Development of a platform for the study of in vitro and in vivo metabolism of natural products, a need for pre-clinical testing system

• Grant number: 09/51812-0
• Support Opportunities: BIOTA-FAPESP Program - Thematic Grants
• Start date: January 01, 2010
• End date: December 31, 2013
• Field of knowledge: Physical Sciences and Mathematics - Chemistry
• Principal Investigator: Norberto Peporine Lopes
• Grantee: Norberto Peporine Lopes
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Pesquisadores principais: Mônica Tallarico Pupo
• Associated research grant(s): 12/08570-8 - International Congress on Natural Products Research, AR.EXT; 10/17087-3 - Visit of professor Matthias Bieckhaulpt to the Chemistry Department of FFCLRP-USP, AV.EXT
• Associated scholarship(s): 13/04188-4 - In vitro metabolism study and enzymatic inhibition of natural product piplartine employing human liver microsomes and supersomes., BP.DR; 12/18031-7 - Application of MALDI-MS/MS in the vicenin-2 and derivatives analyses: Understanding the ionization processes to production of the images, BP.PD; 12/14408-9 - Disposition kinetics, plasma protein binding, metabolism in vitro and in vivo of curcubitacins in rats, BP.DR; + associated scholarships 12/10227-0 - Development and validation of a UPLC-MS/MS method for analysis of Avicularin in rat plasm, BP.IC; 12/03446-7 - In vitro metabolism studies of the antitumor Clerodane diterpene casearin X, BP.DR; 11/13560-9 - In vitro metabolism study of the piplartine alkaloid using rat liver microsomes, BP.MS; 11/13281-2 - Evaluation of alkaloids metabolism of Erythrina verna, BP.PD; 11/13470-0 - Elucidation of the metabolism of nitrosyl ruthenium complex as a new class of metallo-drugs: in vitro and in vivo and in aqueous solution and in system of drug delivery studies., BP.PD; 11/01303-1 - Biotransformation of ²-lapachone using microbial cultures: an alternative to in vitro metabolism studies, BP.MS; 11/01404-2 - In vitro metabolism studies of natural products: microbial biotransformation of piplartine, BP.MS; 11/05800-0 - Evaluation of Microbiological and Chemical Models for the Study of Bio(transformations) of Antibiotic Monensin A, BP.DR; 11/06541-8 - Development and validation of an analytical method for further application in in vitro metabolism study the lignans (-)-grandisin, BP.IC; 11/01089-0 - Development and chromatographic method validation to quantify goyazensolide and derivatives in rat plasma, BP.PD; 10/12765-3 - Transformation of lignan (-)-grandisin by microorganisms and hepatic microsomes: an alternative to new drugs metabolism studies., BP.PD; 10/10564-0 - In vitro metabolism study of a bioliogically active naphthoquinone - lapachol, BP.PD; 10/09137-0 - "In vitro and in vivo metabolism of the major secondary metabolites present in the extract of Lychnophora salicifolia Mart. (Asteraceae: Vernonieae) leaves", BP.DR; 10/07413-0 - In vivo and in vitro evaluation of budlein A metabolism and the determination of pharmacokinetic parameters, BP.DR; 10/06502-0 - Study of in vitro metabolism of biologically active diterpenes, BP.PD - associated scholarships

Abstract

For clinical trials and stability, it is necessary the chemical profiling of plant extracts and bullets, and this step of relevance for the execution of these studies. These standards, in turn, must be obtained and certified as to their identity and purity and some may serve as inspiration for the synthetic and medicinal chemists. A part of these approaches has been held within the program BioProspecta, however, the lack of studies of the metabolism, absorption and distribution of natural assets is one of the major bottlenecks in the country and the implementation of some phases of preclinical studies. Within this scenario, the objective of this proposal is the establishment of a working platform, comprising 4 main groups, being the first collaborative with the groups BioProspecta and components of our researchers in search of new bioactive products. The second structure aims at the development of biomimetic reactions for obtaining derivatives structurally similar to those produced by the human microsomal system. The third pillar is the study of interpretation and application of gas phase decomposition reactions of micromolecules ionized by ESI. Finally the fourth pillar seeks to apply all this information in in vivo models using a reduced number of animals and allowing an interpretation of metabolism of natural products, which are essential in the early stages of preclinical studies. (AU)

