Lapachol in the Design of a New Ruthenium(II)-Diphosphine Complex as a Promising Anticancer Metallodrug

Autor(es)

Oliveira, Katia M. ^{[1, 2]} ; Honorato, Joao ^[1] ; Demidoff, Felipe C. ^[3] ; Schultz, Mario S. ^[3] ; Netto, Chaquip D. ^[3] ; Cominetti, Marcia R. ^[4] ; Correa, Rodrigo S. ^[2] ; Batista, Alzir A. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Carlos UFSCar, Dept Quim, CP 676, BR-13565905 Sao Carlos, SP - Brazil

^[2] Univ Fed Ouro Preto UFOP, Dept Quim, ICEB, BR-35400000 Ouro Preto, MG - Brazil

^[3] Univ Fed Rio de Janeiro UFRJ, Inst Quim, Campus Aloisio Teixeira, BR-27930560 Macae, RJ - Brazil

^[4] Univ Fed Sao Carlos UFSCar, Dept Gerontol, CP 676, BR-13565905 Sao Carlos, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Inorganic Biochemistry; v. 214, JAN 2021.
• Citações Web of Science: 0

Resumo

The preparation of two new Ru(II)/diphosphine complexes containing Lapachol (Lap) and Lawsone (Law): (1) {[}Ru(Lap)(dppm)(2)]PF6 and (2) {[}Ru(Law)(dppm)(2)]PF6, where dppm = bis(diphenylphosphino)methane, is reported here. The complexes were synthetized and fully characterized by elemental analyses, molar conductivity, UV-Vis, IR, P-31[H-1], H-1 and C-13 NMR, and the crystal structure of the complex (1) was determined by X-ray diffraction. Complexes (1) and (2) showed high in vitro cytotoxicity against four cancer cells (MDA-MB-231, MCF-7, A549 and DU-145), with IC50 values in the micromolar range (0.03 to 2.70 mu M). Importantly, complexes (1) and (2) were more active than the cisplatin, the drug used as a reference in the cytotoxic assays. Moreover, complex (1) showed high selectivity to triple-negative breast cancer cells (MDA-MB-231). Studies of the mechanism of action in MDA-MB-231 cancer cells showed that complex (1) inhibits cell migration, colony formation, and induces cell cycle arrest and apoptosis by activation of the mitochondrial pathway through the loss of mitochondrial membrane potential (Delta Psi m). Furthermore, complex (1) induces ROS (Reactive Oxygen Species) generation in MDA-MB-231 cells, which can cause DNA damage. Finally, complexes (1) and (2) interact with DNA by minor grooves and show a moderate interaction with BSA (Bovine Serum Albumin), with the involvement of hydrophobic interactions. Essentially, Ru(II)/diphosphine-naphthoquinone complexes have remarkable cytotoxic effects with high selectivity to triple-negative breast cancer (MDA-MB-231) and could be promising anticancer candidates for cancer treatment. Synopsis: The naphthoquinones Lapachol and Lawsone can form new ruthenium compounds with promising anticancer properties. (AU)

• Processo FAPESP: 16/16312-0 - Citotoxidade e mecanismo de ação de complexos de rutênio contendo produtos naturais ou derivados
• Beneficiário: Alzir Azevedo Batista
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 14/04147-9 - Avaliação das propriedades anticâncer de complexos de rutênio(II) contendo os bioligantes lapachol e lausona
• Beneficiário: Katia Mara de Oliveira
• Modalidade de apoio: Bolsas no Brasil - Doutorado