Interactions of platinum complexes containing cationic, bicyclic, nonplanar piperidinopiperidine ligands with biological nucleophiles.
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.
Najajreh
Yousef
Y
Department of Medicinal Chemistry and Natural Products, Faculty of Pharmacy, Al-Quds University, Jerusalem, P.O. Box 20002, Palestine.
Ardeli-Tzaraf
Yael
Y
Kasparkova
Jana
J
Heringova
Pavla
P
Prilutski
Dmitri
D
Balter
Liliana
L
Jawbry
Seba
S
Khazanov
Elena
E
Perez
Jose Manuel
JM
Barenholz
Yechezkel
Y
Brabec
Viktor
V
Gibson
Dan
D
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
D000588:Amines; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002412:Cations; D009944:Organoplatinum Compounds; D010880:Piperidines; D025801:Ubiquitin; D004247:DNA; D005978:Glutathione