Structural characterization and DNA interactions of new cytotoxic transplatin analogues containing one planar and one nonplanar heterocyclic amine ligand.
trans-Diaminedicholoroplatinum(II) complexes with one planar and one non-planar heterocyclic amine ligand were designed as new potential antitumor drugs. The X-ray crystallographic structures of trans-[PtCl2(4-picoline)(piperidine)] and trans-[PtCl2(4-picoline)(piperazine)].HCl revealed that the piperidine and piperazine ligands bind to the platinum through the equatorial position and that the ligands adopt the chair conformation. The nonplatinated amine of the piperazine can form hydrogen bonds with atoms that are approximately 7.5 A away from the Pt binding site. DNA is considered a major pharmacological target of platinum compounds. Hence, to expand the database correlating structural features of platinum compounds and DNA distortions induced by these compounds, which may facilitate identification of more effective anticancer platinum drugs, we describe the DNA binding mode in a cell-free medium of trans-[PtCl2(4-picoline)(piperidine)] and trans-[PtCl2(4-picoline)(piperazine)].HCl. Interestingly, the overall impact of the replacement of the second ammine group in transplatin by the heterocyclic ligands appears to change the character of the global conformational changes induced in DNA towards that induced by cisplatin. The clinical ineffectiveness of the parent transplatin has been proposed to be also associated with its reduced capability to form bifunctional adducts in double-helical DNA. The results of the present work support the view that replacement of both ammine groups of transplatin by heterocyclic ligands enhances cytotoxicity probably due to the marked enhancement of the stability of intrastrand cross-links in double-helical DNA.
Najajreh
Yousef
Y
Department of Medicinal Chemistry and Natural Products, School of Pharmacy, The Hebrew University of Jerusalem, P.O.Box 12065, Jerusalem, 91120, Israel.
Kasparkova
Jana
J
Marini
Victoria
V
Gibson
Dan
D
Brabec
Viktor
V
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004265:DNA Helicases / Q000737:chemistry; D004278:DNA, Superhelical / Q000737:chemistry / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D007202:Indicators and Reagents; D008024:Ligands; D008958:Models, Molecular; D010984:Platinum / Q000737:chemistry; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000737:chemistry
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004278:DNA, Superhelical; D006571:Heterocyclic Compounds; D007202:Indicators and Reagents; D008024:Ligands; C034697:transplatin; D010984:Platinum; D004247:DNA; D004265:DNA Helicases; D013890:Thiourea; D002945:Cisplatin