title: Cationic nonsymmetric transplatinum complexes with piperidinopiperidine ligands. Preparation, characterization, in vitro cytotoxicity, in vivo toxicity, and anticancer efficacy studies.
abstract: A series of complexes of the general formula trans-[PtCl2(Am)(pip-pip)] x HCl where pip-pip is 4-piperidinopiperidine and Am is NH3, methylamine (MA), dimethylamine (DMA), n-propylamine (NPA), isopropylamine (IPA), n-butylamine (NBA), or cyclohexylamine (CHA) were prepared and characterized, and their cytotoxic properties against ovarian and colon cancer cells were evaluated. The trans-[PtCl2(NH3)(pip-pip)] x HCl was significantly more potent than cisplatin in all the cisplatin-resistant ovarian cancer cell lines and was nearly as cytotoxic as cisplatin against colon cancer cells. In vivo studies in mice showed that the pip-pip complexes are significantly less toxic than cisplatin. Cisplatin was more efficacious than both trans-[PtCl2(NH3)(pip-pip)] x HCl and trans-[PtCl2(NBA)(pip-pip)] x HCl in the A2780 and A2780cisR tumor xenograft models, consistent with its lower IC50 values in A2780 cells but contrary to the higher IC50 values in A2780cisR cells. In the colon cancer cell studies, trans-[PtCl2(NH3)(pip-pip)] x HCl was slightly less potent than cisplatin in the in vitro studies but had efficacy comparable to that of cisplatin in the in vivo xenograft model.
authors.affiliation: Department of Medicinal Chemistry and Natural Products, Faculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem, Palestine.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Najajreh
authors.forename: Elena
authors.initials: E
authors.lastname: Khazanov
authors.forename: Seba
authors.initials: S
authors.lastname: Jawbry
authors.forename: Yael
authors.initials: Y
authors.lastname: Ardeli-Tzaraf
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Perez
authors.forename: Jana
authors.initials: J
authors.lastname: Kasparkova
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
authors.forename: Yechezkel
authors.initials: Y
authors.lastname: Barenholz
authors.forename: Dan
authors.initials: D
authors.lastname: Gibson
mesh_terms: D000588:Amines / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics; D003110:Colonic Neoplasms; D004247:DNA / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D010051:Ovarian Neoplasms; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D012965:Sodium Chloride / Q000494:pharmacology; D012995:Solubility; D012997:Solvents; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; D008024:Ligands; D009944:Organoplatinum Compounds; D010880:Piperidines; D012997:Solvents; D012965:Sodium Chloride; D004247:DNA; D005947:Glucose