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Unusual DNA binding properties of chelate ring-opening platinum complexes
Journal of Inorganic Biochemistry
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METALS IN M E D I C I N E
161
U N U S U A L DNA B I N D I N G P R O P E R T I E S OF C H E L A T E RING-OPENING PLATINUM COMPLEXES
A. H a b t e m a r i a m , a K. N e p l e c h o v a b, V. Brabec, b N. Margiotta a and P.J. Sadler"
Department of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, UK; b Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, 612 65 Brno, Czech Republic Bis(aminophosphine) complexes of Pt(II) combine the presence of two cis nitrogen ligands, a feature found in clinically-used Pt(II) anticancer agents [ 1], with that of phosphine ligands. Diphosphine ligands and metal diphosphine complexes have previously been found to exhibit anticancer activity via a mechanism of action different from that of platinum am(m)ine complexes [2].
Ph
Pxp./N
Me
%,
p/Pt",,Cl
/ Me i..i,,..,i
Ph/
/Me --
Me 1
2
Chelate ring-opening of bis(aminophosphine)Pt(II) complexes creates one or two potential sites for DNA binding, and can be controlled by the choice of substituents on P and N and by the pH and chloride concentration. Remarkably, the binding of 1 to the DNA base guanine is rapid and reversible by chloride competition [3]. It also shows the unusual ability to bind strongly and rapidly to N3 of the DNA base thymine, as well as to the RNA base uracil under physiological conditions [4]. Cytotoxicity studies of bis(aminophosphine)Pt(II) complexes show that none was as potent as cisplatin, cis-[PtC12(NH3)2], which is a very successful antitumour drug, but some of them are active against cisplatin-resistant cell lines. Modification of natural DNAs in cell-free media by 2 was studied by using various biochemical and biophysical methods and show that DNA is modified in a way which is different from that found for cisplatin. Altered DNA binding modes may be responsible for the altered biological properties seen for these series of platinum complexes. [1] [2] [3] [4]
J. Reedijk, JCS Chem. Commun., 801 (1996). S.J. Berners-Price and P.J. Sadler, Struct. Bonding (Berlin), 70, 27 (1988). A. Habtemariam and P.J. Sadler, JCS Chem. Commun., 1785 (1996). N. Margiotta, A. Habtemariam and P.J. Sadler, Angew. Chem., (1997) in press.
Acknowledgment: We thank the BBSRC, EPSRC, MRC, University of Bad (Fellowship for NM), and EC COST programme for their support for this work. We are grateful to Dr R. Palmer (Birkbeck College), Dr S. Parsons (University of Edinburgh) for X-ray structural determinations, and Institute of Cancer Research (Sutton) and EORTC (Amsterdam) for cytotoxicity tests.
E22
METALS IN M E D I C I N E
161
U N U S U A L DNA B I N D I N G P R O P E R T I E S OF C H E L A T E RING-OPENING PLATINUM COMPLEXES
A. H a b t e m a r i a m , a K. N e p l e c h o v a b, V. Brabec, b N. Margiotta a and P.J. Sadler"
Department of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, UK; b Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, 612 65 Brno, Czech Republic Bis(aminophosphine) complexes of Pt(II) combine the presence of two cis nitrogen ligands, a feature found in clinically-used Pt(II) anticancer agents [ 1], with that of phosphine ligands. Diphosphine ligands and metal diphosphine complexes have previously been found to exhibit anticancer activity via a mechanism of action different from that of platinum am(m)ine complexes [2].
Ph
Pxp./N
Me
%,
p/Pt",,Cl
/ Me i..i,,..,i
Ph/
/Me --
Me 1
2
Chelate ring-opening of bis(aminophosphine)Pt(II) complexes creates one or two potential sites for DNA binding, and can be controlled by the choice of substituents on P and N and by the pH and chloride concentration. Remarkably, the binding of 1 to the DNA base guanine is rapid and reversible by chloride competition [3]. It also shows the unusual ability to bind strongly and rapidly to N3 of the DNA base thymine, as well as to the RNA base uracil under physiological conditions [4]. Cytotoxicity studies of bis(aminophosphine)Pt(II) complexes show that none was as potent as cisplatin, cis-[PtC12(NH3)2], which is a very successful antitumour drug, but some of them are active against cisplatin-resistant cell lines. Modification of natural DNAs in cell-free media by 2 was studied by using various biochemical and biophysical methods and show that DNA is modified in a way which is different from that found for cisplatin. Altered DNA binding modes may be responsible for the altered biological properties seen for these series of platinum complexes. [1] [2] [3] [4]
J. Reedijk, JCS Chem. Commun., 801 (1996). S.J. Berners-Price and P.J. Sadler, Struct. Bonding (Berlin), 70, 27 (1988). A. Habtemariam and P.J. Sadler, JCS Chem. Commun., 1785 (1996). N. Margiotta, A. Habtemariam and P.J. Sadler, Angew. Chem., (1997) in press.
Acknowledgment: We thank the BBSRC, EPSRC, MRC, University of Bad (Fellowship for NM), and EC COST programme for their support for this work. We are grateful to Dr R. Palmer (Birkbeck College), Dr S. Parsons (University of Edinburgh) for X-ray structural determinations, and Institute of Cancer Research (Sutton) and EORTC (Amsterdam) for cytotoxicity tests.