Browsing by Author "Deflon, Victor Marcelo"

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    Inhibition of human DNA topoisomerase IB by nonmutagenic ruthenium(ii)-based compounds with antitumoral activity.
    (2016) Camargo, Mariana Santoro de; Silva, Monize Martins da; Correa, Rodrigo de Souza; Vieira, Sara Dourado; Castelli, Silvia; D’Anessa, Ilda; Grandis, Rone De; Varanda, Eliana Aparecida; Deflon, Victor Marcelo; Desideri, Alessandro; Batista, Alzir Azevedo
    Herein we synthesized two new ruthenium(II) compounds [Ru(pySH)(bipy)(dppb)]PF6 (1) and [Ru(HSpym)(bipy)- (dppb)]PF6 (2) that are analogs to an antitumor agent recently described, [Ru(SpymMe2)(bipy)(dppb)]PF6 (3), where [(Spy) = 2-mercaptopyridine anion; (Spym) = 2-mercaptopyrimidine anion and (SpymMe2) = 4,6-dimethyl-2-mercaptopyrimidine anion]. In vitro cell culture experiments revealed significant antiproliferative activity for 1–3 against HepG2 and MDA-MB-231 tumor cells, higher than the standard anticancer drugs doxorubicin and cisplatin. No mutagenicity is detected when compounds are evaluated by cytokinesis-blocked micronucleus cytome and Ames test in the presence and absence of S9 metabolic activation from rat liver. Interaction studies show that compounds 1–3 can bind to DNA through electrostatic interactions and to albumin through hydrophobic interactions. The three compounds are able to inhibit the DNA supercoiled relaxation mediated by human topoisomerase IB (Top1). Compound 3 is the most efficient Top1 inhibitor and the inhibitory effect is enhanced upon pre-incubation with the enzyme. Analysis of different steps of Top1 catalytic cycle indicates that 3 inhibits the cleavage reaction impeding the binding of the enzyme to DNA and slows down the religation reaction. Molecular docking shows that 3 preferentially binds closer to the residues of the active site when Top1 is free and lies on the DNA groove downstream of the cleavage site in the Top1–DNA complex. Thus, 3 can be considered in further studies for a possible use as an anticancer agent.
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    Non-mutagenic Ru(II) complexes : cytotoxicity, topoisomerase IB inhibition, DNA and HSA binding.
    (2019) Silva, Monize Martins da; Camargo, Mariana Santoro de; Correa, Rodrigo de Souza; Castelli, Silvia; Grandis, Rone De; Takarada, Jéssica Emi; Varanda, Eliana Aparecida; Castellano, Eduardo Ernesto; Deflon, Victor Marcelo; Cominetti, Márcia Regina; Desideri, Alessandro; Batista, Alzir Azevedo
    Herein we discuss five ruthenium(II) complexes with good cytotoxicity against cancer cells. These complexes are named [Ru(tzdt)(bipy)(dppb)]PF6 (1), [Ru(mmi)(bipy)(dppb)]PF6 (2), [Ru(dmp)(bipy)(dppb)]PF6 (3), [Ru(mpca)(bipy)(dppb)]PF6 (4) and [Ru(2mq)(bipy)(dppb)]PF6 (5), where tzdt = 1,3-thiazolidine-2-thione, mmi = mercapto-1-methyl-imidazole, dmp = 4,6-diamino-2-mercaptopyrimidine, mpca = 6-mercaptopyridine-3-carboxylic acid, 2mq = 2-mercapto-4(3H)-quinazolinone, bipy = 2,2′-bipyridine and dppb = 1,4-bis(diphenylphosphino)butane. In vitro cell culture experiments revealed significant cytotoxic activity for 1–5 against MDA-MB-231, MCF-7, A549, DU-145 and HepG2 tumor cells, higher than that for the standard anticancer drug cisplatin. Compound/DNA interaction studies were carried out showing that 1–5 interact with DNA by electrostatic force of attraction or by hydrogen bonding. Moreover, the complexes interact, moderately and spontaneously, with human serum albumin (HSA) through the hydrophobic region. The five complexes are able to inhibit the DNA supercoiled relaxation mediated by human topoisomerase IB (TopIB), and complex 1 is found to be the most efficient TopIB inhibitor among the five compounds. The inhibitory effect and analysis of different steps of the TopIB catalytic cycle indicate that complex 1 inhibits the cleavage reaction impeding the binding of the enzyme to DNA and has no effect on the religation step. Complexes 1, 2 and 3 did not show mutagenic activity when they were evaluated by the cytokinesis-block micronucleus cytome assay in HepG2 cells and the Ames test in the presence and absence of mouse liver S9 metabolic activation. Therefore, it is necessary to perform further in-depth analysis of the therapeutic potential of these promising ruthenium complexes as anticancer drugs.
