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    Cytotoxic platinum(II) complexes derived from saccharinate and phosphine ligands: synthesis, structures, DNA cleavage, and oxidative stress-induced apoptosis
    (Springer, 2020) İçsel, Ceyda; Yılmaz, Veysel T.; Cevatemre, Buse; Aygün, Muhittin; Ulukaya, Engin
    A series of the structurally related platinum(II) saccharinate (sac) complexes with alkylphenylphosphines, namely cis-[Pt(sac)(2)(PPh2Me)(2)]center dot DMSO (1), cis-[Pt(sac)(2)(PPhMe2)(2)] (2), cis-[Pt(sac)(2)(PPh2Et)(2)] (3), and cis-[Pt(sac)(2)(PPhEt2)(2)]center dot 2DMSO (4), were synthesized and fully characterized; their structures were determined by X-ray crystallography. All the complexes were investigated for their anticancer potentials on three human cancer cells including A549 (lung), MCF-7 (breast), and HCT116 (colon) in addition to a noncancerous human bronchial epithelial cells (BEAS-2B). Specifically, 1 and 3 showed significant cytotoxic effects against MCF-7 and HCT116 cell lines in comparison to cisplatin, and were considered as the most potent ones in the series. The cytotoxic complexes were found to cleave DNA efficiently. In addition, the binding interactions of the complexes with DNA were confirmed by enzyme inhibition and molecular docking studies. Complexes 1 and 3 were capable of inducing apoptosis and arrested the cell cycle at the DNA synthesis (S) phase in MCF-7 cells. Furthermore, 1 and 3 caused the excessive generation of reactive oxygen species (ROS), leading to mitochondrial dysfunction and double-strand DNA breaks.
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    Novel 5-fluorouracil complexes of Zn(II) with pyridine-based ligands as potential anticancer agents
    (2022) İçsel, Ceyda; Yılmaz, Veysel T; Aygün, Muhittin; Erkısa, Merve; Ulukaya, Engin
    A series of novel Zn(II) complexes of 5-fluorouracilate (5-FU), namely [Zn(5-FU)2(bpy)] (1), [Zn(5-FU)2(phen)] (2), [Zn(5-FU)2(dpya)]·H2O (3), [Zn(5-FU)2(bpyma)]·2H2O (4) and [Zn(5-FU)2(terpy)]·H2O (5), were synthesized and structurally characterized by spectroscopic methods and X-ray crystallography. 5-FU was coordinated to Zn(II) via the deprotonated N3 site and also presented the N1 and N3 linkage isomerism in 4 and 5 due to its tautomerism. The antiproliferative activity of the complexes was studied against lung (A549), breast (MDA-MB-231), colon (HCT116) and prostate (DU145) cancer cell lines. Complexes 1, 4 and 5 except 2 and 3 showed potent growth inhibitory activity towards selected cancer cells. Remarkably, 4 was highly cytotoxic towards A549 and MDA-MB-231 cell lines, being more active than the clinical drugs cisplatin and 5-FU. In addition, 4 was not toxic to normal lung cells (BEAS-2B). The complex exhibited a significantly high affinity towards DNA as assessed by gel electrophoresis and DNA docking. The mechanistic studies of 4 in A549 cells indicated that the complex induced apoptotic cell death as evidenced via caspase 3/7 activity, Bcl2 inactivation, annexin V and DAPI/PI staining. 4 further elevated the levels of reactive oxygen species (ROS), depolarized mitochondria and enhanced the expression of ?-H2AX, thus contributing to its remarkable anticancer activity.
