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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/3
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Publication Metadata only Structures and anticancer activity of chlorido platinum(II) saccharinate complexes with mono- and dialkylphenylphosphines(Elsevier Science Inc, 2019) İçsel, Ceyda; Yılmaz, Veysel T.; Aygün, Muhittin; Ulukaya, Engin; Animal Laboratory; Cevatemre, Buse; Researcher; Animal Laboratory; N/A; N/Acis-[PtCl(sac)(PPh2Me)(2)] (1), cis-[PtCl(sac)(PPhMe2)(2)] (2), trans-[PtCl(sac)(PPh2Et)(2)] (3) and trans- [PtCl(sac) (PPhEt2)(2)] (4) complexes (sac = saccharinate) were synthesized and characterized by elemental analysis and spectroscopic methods. The structures of 2-4 were determined by X-ray single-crystal diffraction. The interaction of the complexes with DNA was studied various biochemical, biophysical and molecular docking methods. Only the cis-configured complexes (1 and 2) showed nuclease activity and their binding affinity towards DNA was considerably higher than those of their trans-congeners (3 and 4). The chlorido ligand in the cis-configured complexes underwent aquation, making them more reactive towards DNA. Furthermore, 1 and 2 exhibited anticancer potency on breast (MCF-7) and colon (HCT116) cancer cells similar to cisplatin, whereas 3 and 4 were biologicallly inactive. Mechanistic studies on MCF-7 cells showed that higher nuclear uptake, cell cycle arrest at the S phase, dramatically increased DNA double-strand breaks, apoptosis induction, elevated levels of reactive oxygen species (ROS) and high mitochondrial membrane depolarization greatly contribute to the anticancer potency of 1 and 2.Publication Metadata only May iron(III) complexes containing phenanthroline derivatives as ligands be prospective anticancer agents?(Elsevier, 2019) Matos, Cristina P.; Adiguzel, Zelal; Yildizhan, Yasemin; Cevik, Ozge; Nunes, Patrique; Ferreira, Liliana P.; Carvalho, Maria Deus; Campos, Debora L.; Pavan, Fernando R.; Pesso, Joao Costa; Garcia, Maria Helena; Tomaz, Ana Isabel; Correia, Isabel; Animal Laboratory; N/A; N/A; Cevatemre, Buse; Önder, Tuğba Bağcı; Ayhan, Ceyda Açılan; Researcher; Faculty Member; Faculty Member; Animal Laboratory; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; School of Medicine; School of Medicine; N/A; 184359; 219658We report the design, synthesis and biological studies on a group of mixed ligand Fe(111) 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 = 2,21-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-phenanthroline5-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 FUR, UV-Vis, H-1 and C-13 NMR and fluorescence spectroscopies. [Fe(phen)Cl-3] and [Fe(amphen)Cl-3] 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 M1T 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 VPAAD 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 gamma H2AX 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-MTh activity than several known second line drugs. Hence, these initial studies show prospective anti-cancer and anti-MTb activity granting promise for further studies.Publication Metadata only Cu(II) and V(IV)O complexes with tri- or tetradentate ligands based on (2-hydroxybenzyl)-L-alanines reveal promising anticancer therapeutic potential(Royal Soc Chemistry, 2021) Ribeiro, Nadia; Bulut, Ipek; Teixeira, Carlos; Yildizhan, Yasemin; Andre, Vania; Adao, Pedro; Pessoa, Joao Costa; Correia, Isabel; Animal Laboratory; N/A; Cevatemre, Buse; Ayhan, Ceyda Açılan; Researcher; Faculty Member; Animal Laboratory; N/A; School of Medicine; N/A; 219658Four new ligand precursors (H2L1-H2L4), derived from the Mannich condensation of two amino acids (L-Val and L-Phe) and two 3,5-disubstituted phenols (t-Bu or Me), and the corresponding oxidovanadium(IV) (1-4) and copper(II) (6-7) complexes are synthesized. Two other related compounds (H2L5 and H2L6), containing an additional 2-methyl-pyridine arm, and the corresponding (VO)-O-IV (5) and Cu-II (8-9) complexes were also obtained. All metal complexes are monomeric in the solid state, having a solvent molecule or a chloride ion in the coordination sphere. The in vitro cytotoxic activity of all compounds is evaluated against cancer cells from different origins. The IC50 values at 72 h are in the range of 6-15 mu M for HeLa cells, 4-17 mu M for A-549 cells and >25 mu M for MDA-MB-231 cells, except for [(VOL1)-O-IV(CH3OH)] (1) and [CuL6(H2O)] (9). With the exception of H2L6, overall, the metal complexes are more cytotoxic than the corresponding ligand precursors. Globally, the cellular viability data show that (i) the L-Phe derived compounds are more cytotoxic than the corresponding L-Val complexes; (ii) the presence of the bulkier t-Bu groups increases the cytotoxicity; (iii) the presence of a 2-methyl-pyridine arm increases considerably the cytotoxicity; and (iv) the Cu-II-complexes are more cytotoxic than the (VO)-O-IV-compounds. Complexes [(VOL3)-O-IV(CH3OH)] (3), [CuL3(H2O)] (7) and [CuL5(H2O)] (8) were further evaluated and their mechanism of action was determined to be apoptosis, evidenced by AnnexinV staining and the increase in caspase 3/7 activity. Compounds 3, 7 and 8 also exhibit DNA cleavage activity, involving the formation of reactive oxygen species and were able to induce genomic damage in cells as determined by COMET assay.