title: Preparation, cytotoxicity and interactions with nucleophiles of three isomeric transplatinum complexes containing methylpiperidine ligands.
abstract: Three isomeric complexes, trans-[PtCl2(NH3)(2-methylpiperidine)], trans-[PtCl2(NH3)(3-methylpiperidine)] and trans-[PtCl2(NH3)(4-methylpiperidine)], were prepared and their cytotoxicities against six ovarian cancer cell lines, three sensitive and three resistant to cisplatin, were measured. There were no significant differences in the cytotoxicities of the three isomers against these cell lines. The interactions of the three complexes with reduced glutathione (GSH) and with ubiquitin (Ub), as a model protein, were studied. The trans-[PtCl2(NH3)(2-methylpiperidine)] reacted approximately twice as slowly with GSH as did the other two isomers. In the 1:1 interactions of the three complexes with ubiquitin (Mr = 8565 amu), trans-[PtCl2(NH3)(3-methylpiperidine)] and trans-[PtCl2(NH3)(4-methylpiperidine)] attained 100% modification while trans-[PtCl2(NH3)(2-methylpiperidine)] reached only less than 50% modification. Trans-[PtCl2(NH3)(2-methylpiperidine)] reacts significantly less efficiently with GSH and proteins than the other two isomers yet this is not reflected in the cytotoxicity values. These results indicate that for these complexes, in these cell lines, cytosolic detoxification probably does not play a dominant role in determining the cytotoxicity of the complexes.
authors.affiliation: Department of Medicinal Chemistry and Natural Products, School of Pharmacy, P.O. Box 12065, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Seba
authors.initials: S
authors.lastname: Jawbry
authors.forename: Inna
authors.initials: I
authors.lastname: Freikman
authors.forename: Yousef
authors.initials: Y
authors.lastname: Najajreh
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Perez
authors.forename: Dan
authors.initials: D
authors.lastname: Gibson
mesh_terms: D002945:Cisplatin / Q000494:pharmacology; D003600:Cytosol / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000633:toxicity*; D010051:Ovarian Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured / Q000473:pathology; D025801:Ubiquitin / Q000737:chemistry
chemical_list: D009944:Organoplatinum Compounds; D025801:Ubiquitin; C505741:diamminedichloro(2-methylpiperidine)platinum(II); C505742:diamminedichloro(3-methylpiperidine)platinum(II); C505743:diamminedichloro(4-methylpiperidine)platinum(II); D005978:Glutathione; D002945:Cisplatin