Metal complexes with dirivative ligands of lawsone and acylthioureas, with anticancer potential activities: study in vitro and in vivo.

• Grant number: 18/19342-2
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2019
• End date: February 28, 2021
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
• Principal Investigator: Alzir Azevedo Batista
• Grantee: Alzir Azevedo Batista
• Host Institution: Centro de Ciências Exatas e de Tecnologia (CCET). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil

Abstract

AbstractIn the search for new coordination compounds with antitumor, and without toxicity, or with less toxicity than the platinum based-compounds, ruthenium compounds are very promising. Thus, it is necessary to evaluate the antitumor potentiality of these new compounds and try to understand the possible relationship between the intracelular localization of the compounds and their mechanism of action. The objective of this project is based on the synthesis and characterization of new ruthenium/biphosphic complexes, containing lawsone derivatives as ligand, because recent study developed in our laboratory showed that this class of complexes, with lawsone or lapachol are very active and selective. Thus, new ruthenium/phosphine complexes will be synthesized, characterized and their cytotoxicity against tumor cells will be evaluated. The localization of the complexes in the cells, characterizing the target associated with the compounds in human tumor cells such as triple-negative breast (MDA-MB-231) and double positive breast (MCF-7), also in non-tumorigenic breast cell (MCF-10A) will be evaluated. The mechanism of action related to the cytotoxicity of the compounds will be evaluated as well, by interaction studies with DNA and HSA, determination of the levels of reactive oxygen species (ROS) intracellular. In addition, the pattern of cell death by flow cytometry and fluorescence microscopy. Western blotting analyzes will improve the understanding the major expressed proteins and their metabolic pathways involved in cytotoxicity and through confocal microscopy it will be possible to relate them to sub-cellular locatization. In addition, in vivo experiment will be performed in this work in embryonic chicken egg chorio-allantoid membrane to evaluate toxicity and antiangiogenic activity of the complexes, respectively. All these results together will provide us subsidies to elucidate the possible mechanisms of action for these complexes, contributing to the rational drug design and development of novel and even more effective anti-cancer agents. (AU)

Scientific publications

(12)

(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)

DE OLIVEIRA, TAMIRES D.; RIBEIRO, GABRIEL H.; HONORATO, JOAO; LEITE, CELISNOLIA M.; SANTOS, ALINE CAROLINE DA S.; SILVA, ELIS D.; PEREIRA, VALERIA REGO A.; PLUTIN, ANA M.; COMINETTI, MARCIA R.; CASTELLANO, EDUARDO E.; et al. Cytotoxic and antiparasitic activities of diphosphine-metal complexes of group 10 containing acylthiourea as ligands. Journal of Inorganic Biochemistry, v. 234, p. 13-pg., 2022-09-01. (18/19342-2)

BECCENERI, AMANDA B.; FUZER, ANGELINA M.; PLUTIN, ANA M.; BATISTA, ALZIR A.; LELIEVRE, SOPHIE A.; COMINETTI, MARCIA R.. Three-dimensional cell culture models for metallodrug testing: induction of apoptosis and phenotypic reversion of breast cancer cells by the trans-[Ru(PPh3)(2)(N,N-dimethyl-N-thiophenyl-thioureato-k(2)O,S)(bipy) ]PF6 complex. INORGANIC CHEMISTRY FRONTIERS, v. 7, n. 16, p. 2909-2919, AUG 21 2020. (17/01287-2, 18/19342-2, 13/07600-3, 17/20055-5, 15/24940-8, 14/25121-8)

ALVES, KAMILLA M.; HONORATO, JOAO; LIAO, LUCIANO M.; VELOZO-SA, VIVIANNE S.; GUEDES, ADRIANA P. M.; DUTRA, JOCELY DE L.; AYALLA, ALEJANDO P.; ELLENA, JAVIER; BATISTA, ALZIR A.; GONCALVES, PABLO J.. meso-Tetra-(4-pyridyl)porphyrin/palladium(ii) complexes as anticancer agents. DALTON TRANSACTIONS, v. 50, n. 44, SEP 2021. (21/02522-0, 21/04876-4, 18/19342-2, 17/15850-0)

DE OLIVEIRA, TAMIRES D.; PLUTIN, ANA M.; LUNA-DULCEY, LIANY; CASTELLANO, EDUARDO E.; COMINETTI, MARCIA R.; BATISTA, ALZIR A.. Cytotoxicity of ruthenium-N,N-disubstituted-N `-acylthioureas complexes. Materials Science & Engineering C-Materials for Biological Applications, v. 115, OCT 2020. (18/05594-0, 18/19342-2)

