In vitro cytotoxicity and structure-activity relationship approaches of ent-kaurenoic acid derivatives against human breast carcinoma cell line

Author(s):Show less -

da Costa, Ricardo M. ^{[1, 2]} ; Bastos, Jairo K. ^[3] ; Costa, Maria C. A. ^[4] ; Ferreira, Marcia M. C. ^[4] ; Mizuno, Cassia S. ^[5] ; Caramori, Giovanni F. ^[6] ; Nagurniak, Glaucio R. ^[6] ; Simao, Marilia R. ^[1] ; dos Santos, Raquel A. ^[1] ; Veneziani, Rodrigo C. S. ^[1] ; Ambrosio, Sergio R. ^[1] ; Parreira, Renato L. T. ^[1]

Affiliation

^[1] Univ Franca Unifran, Nucleo Pesquisa Ciencias Exatas & Tecnol, Franca, SP - Brazil

^[2] Informat Aplicada Ciencias IFSULDEMINAS, Muzambinho, MG - Brazil

^[3] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Ribeirao Preto, SP - Brazil

^[4] Univ Campinas Unicamp, Inst Chem, Theoret & Appl Chemometr Lab LQTA, Campinas, SP - Brazil

^[5] Univ New England, Coll Pharm, Dept Pharmaceut Sci, Portland, ME - USA

^[6] Univ Fed Santa Catarina, Dept Quim, Campos Univ Trindade, Florianopolis, SC - Brazil

• Document type: Journal article
• Source: Phytochemistry; v. 156, p. 214-223, DEC 2018.
• Web of Science Citations: 1

Abstract

In this study, ent-kaurenoic acid derivatives were obtained by microbial transformation methodologies and tested against breast cancer cell lines (MCF-7). A multivariate quantitative-structure activity relationship (QSAR) analysis was performed taking into account both microbial transformation derivatives and other analogues previously reported in literature to give some insight into the main features behind the cytotoxic activity displayed by kaurane-type diterpenes against MCF-7 cells. The partial least square regression (PLS) method was employed in the training set and the best PLS model was built with a factor describing 69.92% of variance and three descriptors (logP, epsilon(HOMO) and epsilon(HOMO-1)) selected by the Ordered Predictors Selection (OPS) algorithm. The QSAR model provided reasonable regression (Q(2) = 0.64, R-2 = 0.72, SEC = 0.29 and SEV = 0.33). The model was validated by leave-N-out cross-validation, y-randomization and external validation (R(2)pred = 0.89 and SEP = 0.27). The selected descriptors indicated that the activity was mainly related to electronic parameters (HOMO and HOMO-1 molecular orbital energies), as well as to logP. These findings suggest that higher activity values are directly related with both higher logP and frontier orbital energy values. The positive relationship between these orbitals and the activity suggests that the ent-kaurenoic acid analogues interaction with the target involves charge displacement, which is entirely consistent with the literature. Based on these findings, three compounds were proposed and one of them was synthesized and tested. The experimental result confirmed the activity predicted by the model. (AU)

• FAPESP's process: 11/13630-7 - Chemical and pharmacological validation of extracts and active compounds of Copaifera species
• Grantee: Jairo Kenupp Bastos
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 11/23028-2 - Evaluation of biological activity of ent-kaurenoic acid derivatives by biotransformation and semi synthesis
• Grantee: Marilia Rodrigues Simão
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 07/54762-8 - 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
• Grantee: Sergio Ricardo Ambrosio
• Support Opportunities: BIOTA-FAPESP Program - Young Investigators Grants
• FAPESP's process: 11/07623-8 - The use of quantum-mechanical methods to study the bonds and chemical interactions in self-organizing systems with applications in catalysis, medicinal chemistry, electrochromism, energy storage and conversion
• Grantee: Renato Luis Tame Parreira
• Support Opportunities: Research Grants - Young Investigators Grants