Inhibition of human DNA topoisomerase IB by nonmutagenic ruthenium( II)-based compounds with antitumoral activity

Autor(es):Mostrar menos -

de Camargo, Mariana S. ^[1] ; da Silva, Monize M. ^[1] ; Correa, Rodrigo S. ^[2] ; Vieira, Sara D. ^[3] ; Castelli, Silvia ^[3] ; D'Anessa, Ilda ^[3] ; De Grandis, Rone ^[4] ; Varanda, Eliana ^[4] ; Deflon, Victor M. ^[5] ; Desideri, Alessandro ^[3] ; Batista, Alzir A. ^[1]

Afiliação do(s) autor(es)

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

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

^[3] Univ Roma Tor Vergata, Dipartimento Biol, I-00133 Rome - Italy

^[4] UNESP, Fac Ciencias Farmaceut, Dept Ciencias Biol, BR-14800900 Araraquara, SP - Brazil

^[5] Univ Sao Paulo, Inst Quim Sao Carlos, CP 780, BR-13560970 Sao Carlos, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: METALLOMICS; v. 8, n. 2, p. 179-192, 2016.
• Citações Web of Science: 18

Resumo

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(SpymMe(2))(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 anti-proliferative 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. (AU)

• Processo FAPESP: 14/10516-7 - Busca por complexos de rutênio (II), com propriedades quimioterapêuticas: avaliação de possíveis efeitos sinergísticos e possíveis mecanismo de ação
• Beneficiário: Alzir Azevedo Batista
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/21529-7 - "avaliação da atividade antitumoral de compostos de rutênio: estudo do potencial mutagênico, citotóxico, inibição de topoisomerases e alterações sobre a expressão gênica"
• Beneficiário: Mariana Santoro de Camargo
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 13/20078-4 - Efeitos de compostos de rutênio sobre a enzima topoisomerase i como mecanismo antitumoral
• Beneficiário: Mariana Santoro de Camargo
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado