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Obtaining structural analogues of pimaradienoic acid through the process of fungal biotransformation and study of the effect of these metabolites on the activity of the TcDHODH enzyme and on the contraction of the vascular smooth muscle of the aorta artery of mice

Grant number: 07/54762-8
Support type:BIOTA-FAPESP Program - Young Investigators Grants
Duration: February 01, 2008 - January 31, 2012
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Sergio Ricardo Ambrosio
Grantee:Sergio Ricardo Ambrosio
Home Institution: Pró-Reitoria Adjunta de Pesquisa e Pós-Graduação. Universidade de Franca (UNIFRAN). Franca , SP, Brazil
Associated scholarship(s):11/21638-8 - Biotransformation of kaurenoic acid by filamentous fungi and evaluation of the anti-phytopathogenic properties of the obtained metabolites, BP.DR
11/23028-2 - Evaluation of biological activity of ent-kaurenoic acid derivatives by biotransformation and semi synthesis, BP.DD
09/12458-6 - Fungal biotransformation of the pimaradienoic acid by Aspergillus niger and evaluation of the inhibitory effect on rat aorta contraction of the obtained derivatives, BP.MS
09/12976-7 - Fungal biotransformation of the caurenoic acid by Aspergillus terreus and evaluation of the inhibitory effect on rat aorta contraction of the obtained derivatives, BP.MS
08/07696-2 - Studies on the biotransformation of two fungal diterpene class of pimaranos by Aspergillus ochraceus and biological evaluation of the metabolites obtained, BP.MS

Abstract

The present work has the general objective of obtaining structural analogues of pimaradienoic acid, a diterpene present in large quantity in the roots of Viguiera arenaria Baker, which has proven a significant capacity to inhibit the contractile response of the vascular smooth muscle of mice, due to its capacity to reduce the influx of Ca+2 through the blocking of the channels operated by voltage and receiver. In addition to this well-established activity, preliminary studies showed the arterial pressure of mice normotense in vivo, as well as inhibiting the dihydroorotate dehydrogenase enzyme of Trypanossoma cruzi (TcDHODH), an excellent pharmacological target for the discovery of new potentially promising substances to combat parasites that cause Chagas disease. The structural modifications proposed in this Project will be achieved through the technique of fungal biotransformation, using four different genuses of fungus, so as to guarantee the variability of the analogues produced. The diterpenes isolated and identified will then be evaluated on the inhibitory capacity of the TcDHODH enzyme and the contraction of the vascular smooth muscle in the aorta of mice, with the aim of selecting new compounds more active than pimaradienoic acid, so that in a stage beyond the development of this Project they can be tested with regard to their antihypertensive and trypanocide potential. (AU)

