

In vitro metabolism studies of erythraline, the major spiroalkaloid from Erythrina verna

Guaratini

Silva

Bizaro

et al. 2014

BMC Complement Altern Med

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“…LPSF/AC04 revealed antitumor activity with tumor inhibition of more than 85% in a murine sarcoma 180 model after 8 days of treatment with 100 mg/kg i.p./day (7). In addition, a recent study presented a preliminary pharmacokinetics of LPSF/AC04 with a half-life of 66 h, which accumulated in different tissues (8). However, heterocyclic acridine derivatives such as LPSF/AC04 are characterized by low solubility in aqueous solutions, as a result of which clinical trials and its therapeutic use have remained limited.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Antiproliferative Activity of the New Anticancer Candidate LPSF/AC04 in Cyclodextrin Inclusion Complexes Encapsulated into Liposomes

Mendonça

Lira

Rabello³

et al. 2012

AAPS PharmSciTech

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Abstract. LPSF/AC04 (5Z)-[5-acridin-9-ylmethylene-3-(4-methyl-benzyl)-thiazolidine-2,4-dione] is an acridine-based derivative, part of a series of new anticancer agents synthesized for the purpose of developing more effective and less toxic anticancer drugs. However, the use of LPSF/AC04 is limited due to its low solubility in aqueous solutions. To overcome this problem, we investigated the interaction of LPSF/AC04 with hydroxypropyl-β-cyclodextrin (HP-β-CyD) and hydroxypropyl-γ-cyclodextrin (HP-γ-CyD) in inclusion complexes and determine which of the complexes formed presents the most significant interactions. In this paper, we report the physical characterization of the LPSF/AC04-HP-CyD inclusion complexes by thermogravimetric analysis, differential scanning calorimetry, infrared spectroscopy absorption, Raman spectroscopy, 1 HNMR, scanning electron microscopy, and by molecular modeling approaches. In addition, we verified that HP-β-CyD complexation enhances the aqueous solubility of LPSF/AC04, and a significant increase in the antiproliferative activity of LPSF/AC04 against cell lines can be achieved by the encapsulation into liposomes. These findings showed that the nanoencapsulation of LPSF/AC04 and LPSF/AC04-HP-CyD inclusion complexes in liposomes leads to improved drug penetration into the cells and, as a result, an enhancement of cytotoxic activity. Further in vivo studies comparing free and encapsulated LPSF/AC04 will be undertaken to support this investigation.

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“…[26][27][28] The fragmentation pathways of organic compounds are also important for characterization and structural elucidation of substances in metabolomic studies. [29] Computational quantum calculations provide the information required to identify the ionization sites and the stability of each ionic species formed during the fragmentation in MS/MS experiments. [30][31][32] Thus, the combination of MS/MS with computational chemistry provides valuable information for understanding gas-phase fragmentation and to support the characterization of organic compounds in general.…”

Section: Introductionmentioning

confidence: 99%

Gas‐phase fragmentation of protonated piplartine and its fungal metabolites using tandem mass spectrometry and computational chemistry

et al. 2017

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Piplartine, an alkaloid produced by plants in the genus Piper, displays promising anticancer activity. Understanding the gas-phase fragmentation of piplartine by electrospray ionization tandem mass spectrometry can be a useful tool to characterize biotransformed compounds produced by in vitro and in vivo metabolism studies. As part of our efforts to understand natural product fragmentation in electrospray ionization tandem mass spectrometry, the gas-phase fragmentation of piplartine and its two metabolites 3,4-dihydropiplartine and 8,9-dihydropiplartine, produced by the endophytic fungus Penicillium crustosum VR4 biotransformation, were systematically investigated. Proposed fragmentation reactions were supported by ESI-MS/MS data and computational thermochemistry. Cleavage of the C-7 and N-amide bond, followed by the formation of an acylium ion, were characteristic fragmentation reactions of piplartine and its analogs. The production of the acylium ion was followed by three consecutive and competitive reactions that involved methyl and methoxyl radical eliminations and neutral CO elimination, followed by the formation of a four-member ring with a stabilized tertiary carbocation. The absence of a double bond between carbons C-8 and C-9 in 8,9-dihydropiplartine destabilized the acylium ion and resulted in a fragmentation pathway not observed for piplartine and 3,4-dihydropiplartine. These results contribute to the further understanding of alkaloid gas-phase fragmentation and the future identification of piplartine metabolites and analogs using tandem mass spectrometry techniques. Copyright © 2017 John Wiley & Sons, Ltd.

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Metabolism evaluation of the anticancer candidate AC04 by biomimetic oxidative model and rat liver microsomes

Cited by 19 publications

References 31 publications

In vitro metabolism studies of erythraline, the major spiroalkaloid from Erythrina verna

In vitro metabolism studies of erythraline, the major spiroalkaloid from Erythrina verna

Enhanced Antiproliferative Activity of the New Anticancer Candidate LPSF/AC04 in Cyclodextrin Inclusion Complexes Encapsulated into Liposomes

Gas‐phase fragmentation of protonated piplartine and its fungal metabolites using tandem mass spectrometry and computational chemistry

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