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

Author(s):Show less -

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]

Affiliation

^[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

• Document type: Journal article
• Source: NEW JOURNAL OF CHEMISTRY; v. 43, n. 45, p. 17831-17840, DEC 7 2019.
• Web of Science Citations: 0

Abstract

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)

• FAPESP's process: 11/50318-1 - Development of compounds with pharmacological or medicinal interest and of systems for their transport, detection and recognition in biological media
• Grantee: Ana Maria da Costa Ferreira
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC