title: Interactions of platinum complexes containing cationic, bicyclic, nonplanar piperidinopiperidine ligands with biological nucleophiles.
abstract: The determination of the structures and DNA interactions and the reactions with GSH and ubiquitin 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 performed. X-ray structures and NMR studies of the NH3 and MA complexes showed that both pip rings were in the chair conformation and that the second pip ring is fluxional. The DNA binding studies showed that these complexes bind to calf thymus DNA nearly an order of magnitude more quickly than cisplatin and form covalent adducts that stabilize the double helix. The binding of the pip-pip complexes to DNA results in high unwinding angles (approximately 30 degrees) and in the formation of approximately 25% interstrand cross-links. The pip-pip complexes reacted with GSH more quickly than cisplatin and transplatin, and the rate of reaction decreased with increasing steric bulk of the ligand trans to the pip-pip. The reactions with ubiquitin resulted in monofunctional binding to Met1. Only the NH3, MA, and DMA complexes reacted with ubiquitin in a slower and less efficient fashion than cisplatin.
authors.affiliation: Department of Medicinal Chemistry and Natural Products, Faculty of Pharmacy, Al-Quds University, Jerusalem, P.O. Box 20002, Palestine.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Najajreh
authors.forename: Yael
authors.initials: Y
authors.lastname: Ardeli-Tzaraf
authors.forename: Jana
authors.initials: J
authors.lastname: Kasparkova
authors.forename: Pavla
authors.initials: P
authors.lastname: Heringova
authors.forename: Dmitri
authors.initials: D
authors.lastname: Prilutski
authors.forename: Liliana
authors.initials: L
authors.lastname: Balter
authors.forename: Seba
authors.initials: S
authors.lastname: Jawbry
authors.forename: Elena
authors.initials: E
authors.lastname: Khazanov
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Perez
authors.forename: Yechezkel
authors.initials: Y
authors.lastname: Barenholz
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
authors.forename: Dan
authors.initials: D
authors.lastname: Gibson
mesh_terms: D000588:Amines / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry*; D002412:Cations; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry; D005978:Glutathione / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry*; D044366:Transition Temperature; D025801:Ubiquitin / Q000737:chemistry
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002412:Cations; D009944:Organoplatinum Compounds; D010880:Piperidines; D025801:Ubiquitin; D004247:DNA; D005978:Glutathione