Scientific publications

(23)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MAURIZ MARQUES, LUCAS MACIEL; AGUIAR, FERNANDO ARMANI; DA SILVA, DENISE BRENTAN; CALLEJON, DANIEL ROBERTO; MORAES DE OLIVEIRA, ANDERSON RODRIGO; LOPES, NORBERTO PEPORINE; CALLEGARI LOPES, JOAO LUIS; GUARATINI, THAIS. Microsomal metabolism of erythraline: an anxiolitic spiroalkaloid. REVISTA BRASILEIRA DE FARMACOGNOSIA-BRAZILIAN JOURNAL OF PHARMACOGNOSY, v. 25, n. 5, p. 529-532, SEP-OCT 2015. (09/51812-0, 14/20302-4, 12/18031-7, 11/13281-2, 14/50265-3)

PALUDO, CAMILA RAQUEL; DA SILVA-JUNIOR, EDUARDO AFONSO; SILVA, ELIANE DE OLIVEIRA; VESSECCHI, RICARDO; LOPES, NORBERTO PEPORINE; PUPO, MONICA TALLARICO; EMERY, FLAVIO DA SILVA; GONCALVES, NATALIA DOS SANTOS; DOS SANTOS, RAQUEL ALVES; JACOMETTI CARDOSO FURTADO, NIEGE ARACARI. Inactivation of beta-Lapachone Cytotoxicity by Filamentous Fungi that Mimic the Human Blood Metabolism. EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, v. 42, n. 2, p. 213-220, APR 2017. (11/21700-5, 11/01303-1, 09/51812-0)

DA SILVA-JUNIOR, E. A.; PALUDO, C. R.; GOUVEA, D. R.; KATO, M. J.; FURTADO, N. A. J. C.; LOPES, N. P.; VESSECCHI, R.; PUPO, M. T.. Gas-phase fragmentation of protonated piplartine and its fungal metabolites using tandem mass spectrometry and computational chemistry. Journal of Mass Spectrometry, v. 52, n. 8, p. 517-525, AUG 2017. (11/01404-2, 09/51812-0, 14/23604-1)

SOUSA, JOAO PAULO B.; NOGUEIRA, ELIDIA F.; FERREIRA, LEANDRO S.; LOPES, NORBERTO P.; LOPES, JOAO LUIS C.. Validation of analytical procedures using HPLC-ELSD to determine six sesquiterpene lactones in Eremanthus species. BIOMEDICAL CHROMATOGRAPHY, v. 30, n. 3, p. 484-493, MAR 2016. (11/01089-0, 09/51812-0)

BARTH, THIAGO; HABENSCHUS, MAISA DANIELA; MOREIRA, FERNANDA LIMA; FERREIRA, LEANDRO DE SANTIS; LOPES, NORBERTO PEPORINE; MORAES DE OLIVEIRA, ANDERSON RODRIGO. In vitro metabolism of the lignan (-)-grandisin, an anticancer drug candidate, by human liver microsomes. DRUG TESTING AND ANALYSIS, v. 7, n. 9, p. 780-786, SEP 2015. (13/17658-9, 09/51812-0)

SANTOS, GABRIELA B.; ALMEIDA, MARILIA O.; CARDOSO, IARA A.; MANFRIM, VIVIANE; CHAGAS, FERNANDA O.; TOLEDO, JULIANO S.; PINZAN, CAMILA C.; DE ARAUJO, ALEXANDRE SUMAN; CRUZ, ANGELA K.; PUPO, MONICA T.; et al. The semisynthetic landscape of aphidicolin: inspiration towards leishmanicidal compounds. Journal of the Brazilian Chemical Society, v. 25, n. 10, p. 1885+, OCT 2014. (09/51812-0, 09/14184-0)

DA SILVA JUNIOR, EUFRANIO N.; DE MELO, ISADORA M. M.; DIOGO, EMILAY B. T.; COSTA, VERENICE A.; DE SOUZA FILHO, JOSE D.; VALENCA, WAGNER O.; CAMARA, CELSO A.; DE OLIVEIRA, RONALDO N.; DE ARAUJO, ALEXANDRE S.; EMERY, FLAVIO S.; et al. On the search for potential anti-Trypanosoma cruzi drugs: Synthesis and biological evaluation of 2-hydroxy-3-methylamino and 1,2,3-triazolic naphthoquinoidal compounds obtained by click chemistry reactions. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 52, p. 304-312, JUN 2012. (09/51812-0, 09/14184-0)