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    Palladium(II) and platinum(II) saccharinate complexes with bis(diphenylphosphino)methane/ethane: synthesis, S-phase arrest and ROS-mediated apoptosis in human colon cancer cells
    (Royal Soc Chemistry, 2018) İçsel, Ceyda; Yılmaz, Veysel T.; Aygün, Muhittin; Cevatemre, Buse; Alper, Pınar; Ulukaya, Engin
    New neutral [M(sac)(2)(diphos)] and cationic [M(diphos)(2)](sac)(2) complexes, where M = Pd-II or Pt-II, sac = saccharinate, and diphos = 1,1-bis(diphenylphosphino)methane (dppm) or 1,2-bis(diphenylphosphino)ethane (dppe), were synthesized and structurally characterized. The anticancer activity of the complexes was investigated against MCF-7 (breast), A549 (lung), HCT116 (colon), DU145 (prostate) cancer and BEAS-2B (normal bronchial epithelial) cells. Neutral Pt-dppm (2) and Pd-dppe complexes (5) did not show any biological activity. The cationic Pd-dppe (7) complex displayed antiproliferative activity, while the rest of the complexes exhibited potent cytotoxicity compared with cisplatin. The active Pd(ii)/Pt(ii) complexes were then included in further studies including interaction with DNA/HSA, nuclease activity, cellular uptake and lipophilicity. The potent complexes induced the apoptotic cell death as probed through annexin V positivity and caspase activation. Mechanistic studies on HCT116 cells showed that the complexes cause cell cycle arrest at the DNA synthesis (S) phase and excessive generation of reactive oxygen species (ROS), damaging to both mitochondria and DNA.
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    Pd(II) and Pt(II) saccharinate complexes of bis(diphenylphosphino) propane/butane: synthesis, structure, antiproliferative activity and mechanism of action
    (Elsevier France-Editions Scientifiques Medicales Elsevier, 2018) Yılmaz, Veysel T.; İçsel, Ceyda; Aygün, Muhittin; Erkısa Genel, Merve; Ulukaya, Engin
    [M(sac)(2)(dppp)] (1 and 2), [M(dppp)(2)](sac)(2) (3 and 4) and [M(sac)(2)(dppb)] (5 and 6) complexes, where M = Pd-II (1, 3 and 5) and Pt-II (2, 4 and 6), sac = saccharinate, dppp = 1,3-bis(diphenylphosphino)propane and dppb = 1,4-bis(diphenylphosphino)butane, were synthesized and characterized by IR, NMR, ESI-MS and X-ray diffraction. The anticancer activity of the complexes against human lung (A549), breast (MCF-7), prostate (DU145) and colon (HCT116) cancer cell lines showed that the cationic complexes of dppp (3 and 4) and neutral Pt complex of dppb (6) were the most active agents of series. 3 and 4 exhibited antiproliferative activity, while 6 was highly cytotoxic compared to cisplatin. These complexes were therefore subjected to further investigations to ascertain the possible role of lipophilicity, cellular uptake and DNA/EISA binding in their biological activity. Flow cytometry analysis revealed that complex 6 induced apoptotic cell death in A549 and HCT116 cells and caused the cell cycle arrest at the S phase and overproduction of reactive oxygen species (ROS), giving rise to mitochondria) depolarization and DNA damage. (C) 2018 Elsevier Masson SAS. All rights reserved.
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    Silver N-heterocyclic carbene complexes bearing fluorinated benzyl group: synthesis, characterization, crystal structure, computational studies, and inhibitory properties against some metabolic enzymes
    (WILEY, 2021) Bal, Selma; Demirci, Özlem; Şen, Betül; Taşkın Tok, Tuğba; Taslimi, Parham; Aktaş, Aydın; Gök, Yetkin; Aygün, Muhittin; Gülçin, İlhami
    A series of the silver N-heterocyclic carbene (NHC) complexes have been synthesized from the reactions between benzimidazolium salts bearing fluorinated benzyl group and Ag2O via the deprotonation method. All Ag(I)NHC complexes were characterized by known spectroscopic techniques (H-1 nuclear magnetic resonance [NMR], C-13 NMR, and Fourier transform infrared [FT-IR]) and elemental analysis. The molecular structures of the two complexes were unambiguously elucidated through single-crystal X-ray diffraction analysis. Namely, X-ray studies show that the coordination geometry around the Ag(I) atom in the case of complex 2c is revealed to be almost linear with C-Ag-Cl angle, whereas in complex 2e, it appears as a nonlinear structure. The inhibitory profiles of these new complexes are investigated on some metabolic enzymes. Representatively, the most potent complex against human carbonic anhydrase isoenzymes I and II (hCAs I and II), 2d, was 1.8 times more potent than standard inhibitor acetazolamide against hCAs I and II. On the other hand, complexes 2c and 2b as most potent compounds against both cholinesterase enzymes was around 5 and 1.6 times more potent than tacrine against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), respectively. The most active alpha-glucosidase inhibitor 2d had similar activity to acarbose as a standard inhibitor. Furthermore, it confirms its in vitro studies as a result of molecular docking studies for each enzyme with (i) binding energy and inhibition constant values and (ii) the definition of the best conformation and nonbonding interactions of the related complexes (2b, 2c, and 2d) against the different target proteins.
