DNA binding, cytotoxic effects and probable targets of an oxindolimine-vanadyl complex as an antitumor agent

Autor(es):Mostrar menos -

Dario, Bruno Soares ^{[1, 2]} ; Neto, Francisco Fernandes ^[2] ; Portes, Marcelo Cecconi ^[2] ; Fazzi, Rodrigo Boni ^[2] ; da Silva, Daniel Rodrigues ^[2] ; Peterson, Erica J. ^[1] ; Farrell, Nicholas Patrick ^[1] ; Castelli, Silvia ^[3] ; Desideri, Alessandro ^[3] ; Divina Petersen, Philippe Alexandre ^[4] ; Petrilli, Helena Maria ^[4] ; Da Costa Ferreira, Ana Maria ^[2]

Afiliação do(s) autor(es)

^[1] Virginia Commonwealth Univ, Richmond, VA - USA

^[2] Univ Sao Paulo, Inst Quim, Ave Prof Lineu Prestes 748, BR-05508000 Sao Paulo, SP - Brazil

^[3] Univ Tor Vergata Rome, Rome - Italy

^[4] Univ Sao Paulo, Inst Fis, Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: NEW JOURNAL OF CHEMISTRY; v. 43, n. 45, p. 17831-17840, DEC 7 2019.
• Citações Web of Science: 0

Resumo

The biological activity of an oxindolimine-oxidovanadium(IV) complex, with significant antiproliferative action against different tumor cells, has been investigated and compared to that of analogous copper(II) or zinc(II) compounds. This vanadyl complex, {[}VO(isapn)]SO4, was synthesized and characterized by the usual spectroscopic techniques (UV/Vis, IR, and EPR), and its interactions with vital biomolecules were verified. In experiments using a Hoechst 33258 dye bound to DNA, a decrease in the intensity of fluorescence was observed with the increase in the concentration of this complex, revealing its probable binding in grooves of DNA. The determined binding constants indicated a significant change in values with increasing incubation times, which is attributed to probable changes in the metal coordination sphere. However, its influence on the melting point of CT-DNA was negligible, suggesting very little disturbance to the nucleic acid structure. In comparative studies, Delta T = similar to 8 degrees C was observed with the analogous copper(II) complex, {[}Cu(isapn)](+). In addition, promising results were verified for the cytotoxicity of {[}VO(isapn)](+) toward human colon and breast cancer cells, with IC50 in the range 5 to 10 mu M, after 24 h of treatment at 37 degrees C. However, the reactivity was much lower against HeLa cells under the same conditions (IC50 +/- 100 mu M). Further studies pointed to topoisomerase IB (Topo I) as a probable additional target of this compound. It inhibited the cleavage step but not the religation, interacting directly with the enzyme and preventing its binding to DNA, similar to what was observed with analogous copper(II) and zinc(II) complexes. Molecular docking simulations showed interactions of the {[}VO(isapn)](+) complex at different sites of Topo I, corroborating the experimental data. (AU)

• Processo FAPESP: 11/20976-7 - Estudos da reatividade de complexos de vanádio com ligantes nitrogenados e carboxilados
• Beneficiário: Bruno Soares Dário
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 11/50318-1 - Desenvolvimento de compostos com interesse farmacológico ou medicinal e de sistemas para seu transporte, detecção e reconhecimento no meio biológico
• Beneficiário: Ana Maria da Costa Ferreira
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/07937-8 - Redoxoma
• Beneficiário: Ohara Augusto
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs