Novel anticancer candidates: design, synthesis, antitumoral activity and mode of action of novel capsaicinoids and capsinoids analogues

• Grant number: 13/18160-4
• Support Opportunities: Regular Research Grants
• Duration: January 01, 2014 - December 31, 2015
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Roberto Parise Filho
• Grantee: Roberto Parise Filho
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Currently, cancer is a leading cause of death worldwide. Although there are many drugs for cancer control, problems such as low selectivity and high toxicity stimulate the search for new antitumor molecules. Natural products have played an important role in the introduction of new drugs or even as molecular patterns in order to obtain new bioactive substances. Recent studies reported that capsaicinoids and capsinoids, substances found in several species of peppers, have presented considerable antiproliferative effect by inducing selective apoptosis in tumors. Thus, the use of these compounds as structural models for the synthesis of analogues with potentially higher activity is a subject of great interest. Thus, this project aims to synthesize capsaicinoids and capsinoids analogues, using molecular modification strategy (hybridization, bioisosterism and homology), evaluate their antiproliferative activity, and propose new analogues from theoretical models obtained by quantitative structure-activity relationship (QSAR). The analogues will be synthesized using classical methodologies such as acylation, sulfonylation and thioacylating and subsequently they will be evaluated for their cytotoxic capacity in normal and tumor cells. Regarding the most promising analogues, pro-apoptotic properties and activity on the cell cycle will be explored in order to elucidate the mode of action of those compounds. In order to identify similarities between the compounds molecular properties, chemometric approaches will be applied to classify all synthesized compounds. Moreover, with the determination of experimental data (IC50), mathematical models (multivariate QSAR) will be constructed and validated for the prediction of new chemical entities with potential antitumor activity. It is hoped that new anticancer agents could be obtained, which may benefit public health in control of the disease. (AU)

Scientific publications

(9)

(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)

KRONENBERGER, THALES; FERREIRA, GLAUCIO MONTEIRO; FERREIRA DE SOUZA, ALFREDO DANILO; SANTOS, SORAYA DA SILVA; POSO, ANTTI; RIBEIRO, JOAO AUGUSTO; TAVARES, MAURICIO TEMOTHEO; PAVAN, FERNANDO ROGERIO; GOULART TROSSINI, GUSTAVO HENRIQUE; BERTACINE DIAS, MARCIO VINICIUS; et al. Design, synthesis and biological activity of novel substituted 3-benzoic acid derivatives as MtDHFR inhibitors. Bioorganic & Medicinal Chemistry, v. 28, n. 15, AUG 1 2020. (13/18160-4, 17/00689-0, 13/15906-5, 17/25543-8)

YANG, ROSANIA; TAVARES, MAURICIO T.; TEIXEIRA, SARAH F.; AZEVEDO, RICARDO A.; PIETRO, DIEGO C.; FERNANDES, THAIS B.; FERREIRA, ADILSON K.; TROSSINI, GUSTAVO H. G.; BARBUTO, JOSE A. M.; PARISE-FILHO, ROBERTO. Toward chelerythrine optimization: Analogues designed by molecular simplification exhibit selective growth inhibition in non-small-cell lung cancer cells. Bioorganic & Medicinal Chemistry, v. 24, n. 19, p. 4600-4610, OCT 1 2016. (13/18160-4)

CUNHA, MICAEL R.; TAVARES, MAURICIO T.; CARVALHO, CAMILA F.; SILVA, NUNO A. T.; SOUZA, ALFREDO D. F.; PEREIRA, GUSTAVO J. V.; FERREIRA, FABIO F.; PARISE-FILHO, ROBERTO. Environmentally Safe Condition for the Synthesis of Aryl and Alkyl Sulfonyl Hydrazones via One-Pot Reaction. ACS SUSTAINABLE CHEMISTRY & ENGINEERING, v. 4, n. 4, p. 1899-1905, APR 2016. (13/18160-4)

FERNANDES, THAIS B.; SEGRETTI, MARIANA C. F.; POLLI, MICHELLE C.; PARISE-FILHO, ROBERTO. Analysis of the Applicability and Use of Lipinski's Rule for Central Nervous System Drugs. LETTERS IN DRUG DESIGN & DISCOVERY, v. 13, n. 10, p. 999-1006, 2016. (13/18160-4)

FERREIRA, ADILSON KLEBER; TAVARES, MAURICIO TEMOTHEO; MESQUITA PASQUALOTO, KERLY FERNANDA; DE AZEVEDO, RICARDO ALEXANDRE; TEIXEIRA, SARAH FERNANDES; FERREIRA-JUNIOR, WILSON ALVES; BERTIN, ARIANE MATIELLO; DE-SA-JUNIOR, PAULO LUIZ; MARZAGO BARBUTO, JOSE ALEXANDRE; FIGUEIREDO, CARLOS ROGERIO; et al. RPF151, a novel capsaicin-like analogue: in vitro studies and in vivo preclinical antitumor evaluation in a breast cancer model. TUMOR BIOLOGY, v. 36, n. 9, p. 7251-7267, SEP 2015. (13/07273-2, 13/18160-4, 12/23233-8)

CUNHA, MICAEL RODRIGUES; TAVARES, MAURICIO TEMOTHEO; FERNANDES, THAIS BATISTA; PARISE-FILHO, ROBERTO. Peppers: A ``Hot{''} Natural Source for Antitumor Compounds. Molecules, v. 26, n. 6, MAR 2021. (13/18160-4, 17/00689-0)

VASSILIADES, SANDRA VALERIA; NAVARAUSCKAS, VITOR BASTOS; BERTACINE DIAS, MARCIO VINICIUS; PARISE-FILHO, ROBERTO. Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors: State of Art Past 20 Years. BIOINTERFACE RESEARCH IN APPLIED CHEMISTRY, v. 13, n. 1, p. 19-pg., 2023-02-15. (17/00689-0, 13/18160-4)

TAVARES, M.; DAMIAO, M.; FERREIRA, A.; RODRIGUES, C.; BARBUTO, J.; AZEVEDO, R.; DE-SA-JUNIOR, P.; PARISE-FILHO, R.; FERREIRA, F.. Synthesis and crystal structure of a new anticancer candidate: RPF151. ACTA CRYSTALLOGRAPHICA A-FOUNDATION AND ADVANCES, v. 70, p. 1-pg., 2014-08-01. (08/10537-3, 12/23233-8, 13/18160-4)

TAVARES, MAURICIO T.; PASQUALOTO, KERLY F. M.; VAN DE STREEK, JACCO; FERREIRA, ADILSON K.; AZEVEDO, RICARDO A.; DAMIAO, MARIANA C. F. C. B.; RODRIGUES, CECILIA P.; DE-SA-JUNIOR, PAULO L.; BARBUTO, JOSE A. M.; PARISE-FILHO, ROBERTO; et al. Synthesis, characterization, in silico approach and in vitro antiproliferative activity of RPF151, a benzodioxole sulfonamide analogue designed from capsaicin scaffold. Journal of Molecular Structure, v. 1088, p. 138-146, MAY 15 2015. (13/18160-4, 08/10537-3, 12/23233-8)