Scientific publications (8)
(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)
DA COSTA, RICARDO M.; BASTOS, JAIRO K.; COSTA, MARIA C. A.; FERREIRA, MARCIA M. C.; MIZUNO, CASSIA S.; CARAMORI, GIOVANNI F.; NAGURNIAK, GLAUCIO R.; SIMAO, MARILIA R.; DOS SANTOS, RAQUEL A.; VENEZIANI, RODRIGO C. S.; AMBROSIO, SERGIO R.; PARREIRA, RENATO L. T. In vitro cytotoxicity and structure-activity relationship approaches of ent-kaurenoic acid derivatives against human breast carcinoma cell line. Phytochemistry, v. 156, p. 214-223, DEC 2018. Web of Science Citations: 0.
PORTO, THIAGO S.; SIMAO, MARILIA R.; CARLOS, LUCAS Z.; MARTINS, CARLOS H. G.; FURTADO, NIEGE A. J. C.; SAID, SURAIA; ARAKAWA, NILTON S.; DOS SANTOS, RAQUEL A.; VENEZIANI, RODRIGO C. S.; AMBROSIO, SERGIO R. Pimarane-type Diterpenes Obtained by Biotransformation: Antimicrobial Properties Against Clinically Isolated Gram-positive Multidrug-resistant Bacteria. Phytotherapy Research, v. 27, n. 10, p. 1502-1507, OCT 2013. Web of Science Citations: 10.
SEVERIANO, MARCELA E.; SIMAO, MARILIA R.; RAMOS, HENRIQUE P.; PARREIRA, RENATO L. T.; ARAKAWA, NILTON S.; SAID, SURAIA; FURTADO, NIEGE A. J. C.; DE OLIVEIRA, DIONEIA C. R.; GREGORIO, LUIS E.; TIRAPELLI, CARLOS R.; VENEZIANI, RODRIGO C. S.; AMBROSIO, SERGIO R. Biotransformation of ent-pimaradienoic acid by cell cultures of Aspergillus niger. Bioorganic & Medicinal Chemistry, v. 21, n. 18, p. 5870-5875, SEP 15 2013. Web of Science Citations: 6.
PORTO, THIAGO S.; DA SILVA FILHO, ADEMAR A.; MAGALHAES, LIZANDRA G.; DOS SANTOS, RAQUEL A.; FURTADO, NIEGE A. J. C.; ARAKAWA, NILTON S.; SAID, SURAIA; DE OLIVEIRA, DIONEIA C. R.; GREGORIO, LUIZ E.; RODRIGUES, VANDERLEI; VENEZIANI, RODRIGO C. S.; AMBROSIO, SERGIO R. Fungal Transformation and Schistosomicidal Effects of Pimaradienoic Acid. CHEMISTRY & BIODIVERSITY, v. 9, n. 8, p. 1465-1474, AUG 2012. Web of Science Citations: 12.
SOUZA, ARIANA B.; MARTINS, CARLOS H. G.; SOUZA, MARIA G. M.; FURTADO, NIEGE A. J. C.; HELENO, VLADIMIR C. G.; DE SOUSA, JOAO P. B.; ROCHA, ERILDA M. P.; BASTOS, JAIRO K.; CUNHA, WILSON R.; VENEZIANI, RODRIGO C. S.; AMBROSIO, SERGIO R. Antimicrobial Activity of Terpenoids from Copaifera langsdorffii Desf. Against Cariogenic Bacteria. Phytotherapy Research, v. 25, n. 2, p. 215-220, FEB 2011. Web of Science Citations: 62.
SEVERIANO, MARCELA E.; SIMAO, MARILIA R.; PORTO, THIAGO S.; MARTINS, CARLOS H. G.; VENEZIANI, RODRIGO C. S.; FURTADO, NIEGE A. J. C.; ARAKAWA, NILTON S.; SAID, SURAIA; DE OLIVEIRA, DIONEIA C. R.; CUNHA, WILSON R.; GREGORIO, LUIZ E.; AMBROSIO, SERGIO R. Anticariogenic Properties of ent-Pimarane Diterpenes Obtained by Microbial Transformation. Molecules, v. 15, n. 12, p. 8553-8566, 2010. Web of Science Citations: 16.
PORTO, THIAGO SOUZA; FURTADO, NIEGE A. J. C.; HELENO, VLADIMIR C. G.; MARTINS, CARLOS H. G.; DA COSTA, FERNANDO B.; SEVERIANO, MARCELA E.; SILVA, ALINE N.; VENEZIANI, RODRIGO C. S.; AMBROSIO, SERGIO R. Antimicrobial ent-pimarane diterpenes from Viguiera arenaria against Gram-positive bacteria. Fitoterapia, v. 80, n. 7, p. 432-436, OCT 2009. Web of Science Citations: 41.
PORTO, THIAGO S.; RANGEL, RANDER; FURTADO, NIEGE A. J. C.; DE CARVALHO, TATIANE C.; MARTINS, CARLOS H. G.; VENEZIANI, RODRIGO C. S.; DA COSTA, FERNANDO B.; VINHOLIS, ADRIANA H. C.; CUNHA, WILSON R.; HELENO, VLADIMIR C. G.; AMBROSIO, SERGIO R. Pimarane-type Diterpenes: Antimicrobial Activity against Oral Pathogens. Molecules, v. 14, n. 1, p. 191-199, JAN 2009. Web of Science Citations: 68.

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