May iron(III) complexes containing phenanthroline derivatives as ligands be prospective anticancer agents?
| Autor: | Liliana P. Ferreira, Maria Deus Carvalho, Cristina P. Matos, Débora L. Campos, Maria Helena Garcia, Ana Isabel Tomaz, Isabel Correia, Fernando Rogério Pavan, Ozge Cevik, Buse Cevatemre, Yasemin Yildizhan, Zelal Adiguzel, Tugba Bagci Onder, João Costa Pessoa, Ceyda Acilan, Patrique Nunes |
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| Přispěvatelé: | Universidade de Lisboa, Genetic Engineering and Biotechnology Institute, Koc University Research Center for Translational Medicine (KUTTAM), Medical School, School of Medicine, University of Coimbra, Universidade Estadual Paulista (Unesp) |
| Rok vydání: | 2019 |
| Předmět: |
Conformational change
Iron Cytotoxicity Phenanthroline Antitubercular Agents Antineoplastic Agents Apoptosis DNA Fragmentation Ligands 01 natural sciences Medicinal chemistry Anti tuberculosis HeLa 03 medical and health sciences chemistry.chemical_compound Drug Stability Coordination Complexes Fe(III)-complexes Cell Line Tumor Drug Discovery medicine Humans DNA Breaks Double-Stranded Prospective Studies N-heterocycles 030304 developmental biology Pharmacology 0303 health sciences biology 010405 organic chemistry Ligand Organic Chemistry DNA Mycobacterium tuberculosis General Medicine biology.organism_classification 0104 chemical sciences Comet assay Anticancer chemistry Mechanism of action Drug Design Amine gas treating Genotoxicity medicine.symptom Reactive Oxygen Species Phenanthrolines |
| Zdroj: | Scopus Repositório Institucional da UNESP Universidade Estadual Paulista (UNESP) instacron:UNESP |
| ISSN: | 0223-5234 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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