Molekulární biofyzika a farmakologie
Interactions of platinum complexes containing cationic, bicyclic, nonplanar piperidinopiperidine ligands with biological nucleophiles
Publikace: JOURNAL OF MEDICINAL CHEMISTRY 49, 4674-4683 Autoři: Najajreh, Y., Ardeli-Tzaraf, Y., Kasparkova, J., Heringova, P., Prilutski, D., Balter, L., Jawbry, S., Khazanov, E., Perez, JM., Barenholz, Y., Brabec, V., Gibson, D. Rok: 2006
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)]center dot 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 magnitutde 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 (similar to 30 degrees) and in the formation of similar to 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.