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    Structures and anticancer activity of chlorido platinum(II) saccharinate complexes with mono- and dialkylphenylphosphines
    (Elsevier Science Inc, 2019) İçsel, Ceyda; Yılmaz, Veysel T.; Cevatemre, Buse; Aygün, Muhittin; Ulukaya, Engin
    cis-[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.
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    Synthesis, structures and anticancer potentials of platinum(II) saccharinate complexes of tertiary phosphines with phenyl and cyclohexyl groups targeting mitochondria and DNA
    (Elsevier France-Editions Scientifiques Medicales Elsevier, 2018) Yılmaz, Veysel T.; İçsel, Ceyda; Turgut, Ömer R.; Aygün, Muhittin; Erkısa Genel, Merve; Türkdemir, Mehmet H.; Ulukaya, Engin
    A series of new Pt(II) saccharinate complexes containing PR3 ligands (PPh3, PPh2Cy, PPhCy2 and PCy3) with progressive phenyl (Ph) replacement by cyclohexyl (Cy) were synthesized and structurally characterized by lR, NMR, ESI-MS and X-ray diffraction. The anticancer activity of the complexes was tested against human breast (MCF-7), lung (A549), colon (HCT116), and prostate (DU145) cancer cell lines as well as against normal bronchial epithelial (BEAS-2B) cells. Trans-configured complexes 1, 3 and 5 emerged as potential anticancer drug candidates. The mechanism of action of the potent complexes was then investigated in detail. The three complexes interacted with DNA by groove binding and with HSA via hydrophobic IIA subdomain. Furthermore, the complexes cleaved plasmid DNA efficiently. Cellular uptake studies in MCF-7 cells showed that the biologically active complexes were mainly localized in cytoplasm. The cytotoxic activity was a function of the lipophilicity and cellular accumulation of the complexes. As determined by M30, Annexin V and Caspase 3/7 activity assays, the complexes induced apoptosis in MCF-7 and HCT116 cells. Mechanistic studies showed that the potent complexes cause excessive generation of reactive oxygen species (ROS) and display a dual action, concurrently targeting both mitochondria and genomic DNA. (C) 2018 Elsevier Masson SAS. All rights reserved.
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    Trans-Pd/Pt(II) saccharinate complexes with a phosphine ligand: Synthesis, cytotoxicity and structure-activity relationship
    (Pergamon-Elsevier Science Ltd, 2020) İçsel, Ceyda; Yılmaz, Veysel T.; Aygün, Muhittin; Ulukaya, Engin
    New trans-[Pd(sac)(2)(PPhMe2)(DMSO)]center dot H2O (Pd) and trans-[Pt(sac)(2)(PPhMe2)(2)]center dot H2O (Pt) complexes (sac = saccharinate and PPhMe 2 = dimethylphenylphosphine) were synthesized and characterized by elemental analysis, IR, NMR, ESI-MS spectral analyses and X-ray diffraction. The complexes were evaluated for their in vitro cytotoxicity against breast (MCF-7), colon (HCT116) and lung (A549) human cancer cell lines. The ATP viability assay displayed that Pd was biologically inactive, but Pt showed significant anticancer potency on MCF-7 cancer cells, similar to cisplatin. The results suggested that Pt targeted DNA, whereas Pd displayed higher binding affinity towards human serum albumin (HSA). Mechanism of action studies of Pt suggested apoptotic cell death due to significant increase in intracellular ROS (reactive oxygen species) levels, mitochondrial damage and formation of DNA double-strand breaks. Finally, this work represents a new example of potent transplatin anticancer complexes.