Artículos de revistas
Non-mutagenic Ru(ii) complexes: Cytotoxicity, topoisomerase IB inhibition, DNA and HSA binding
Fecha
2019-01-01Registro en:
Dalton Transactions, v. 48, n. 39, p. 14885-14897, 2019.
1477-9234
1477-9226
10.1039/c9dt01905g
2-s2.0-85072992950
Autor
UniversitàTorVergatadi Roma
Universidade Federal de São Carlos (UFSCar)
Universidade Federal de Ouro Preto
Universidade Estadual Paulista (Unesp)
Universidade DeSão Paulo
Universidade de São Paulo (USP)
Institución
Resumen
Herein we discuss five ruthenium(ii) complexes with good cytotoxicity against cancer cells. These complexes are named [Ru(tzdt)(bipy)(dppb)]PF6 (1), [Ru(mmi)(bipy)(dppb)]PF6 (2), [Ru(dmp)(bipy)(dppb)]PF6 (3), [Ru(mpca)(bipy)(dppb)]PF6 (4) and [Ru(2mq)(bipy)(dppb)]PF6 (5), where tzdt = 1,3-thiazolidine-2-thione, mmi = mercapto-1-methyl-imidazole, dmp = 4,6-diamino-2-mercaptopyrimidine, mpca = 6-mercaptopyridine-3-carboxylic acid, 2mq = 2-mercapto-4(3H)-quinazolinone, bipy = 2,2′-bipyridine and dppb = 1,4-bis(diphenylphosphino)butane. In vitro cell culture experiments revealed significant cytotoxic activity for 1-5 against MDA-MB-231, MCF-7, A549, DU-145 and HepG2 tumor cells, higher than that for the standard anticancer drug cisplatin. Compound/DNA interaction studies were carried out showing that 1-5 interact with DNA by electrostatic force of attraction or by hydrogen bonding. Moreover, the complexes interact, moderately and spontaneously, with human serum albumin (HSA) through the hydrophobic region. The five complexes are able to inhibit the DNA supercoiled relaxation mediated by human topoisomerase IB (TopIB), and complex 1 is found to be the most efficient TopIB inhibitor among the five compounds. The inhibitory effect and analysis of different steps of the TopIB catalytic cycle indicate that complex 1 inhibits the cleavage reaction impeding the binding of the enzyme to DNA and has no effect on the religation step. Complexes 1, 2 and 3 did not show mutagenic activity when they were evaluated by the cytokinesis-block micronucleus cytome assay in HepG2 cells and the Ames test in the presence and absence of mouse liver S9 metabolic activation. Therefore, it is necessary to perform further in-depth analysis of the therapeutic potential of these promising ruthenium complexes as anticancer drugs.