CRIZOSTOMO KOCK, FLAVIO VINICIUS; COSTA, ANALU ROCHA; DE OLIVEIRA, KATIA MARA; BATISTA, ALZIR AZEVEDO; FERREIRA, ANTONIO GILBERTO; VENANCIO, TIAGO. A Supramolecular Interaction of a Ruthenium Complex With Calf-Thymus DNA: A Ligand Binding Approach by NMR Spectroscopy. FRONTIERS IN CHEMISTRY, v. 7, NOV 8 2019. (18/09145-5, 18/16040-5, 18/19342-2)

RINALDI-NETO, FRANCISCO; RIBEIRO, ARTHUR BARCELOS; FERREIRA, NATALIA HELEN; SQUARISI, IARA SILVA; OLIVEIRA, KATIA MARA; ORENHA, RENATO PEREIRA; TAME PARREIRA, RENATO LUIS; BATISTA, ALZIR AZEVEDO; TAVARES, DENISE CRISPIM. nti-melanoma effect of ruthenium(II)-diphosphine complexes containing naphthoquinone ligan. Journal of Inorganic Biochemistry, v. 222, SEP 2021. (16/24269-7, 18/19342-2)

LEITE, CELISNOLIA M.; HONORATO, JOAO; MARTIN, ANA CAROLINA B. M.; SILVEIRA, RAFAEL G.; COLOMBARI, FELIPPE M.; AMARAL, JESSICA C.; COSTA, ANALU R. .; COMINETTI, MARCIA R. .; PLUTIN, ANA M.; DE AGUIAR, DEBORA; et al. xperimental and Theoretical DFT Study of Cu(I)/N,N-Disubstituted-N `-acylthioureato Anticancer Complexes: Actin Cytoskeleton and Induction of Death by Apoptosis in Triple-Negative Breast Tumor Cell. Inorganic Chemistry, DEC 2021. (21/04876-4, 18/19342-2)

DA SILVA, MONIZE M.; RIBEIRO, GABRIEL H.; DE CAMARGO, MARIANA S.; FERREIRA, ANTONIO G.; RIBEIRO, LEANDRO; BARBOSA, MARILIA I. F.; DEFLON, VICTOR M.; CASTELLI, SILVIA; DESIDERI, ALESSANDRO; CORREA, RODRIGO S.; et al. Ruthenium(II) Diphosphine Complexes with Mercapto Ligands That Inhibit Topoisomerase IB and Suppress Tumor Growth In Vivo. Inorganic Chemistry, v. 60, n. 18, p. 14174-14189, SEP 20 2021. (18/19342-2)

PLUTIN, ANA M.; RAMOS, RAUL; MOCELO, RAUL; ALVAREZ, ANISLAY; CASTELLANO, EDUARDO E.; COMINETTI, MARCIA R.; OLIVEIRA, KATIA M.; DE OLIVEIRA, TAMIRES DONIZETH; SILVA, THALES E. M.; CORREA, RODRIGO S.; et al. Antitumor activity of Pd(II) complexes with N,S or O,S coordination modes of acylthiourea ligands. Polyhedron, v. 184, JUL 1 2020. (18/19342-2)

RIBEIRO, GABRIEL H.; COSTA, ANALU R.; DE SOUZA, APARECIDO R.; DA SILVA, FABIANA V.; MARTINS, FELIPE T.; PLUTIN, ANA M.; BATISTA, ALZIR A.. An overview on the anticancer activity of Ru(II)/acylthiourea complexes. Coordination Chemistry Reviews, v. 488, p. 23-pg., 2023-04-28. (20/14561-8, 18/19342-2)

VELOZO-SA, VIVIANNE S.; OLIVEIRA, REGINA M. M.; LEITE, CELISNOLIA M.; COMINETTI, MARCIA R.; BARBOSA, ISABELY M. M.; SILVA, FABRICIO L. S.; FEITOSA, NATALIA MARTINS; SCHULTZ, MARIO S.; BATISTA, ALZIR A.. Scavenging capacity and cytotoxicity of new Ru(II)-diphosphine/α-amino acid complexes. Polyhedron, v. 201, p. 13-pg., 2021-04-05. (12/13042-0, 18/19342-2)

CRIZOSTOMO KOCK, FLAVIO VINICIUS; COSTA, ANALU ROCHA; DE OLIVEIRA, KATIA MARA; BATISTA, ALZIR AZEVEDO; FERREIRA, ANTONIO GILBERTO; VENANCIO, TIAGO. A Supramolecular Interaction of a Ruthenium Complex With Calf-Thymus DNA: A Ligand Binding Approach by NMR Spectroscopy. RONTIERS IN CHEMISTR, v. 7, p. 10-pg., 2019-11-08. (18/19342-2, 18/16040-5, 18/09145-5)