BARRETO SOUSA, JOAO PAULO; TOMAZ, JOSE CARLOS; DA SILVA, CECILIA C. P.; ELLENA, JAVIER; LOPES, NORBERTO PEPORINE; CALLEGARI LOPES, JOAO LUIS. Novel sesquiterpene lactones from Eremanthus seidelii. Tetrahedron Letters, v. 53, n. 47, p. 6339-6342, NOV 21 2012. (11/01089-0, 09/51812-0)

BOLZON, LUCAS B.; DOS SANTOS, JOICY S.; SILVA, DENISE B.; CREVELIN, EDUARDO J.; MORAES, LUIZ A. B.; LOPES, NORBERTO P.; ASSIS, MARILDA D.. Apigenin-7-O-glucoside oxidation catalyzed by P450-bioinspired systems. Journal of Inorganic Biochemistry, v. 170, p. 117-124, MAY 2017. (09/51812-0)

BORGES, LETICIA DA SILVA; CARVALHO BATISTA, JOAO HENRIQUE; BOZZINI, LEANDRO; LOURENCO JR, CELSO DONIZETE; LOPES, NORBERTO PEPORINE; CLOSOSKI, GIULIANO CESAR; VESSECCHI, RICARDO. Are benzoylium and nitrilium ions produced from substituted 2-arene-2-oxazolines during mass spectrometry? A study based on density functional theory calculations, quantum theory of atoms in molecules, and electrospray ionization tandem mass spectrometry. RAPID COMMUNICATIONS IN MASS SPECTROMETRY, v. 37, n. 4, p. 11-pg., 2023-02-28. (17/04819-5, 09/51812-0, 09/08281-3, 14/50265-3, 20/02207-5, 18/14150-8, 14/23604-1)

DUARTE, DIEGO A.; ROSALES, MARIANA AP. B.; PAPADIMITRIOU, ALEXANDROS; SILVA, KAMILA C.; AMANCIO, VITOR HUGO O.; MENDONCA, JACQUELINE N.; LOPES, NORBERTO P.; LOPES DE FARIA, JOSE B.; LOPES DE FARIA, JACQUELINE M.. Polyphenol-enriched cocoa protects the diabetic retina from glial reaction through the sirtuin pathway. JOURNAL OF NUTRITIONAL BIOCHEMISTRY, v. 26, n. 1, p. 64-74, JAN 2015. (08/57560-0, 09/51812-0, 10/11514-7)

MAURIZ MARQUES, LUCAS MACIEL; DA SILVA-JUNIOR, EDUARDO AFONSO; GOUVEA, DAYANA RUBIO; VESSECCHI, RICARDO; PUPO, MONICA TALLARICO; LOPES, NORBERTO PEPORINE; KATO, MASSUO JORGE; MORAES DE OLIVEIRA, ANDERSON RODRIGO. In vitro metabolism of the alkaloid piplartine by rat liver microsomes. Journal of Pharmaceutical and Biomedical Analysis, v. 95, p. 113-120, JUL 2014. (11/17508-1, 11/13560-9, 09/51812-0)

SILVA, ELIANE O.; RUANO-GONZALEZ, ANTONIO; DOS SANTOS, RAQUEL A.; SANCHEZ-MAESTRE, ROSARIO; FURTADO, NIEGE A. J. C.; COLLADO, ISIDRO G.; ALEU, JOSEFINA. Antifungal and Cytotoxic Assessment of Lapachol Derivatives Produced by Fungal Biotransformation. NATURAL PRODUCT COMMUNICATIONS, v. 11, n. 1, p. 95-98, JAN 2016. (11/21700-5, 09/51812-0)

DE OLIVEIRA, ANA LIGIA L.; VESSECCHI, RICARDO; LOPES, NORBERTO P.; DEBONSI, HOSANA M.. Collision-Induced Dissociation Analysis of Brevianamide A and C in Electrospray Ionization Mass Spectrometry. Journal of the Brazilian Chemical Society, v. 26, n. 4, p. 822-827, APR 2015. (09/51812-0)

PALUDO, CAMILA R.; DA SILVA-JUNIOR, EDUARDO A.; SANTOS, RAQUEL A.; PUPO, MONICA T.; EMERY, FLAVIO S.; FURTADO, NIEGE A. J. C.. Microbial transformation of beta-lapachone to its glycosides by Cunninghamella elegans ATCC 10028b. PHYTOCHEMISTRY LETTERS, v. 6, n. 4, p. 657-661, NOV 2013. (11/21700-5, 11/01303-1, 09/51812-0)

