title: Novel methylene modified cyclohexyl ethylenediamine-N,N'-diacetate ligands and their platinum(IV) complexes. Influence on biological activity.
abstract: This paper focuses on the synthesis, characterization and biological activity of new N,N'-methylene modified cyclohexyl ethylenediamine-N,N'-diacetate (edda)-type ligands and their Pt(IV) complexes. Both the ligands and complexes were characterized by infrared, UV-vis, ESI-MS, 1D ((1)H, (13)C, (195)Pt) and 2D (COSY, HSQC, HMBC) NMR spectroscopy and elemental analysis. The possible correlation between the reduction potentials and the cytotoxicity of the complexes was examined. The potential antitumoral activity of all compounds was tested in vitro on human melanoma A375, human glioblastoma U251, human prostate cancer PC3, human colon cancer HCT116, mouse melanoma B16 and mouse colon cancer CT26CL25 cells, as well as primary fibroblasts and keratinocytes. The results obtained revealed strong antitumor potential of the newly synthesized drugs with preserved efficacy against cisplatin resistant lines and less toxicity towards nonmalignant counterparts. The mechanism found to be responsible for the observed tumoricidal action of each synthesized compound was induction of apoptosis generally accompanied with caspase activation. Taken together, the effective response to the treatment of a wide range of different cell lines, including cisplatin resistant subclones, as well as induction of apoptosis, as the mechanism suggested to be the most desirable way of eliminating malignant cells, represents a great advantage of this novel group of drugs in comparison to other members in this metallo-drug family.
authors.affiliation: Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia.
authors.forename: Ljiljana E
authors.initials: LE
authors.lastname: Mihajlović
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Savić
authors.forename: Jelena
authors.initials: J
authors.lastname: Poljarević
authors.forename: Ivan
authors.initials: I
authors.lastname: Vučković
authors.forename: Marija
authors.initials: M
authors.lastname: Mojić
authors.forename: Mirna
authors.initials: M
authors.lastname: Bulatović
authors.forename: Danijela
authors.initials: D
authors.lastname: Maksimović-Ivanić
authors.forename: Sanja
authors.initials: S
authors.lastname: Mijatović
authors.forename: Goran N
authors.initials: GN
authors.lastname: Kaluđerović
authors.forename: Stanislava
authors.initials: S
authors.lastname: Stošić-Grujičić
authors.forename: Đorđe
authors.initials: Đ
authors.lastname: Miljković
authors.forename: Sanja
authors.initials: S
authors.lastname: Grgurić-Šipka
authors.forename: Tibor J
authors.initials: TJ
authors.lastname: Sabo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004492:Edetic Acid / Q000737:chemistry; D005029:Ethylenediamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D003510:Cyclohexanes; D005029:Ethylenediamines; D009944:Organoplatinum Compounds; D004492:Edetic Acid