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    Ru(II)-naphthoquinone complexes with high selectivity for triple negative breast cancer.
    (2020) Oliveira, Katia Mara de; Peterson, Erica J.; Carroccia, Murilo César; Cominetti, Márcia Regina; Deflon, Victor Marcelo; Farrell, Nicholas P.; Batista, Alzir Azevedo; Correa, Rodrigo de Souza
    Six new ruthenium(II) complexes with lapachol (Lap) and lawsone (Law) with the general formula [Ru(L)(P– P)(bipy)]PF6, where L = Lap or Law, P–P = 1,2’-bis(diphenylphosphino)ethane (dppe), 1,4’-bis(diphenyl phosphino)butane (dppb), 1,1’-bis(diphenylphosphino)ferrocene (dppf) and bipy = 2,2’-bipyridine, were synthesized, fully characterized by elemental analysis, molar conductivity, NMR, cyclic voltammetry, UV vis, IR spectroscopies and three of them by X-ray crystallography. All six complexes were active against breast (MCF-7 and MDA-MB-231) and prostate (DU-145) cancer cell lines with lower IC50 values than cis platin. Complex [Ru(Lap)(dppe)(bipy)]PF6 (1a) showed significant selectivity for MDA-MB-231, a model of triple-negative breast cancer (TNBC), as compared to the “normal-like” human breast epithelial cell line, MCF-10A. Complex (1a) inhibited TNBC colony formation and induced loss of cellular adhesion. Furthermore, the complex (1a) induced mitochondrial dysfunction and generation of ROS, as is involved in the apoptotic cell death pathway. Preferential cellular uptake of complex (1a) was observed in MDA-MB-231 cells compared to MCF-10A cells, consistent with the observed selectivity for tumorigenic vs. non-tumorigenic cells. Taken together, these results indicate that ruthenium complexes containing lapachol and lawsone as ligands are promising candidates as chemotherapeutic agents.
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    Ru(II)/diclofenac-based complexes : DNA, BSA interaction and their anticancer evaluation against lung and breast tumor cells.
    (2020) Oliveira, Katia Mara de; Peterson, Erica J.; Carroccia, Murilo César; Cominetti, Márcia Regina; Deflon, Victor Marcelo; Farrell, Nicholas P.; Batista, Alzir Azevedo; Correa, Rodrigo de Souza
    Six new ruthenium(II) complexes with lapachol (Lap) and lawsone (Law) with the general formula [Ru(L)(P– P)(bipy)]PF6, where L = Lap or Law, P–P = 1,2’-bis(diphenylphosphino)ethane (dppe), 1,4’-bis(diphenyl phosphino)butane (dppb), 1,1’-bis(diphenylphosphino)ferrocene (dppf) and bipy = 2,2’-bipyridine, were synthesized, fully characterized by elemental analysis, molar conductivity, NMR, cyclic voltammetry, UV vis, IR spectroscopies and three of them by X-ray crystallography. All six complexes were active against breast (MCF-7 and MDA-MB-231) and prostate (DU-145) cancer cell lines with lower IC50 values than cis platin. Complex [Ru(Lap)(dppe)(bipy)]PF6 (1a) showed significant selectivity for MDA-MB-231, a model of triple-negative breast cancer (TNBC), as compared to the “normal-like” human breast epithelial cell line, MCF-10A. Complex (1a) inhibited TNBC colony formation and induced loss of cellular adhesion. Furthermore, the complex (1a) induced mitochondrial dysfunction and generation of ROS, as is involved in the apoptotic cell death pathway. Preferential cellular uptake of complex (1a) was observed in MDA-MB-231 cells compared to MCF-10A cells, consistent with the observed selectivity for tumorigenic vs. non-tumorigenic cells. Taken together, these results indicate that ruthenium complexes containing lapachol and lawsone as ligands are promising candidates as chemotherapeutic agents.