SARTORI, LUCAS ROSSI; VESSECCHI, RICARDO; HUMPF, HANS-ULRICH; DA COSTA, FERNANDO BATISTA; LOPES, NORBERTO PEPORINE. A systematic investigation of the fragmentation pattern of two furanoheliangolide C-8 stereoisomers using electrospray ionization mass spectrometry. RAPID COMMUNICATIONS IN MASS SPECTROMETRY, v. 28, n. 7, p. 723-730, APR 15 2014. (10/07413-0, 09/51812-0)

ROCHA, BRUNO A.; ASSIS, MARILDA D.; PETI, ANA P. F.; MORAES, LUIZ A. B.; MOREIRA, FERNANDA L.; LOPES, NORBERTO P.; POSPISIL, STANISLAV; GATES, PAUL J.; DE OLIVEIRA, ANDERSON R. M.. In vitro metabolism of monensin A: microbial and human liver microsomes models. XENOBIOTICA, v. 44, n. 4, p. 326-335, APR 2014. (11/17508-1, 11/05800-0, 09/51812-0)

GARCIA-CAIRASCO, NORBERTO; MOYSES-NETO, MIGUEL; DEL VECCHIO, FLAVIO; OLIVEIRA, JOSE A. C.; DOS SANTOS, FRANCISCO L.; CASTRO, OLAGIDE W.; ARISI, GABRIEL M.; DANTAS, MARCIO; CAROLINO, RUITHER O. G.; COUTINHO-NETTO, JOAQUIM; et al. Elucidating the Neurotoxicity of the Star Fruit. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, v. 52, n. 49, p. 13067-13070, DEC 2 2013. (09/51812-0)

SILVA, DENISE BRENTAN; GUARATINI, THAIS; VESSECCHI, RICARDO; LOPES, NORBERTO PEPORINE; CRAMER, BENEDIKT; HUMPF, HANS-ULRICH; CALTEGARI LOPES, JOAO LUIS. H-2 unimolecular elimination in electrospray ionization mass spectrometry from erythraline, a spirocyclic alkaloid. EUROPEAN JOURNAL OF MASS SPECTROMETRY, v. 19, n. 5, p. 345-350, 2013. (11/13281-2, 12/18031-7, 09/51812-0)

DE TOLEDO, JULIANO S.; JUNIOR, PAULO E. S.; MANFRIM, VIVIANE; PINZAN, CAMILA F.; DE ARAUJO, ALEXANDRE S.; CRUZ, ANGELA K.; EMERY, FLAVIO S.. Synthesis, Cytotoxicity and In Vitro Antileishmanial Activity of Naphthothiazoles. CHEMICAL BIOLOGY & DRUG DESIGN, v. 81, n. 6, p. 749-756, JUN 2013. (09/51812-0, 09/14184-0)

ALVES FERNANDES, EDUARDO FELIPE; MELONI, FERNANDO; BORELLA, JULIO CEZAR; LOPES, NORBERTO PEPORINE. Effect of fertilisation and harvest period on polar metabolites of Calendula oficcinalis. REVISTA BRASILEIRA DE FARMACOGNOSIA-BRAZILIAN JOURNAL OF PHARMACOGNOSY, v. 23, n. 5, p. 731-735, SEP-OCT 2013. (09/51812-0, 13/06196-4, 09/00940-8)

OLIVEIRA SILVA, E.; CRUZ DE CARVALHO, T.; PARSHIKOV, I. A.; ALVES DOS SANTOS, R.; SILVA EMERY, F.; JACOMETTI CARDOSO FURTADO, N. A.. Cytotoxicity of lapachol metabolites produced by probiotics. Letters in Applied Microbiology, v. 59, n. 1, p. 108-114, JUL 2014. (11/21700-5, 09/51812-0)

CALLEJON, DANIEL R.; RIUL, THALITA B.; FEITOSA, LUIS G. P.; GUARATINI, THAIS; SILVA, DENISE B.; ADHIKARI, ACHYUT; SHRESTHA, RAM L. (S); MARQUES, LUCAS M. M.; BARUFFI, MARCELO D.; LOPES, JOAO L. C.; et al. Leishmanicidal Evaluation of Tetrahydroprotoberberine and Spirocyclic Erythrina-Alkaloids. Molecules, v. 19, n. 5, p. 5692-5703, MAY 2014. (11/13281-2, 12/18031-7, 09/51812-0)