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

Content Provider	Royal Society of Chemistry (RSC)
Author	Varanda, Eliana Camargo, Mariana S. de D'Anessa, Ilda Castelli, Silvia Desideri, Alessandro Batista, Alzir A. Correa, Rodrigo S. Vieira, Sara D. Grandis, Rone De Deflon, Victor M. Silva, Monize M. da
Copyright Year	2016
Abstract	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(SpymMe2)(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 anti-cancer 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.
Starting Page	179
Ending Page	192
Page Count	14
File Format	HTM / HTML PDF
ISSN	17565901
Volume Number	8
Issue Number	2
Journal	Metallomics
DOI	10.1039/c5mt00227c
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	Cell culture Ruthenium Enzyme Liver Active site Enzyme inhibitor Ion Doxorubicin Cisplatin Amino acid Ames test DNA Micronucleus Topoisomerase IB List of breast cancer cell lines Catalytic cycle
Content Type	Text
Resource Type	Article
Subject	Chemistry Medicine Metals and Alloys Biochemistry Biomaterials Biophysics

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