Inhibition of human DNA topoisomerase IB by nonmut... - BV FAPESP
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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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de Camargo, Mariana S. [1] ; da Silva, Monize M. [1] ; Correa, Rodrigo S. [2] ; Vieira, Sara D. [3] ; Castelli, Silvia [3] ; D'Anessa, Ilda [3] ; De Grandis, Rone [4] ; Varanda, Eliana [4] ; Deflon, Victor M. [5] ; Desideri, Alessandro [3] ; Batista, Alzir A. [1]
Total Authors: 11
Affiliation:
[1] Univ Fed Sao Carlos, Dept Quim, CP 676, BR-13565905 Sao Carlos, SP - Brazil
[2] Univ Fed Ouro Preto, ICEB, Dept Quim, BR-35400000 Ouro Preto, MG - Brazil
[3] Univ Roma Tor Vergata, Dipartimento Biol, I-00133 Rome - Italy
[4] UNESP, Fac Ciencias Farmaceut, Dept Ciencias Biol, BR-14800900 Araraquara, SP - Brazil
[5] Univ Sao Paulo, Inst Quim Sao Carlos, CP 780, BR-13560970 Sao Carlos, SP - Brazil
Total Affiliations: 5
Document type: Journal article
Source: METALLOMICS; v. 8, n. 2, p. 179-192, 2016.
Web of Science Citations: 18
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(SpymMe(2))(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 anticancer 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. (AU)

FAPESP's process: 14/10516-7 - Search for ruthenium (II) complexes, with chemotherapeutic properties: evaluation of possible sinergistic effects and possible action mechanism
Grantee:Alzir Azevedo Batista
Support Opportunities: Regular Research Grants
FAPESP's process: 12/21529-7 - "EVALUATION OF ANTITUMORAL ACTIVITY OF RUTHENIUM COMPOUNDS: STUDY OF MUTAGENICITY, CYTOTOXICITY, TOPOISOMERASES INHIBITION AND ALTERATIONS ON GENIC EXPRESSION"
Grantee:Mariana Santoro de Camargo
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 13/20078-4 - Effects of ruthenium compounds on the topoisomerase i enzyme as antitumoral mechanism
Grantee:Mariana Santoro de Camargo
Support Opportunities: Scholarships abroad - Research Internship - Post-doctor