Effect of oxindolimine copper(II) and zinc(II) complexes on human topoisomerase I activity

Author(s)

Katkar, Prafulla ^[1] ; Coletta, Andrea ^[1] ; Castelli, Silvia ^[1] ; Sabino, Gustavo L. ^[2] ; Alves Couto, Ricardo A. ^[2] ; da Costa Ferreira, Ana M. ^[2] ; Desideri, Alessandro ^[1]

Affiliation

^[1] Univ Roma Tor Vergata, Dipartimento Biol, I-00173 Rome - Italy

^[2] Univ Sao Paulo, Inst Quim, BR-05508000 Sao Paulo - Brazil

• Document type: Journal article
• Source: METALLOMICS; v. 6, n. 1, p. 117-125, 2014.
• Web of Science Citations: 23

Abstract

The ability of oxindolimine copper(II) and zinc(II) complexes, known to have antitumor activity, to inhibit human topoisomerase IB has been tested through enzymatic kinetic assays and molecular docking simulations. These copper and zinc compounds are able to inhibit remarkably the cleavage reaction and only partially the religation step, the copper compound being more efficient than the zinc one. A complete inhibition activity of the cleavage is only obtained when the enzyme is pre-incubated with the compound, the inhibition being irreversible and reversible for the copper and zinc compounds, respectively. The relative stability of such complexes was estimated by competitive equilibria with human serum albumin (HSA), monitored by CD spectroscopy. The copper species shows a log K-CuL = 17.2, while the analogous zinc complex exhibits a log K-ZnL = 7.2. Molecular docking simulation studies show that the almost square planar geometry of the copper compound allows a direct coordination of the metal with two amino acids (Glu492, Asp563) of the enzyme at variance of the zinc compound which has a more tetrahedral geometry. Altogether, the data indicate that the different coordination geometry achieved by the two transition metal ions has an important role in modulating their efficiency as topoisomerase I inhibitors. (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: 12/03080-2 - Studies of interactions between copper complexes with antitumor activity and proteins kinases and topoisomerases
• Grantee: Ana Maria da Costa Ferreira
• Support Opportunities: Research Grants - Visiting Researcher Grant - International