DNA interactions of new cytotoxic tetrafunctional dinuclear platinum complex trans,trans-[{PtCl2(NH3)}2(piperazine)].
A new tetrafunctional dinuclear platinum complex trans,trans-[{PtCl2(NH3)}2(piperazine)] with sterically rigid linking group was designed, synthesized and characterized. In this novel molecule, the DNA-binding features of two classes of the platinum compounds with proven antitumor activity are combined, namely trans oriented bifunctional mononuclear platinum complexes with a heterocyclic ligand and polynuclear platinum complexes. DNA-binding mode of this new complex was analyzed by various methods of molecular biology and biophysics. The complex coordinates DNA in a unique way and interstrand and intrastrand cross-links are the predominant lesions formed in DNA in cell-free media and in absence of proteins. An intriguing aspect of trans,trans-[{PtCl2(NH3)}2(piperazine)] is that, using a semi-rigid linker, interstrand cross-linking is diminished relative to other dinuclear platinum complexes with flexible linking groups and lesions that span several base pairs, such as tri- and tetrafunctional adducts, become unlikely. In addition, in contrast to the inability of trans,trans-[{PtCl2(NH3)}2(piperazine)] to cross-link two DNA duplexes, the results of the present work convincingly demonstrate that this dinuclear platinum complex forms specific DNA lesions which can efficiently cross-link proteins to DNA. The results substantiate the view that trans,trans-[{PtCl2(NH3)}2(piperazine)] or its analogues could be used as a tool for studies of DNA properties and their interactions or as a potential antitumor agent. The latter view is also corroborated by the observation that trans,trans-[{PtCl2(NH3)}2(piperazine)] is a more effective cytotoxic agent than cisplatin against human tumor ovarian cell lines.
Brabec
Viktor
V
Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, CZ-61265 Brno, Czech Republic.
Christofis
Petros
P
Slámová
Martina
M
Kostrhunová
Hana
H
Nováková
Olga
O
Najajreh
Yousef
Y
Gibson
Dan
D
Kaspárková
Jana
J
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001483:Base Sequence; D002417:Cattle; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018736:DNA Adducts / Q000737:chemistry; D004278:DNA, Superhelical / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D010984:Platinum / Q000737:chemistry*; D017671:Platinum Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D011048:Polarography; D013050:Spectrometry, Fluorescence; D013696:Temperature; D014158:Transcription, Genetic
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D004278:DNA, Superhelical; D004268:DNA-Binding Proteins; D008024:Ligands; D010879:Piperazines; D017671:Platinum Compounds; D000077489:Piperazine; D010984:Platinum; D004247:DNA; C427203:calf thymus DNA; D002945:Cisplatin