Synthesis, DNA binding interactions and biological activity of bis platinum (II) complexes of N,N,N',N'-tetrakis(2-aminoethyl)diamines.
A series of dimers of the monofunctional platinum species [Pt(dien)Cl]+, linked by a variety of flexible (polymethylene) and more rigid chains, was prepared and evaluated for DNA interactions and cytotoxic activity. The polymethylene-linked dimers were prepared by acylation of N(1),N(3)-bistrityldiethylenetriamine with alpha, omega-dicarboxylic acid chlorides, followed by reduction with diborane. Platination of these ligands was achieved with K2PtI4 prepared in situ, followed by anion exchange. Solutions of the bis(Pt(dien)Cl)2+ complexes were stable, and shown to be pure by 195Pt NMR, but solid products could not be isolated. All of the bis(Pt(dien)Cl)2+ complexes unwound closed circular supercoiled DNA more efficiently than the monomer, and were more efficient than the difunctional platinum complex cisplatin at cross-linking linearized plasmid DNA, as measured on non-denaturing agarose gels. None of the bis(Pt(dien)Cl)2+ complexes were as cytotoxic as cisplatin in both the wild-type and platinum-resistant P388 murine leukaemia cell lines. The more rigid analogues were equitoxic in both sensitive and cisplatin-resistant cells, but none showed in vitro activity against the P388 tumour.
Palmer
B D
BD
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Wickham
G
G
Craik
D J
DJ
McFadyen
W D
WD
Wakelin
L P
LP
Baguley
B C
BC
Denny
W A
WA
D002460:Cell Line / Q000187:drug effects; D004278:DNA, Superhelical / Q000187:drug effects* / Q000378:metabolism; D015195:Drug Design; D008024:Ligands; D010984:Platinum / Q000737:chemistry*
D004278:DNA, Superhelical; D008024:Ligands; D010984:Platinum