title: Effect of oxindolimine copper(II) and zinc(II) complexes on human topoisomerase I activity.
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 KCuL = 17.2, while the analogous zinc complex exhibits a log KZnL = 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.
authors.affiliation: Dipartimento di Biologia, Università Tor Vergata di Roma, 00173 Roma, Italy. desideri@uniroma2.it.
authors.forename: Prafulla
authors.initials: P
authors.lastname: Katkar
authors.forename: Andrea
authors.initials: A
authors.lastname: Coletta
authors.forename: Silvia
authors.initials: S
authors.lastname: Castelli
authors.forename: Gustavo L
authors.initials: GL
authors.lastname: Sabino
authors.forename: Ricardo A Alves
authors.initials: RA
authors.lastname: Couto
authors.forename: Ana M da Costa
authors.initials: AM
authors.lastname: Ferreira
authors.forename: Alessandro
authors.initials: A
authors.lastname: Desideri
mesh_terms: D001224:Aspartic Acid / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D055162:Biocatalysis / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000737:chemistry* / Q000378:metabolism; D002942:Circular Dichroism; D056831:Coordination Complexes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism*; D004270:DNA, Circular / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009841:Oligonucleotides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D059004:Topoisomerase I Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015032:Zinc / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001643:Bridged Bicyclo Compounds; D056831:Coordination Complexes; D004270:DNA, Circular; D009841:Oligonucleotides; D059004:Topoisomerase I Inhibitors; D001224:Aspartic Acid; D018698:Glutamic Acid; D003300:Copper; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D015032:Zinc