Autor(es):
Matos, Cristina P. ; Adiguzel, Zelal ; Yildizhan, Yasemin ; Cevatemre, Buse ; Onder, Tugba Bagci ; Cevik, Ozge ; Nunes, Patrique ; Ferreira, Liliana P. ; Carvalho, Maria Deus ; Campos, Débora L. [UNESP] ; Pavan, Fernando R. [UNESP] ; Pessoa, João Costa ; Garcia, Maria Helena ; Tomaz, Ana Isabel ; Correia, Isabel ; Acilan, Ceyda
Data: 2019
Identificador Persistente: http://hdl.handle.net/11449/190349
Origem: Oasisbr
Assunto(s): Anti tuberculosis; Anticancer; Cytotoxicity; Fe(III)-complexes; Genotoxicity; N-heterocycles
Descrição
Made available in DSpace on 2019-10-06T17:10:16Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-08-15
Fundação para a Ciência e a Tecnologia
We report the design, synthesis and biological studies on a group of mixed ligand Fe(III) complexes as anti-cancer drug candidates, namely their interaction with DNA, cytotoxicity and mechanism(s) of action. The aim is to obtain stable, efficient and selective Fe-complexes to be used as anti-cancer agents with less damaging side effects than previously reported compounds. Five ternary Fe(III) complexes bearing a tripodal aminophenolate ligand L2−, H2L = N,N-bis(2-hydroxy-3,5-dimethylbenzyl)-N-(2-pyridylmethyl)amine, and different aromatic bases NN = 2,2′-bipyridine [Fe(L)(bipy)]PF6 (1), 1,10-phenanthroline [Fe(L)(phen)]PF6 (2), or a phenanthroline derivative co-ligand: [Fe(L)(amphen)]NO3 (3), [Fe(L)(amphen)]PF6 (3a), [Fe(L)(Clphen)]PF6 (4), [Fe(L)(epoxyphen)]PF6 (5) (where amphen = 1,10-phenanthroline-5-amine, epoxyphen = 5,6-epoxy-5,6-dihydro-1,10-phenanthroline, Clphen = 5-chloro-1,10-phenanthroline) and the [Fe(L)(EtOH)]NO3 (6) complex are synthesized. The compounds are characterized in the solid state and in solution by elemental analysis, ESI-MS, magnetic susceptibility measurements and FTIR, UV–Vis, 1H and 13C NMR and fluorescence spectroscopies. [Fe(phen)Cl3] and [Fe(amphen)Cl3] were also prepared for comparison purposes. Spectroscopic binding studies indicate groove binding as the main interaction for most complexes with DNA, and for those containing amphen a B- to Z-DNA conformational change is proposed to occur. As determined via MTT analysis all compounds 1–6 are cytotoxic against a panel of three different cell lines (HeLa, H1299, MDA-MB-231). For selected compounds with promising cytotoxic activity, apoptosis was evaluated using cell and DNA morphology, TUNEL, Annexin V/7AAD staining and caspase3/7 activity. The compounds induce oxidative DNA damage on plasmid DNA and in cell culture as assessed by 8-oxo-Guanine and γH2AX staining. Comet assay confirmed the presence of genomic damage. There is also increased reactive oxygen species formation following drug treatment, which may be the relevant mechanism of action, thus differing from that normally assumed for cisplatin. The Fe(III)-complexes were also tested against strains of M. Tuberculosis (MTb), complex 2 depicting higher anti-MTb activity than several known second line drugs. Hence, these initial studies show prospective anti-cancer and anti-MTb activity granting promise for further studies.
Centro de Química Estrutural Departamento de Engenharia Química Instituto Superior Técnico Universidade de Lisboa, Av. Rovisco Pais 1
TUBITAK Marmara Research Center Genetic Engineering and Biotechnology Institute, Gebze
Koc University Research Center for Translational Medicine (KUTTAM), Sariyer
Koc University Medical School, Sariyer
Adnan Menderes University School of Medicine
BioISI Faculdade de Ciências Universidade de Lisboa, Lisboa
Department of Physics University of Coimbra
Centro de Química e Bioquímica Faculdade de Ciências Universidade de Lisboa, Lisboa
Faculdade de Ciências Farmacêuticas UNESP, C.P.582, SP
Centro de Quimica Estrutural Faculdade de Ciências Universidade de Lisboa, Lisboa
Faculdade de Ciências Farmacêuticas UNESP, C.P.582, SP
Fundação para a Ciência e a Tecnologia: IF/01179/2013
Fundação para a Ciência e a Tecnologia: RECI/QEQ-MED/0330/2012
Fundação para a Ciência e a Tecnologia: RECI/QEQ-QIN/0189/2012
Fundação para a Ciência e a Tecnologia: UID/BIO/04565/2013
Fundação para a Ciência e a Tecnologia: UID/MULTI/04349/2013
Fundação para a Ciência e a Tecnologia: UID/QUI/00100/2013
