title: Synthesis, characterization and cytotoxic activity of novel platinum(II) iodido complexes.
abstract: Novel Pt(II) complexes of general formula [PtI2(L(1-3))], (C1-C3): where L(1-3) are isobutyl, n-pentyl and isopentyl esters of (S,S)-1,3-propanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid has been synthesized and characterized by elemental analysis, UV/Vis, IR, ((1)H, (13)C and HSQC, Pt) NMR spectroscopy and ESI mass spectrometry. Spectroscopic data and computational studies have shown the usual square planar coordination geometry of synthesized complexes, with coordination of ligands via nitrogen donor atoms. The cytotoxic activity of novel ligands and corresponding complexes were investigated on a palette of different cells line. Complexes C1-C3 exhibited activity comparable to cisplatin, with IC50 values (μM) ranging from 4.6 ± 0.6 to 17.2 ± 2, and showed the highest potential in HeLa, LS-174 and EA.hy.926 cells. Ligands L1-L3 exhibited two- to four-times less activity than corresponding complexes. Analysis of the mode of action in HeLa cells, by ICP-MS study, showed markedly higher intracellular accumulation and DNA binding affinity of C1-C3 versus cisplatin, after 4 h and 20 h post-treatment. Annexin-V-FITC assay, flow cytometry and fluorescence microscopy study demonstrated occurrence of cell death through both apoptotic and necrotic changes. Tested complexes, at corresponding IC50 concentrations, caused considerable "sub-G1" peak, without other substantial alterations of cell cycle, while only C1 induced higher level of phosphatidylserine externalization (11.7%), comparing to ligand L1 (4.9%) and cisplatin (8.4%). Structure-activity comparison indicated variations of C1-C3 cytotoxicity, related to the drug/ligand lipophilicity (C log P value), while intracellular platinum content and DNA platination increased on increase of length and branching of ester chain, in sequence: C1 (isobutyl) < C2 (n-pentyl) < C3 (isopentyl).
authors.affiliation: Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Savić
authors.affiliation: Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia.
authors.forename: Lana
authors.initials: L
authors.lastname: Filipović
authors.affiliation: Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Aranđelović
authors.affiliation: Department of Chemistry, Institute of Chemistry, Technology and Metallurgy, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia.
authors.forename: Biljana
authors.initials: B
authors.lastname: Dojčinović
authors.affiliation: Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia.
authors.forename: Siniša
authors.initials: S
authors.lastname: Radulović
authors.affiliation: Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia.
authors.forename: Tibor J
authors.initials: TJ
authors.lastname: Sabo
authors.affiliation: Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia. Electronic address: sanjag@chem.bg.ac.rs.
authors.forename: Sanja
authors.initials: S
authors.lastname: Grgurić-Šipka
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds
keywords: Amine ligands; Apoptosis; Cancer; Platinum complexes