Binding of platinum and palladium metallointercalation reagents and antitumor drugs to closed and open DNAs

Abstract

The interaction of platinum and palladium complexes with closed and nicked circular and linear DNAs was investigated by a variety of methods. Cationic metal complexes containing flat, aromatic ligands, such as 2,2',2''-terpyridine, o-phenanthroline, and 2,2'-bipyridine, interfere with the usual fluorescence enhancement of ethidium bromide by competing for intercalation sites on calf-thymus DNA. Metal complexes having kinetically exchangable ligands, including the antitumor drugs cis-[(NH3)2PtCl2] and [(en)PtC12], inhibit noncompetitively the DNA-associated ethidium fluorescence enhancement by binding covalently to the bases and blocking potential intercalation sites. Only the metallointercalators were capable of altering the DNA duplex winding, as judged by the effects of these reagents upon the electrophoretic mobility and sedimentation behavior of PM-2 DNAs. Long-term (t greater than 120 h) interactions of metal complexes with PM-2 DNAs I, I0, and II, corresponding to superhelical, closed relaxed, and nicked circles, respectively, showed that covalent binding occurs the most readily to DNA I, possibly because of the presence of underwound duplex regions in this tightly wound superhelical DNA. The active antitumor drugs cis-[(NH3)2PtC12] and [(en)PtC12] bind covalently to DNA I under conditions where the inactive trans- [(NH3)2PtC12] does not. Most of the complexes studied were capable of producing chain scissions in PM-2DNA I. Exceptions are the kinetically inert complexes [(bipy)Pt(en)]2+ and (terpy)Pt(SCH2CH2OH)]+, suggesting that covalent binding might be a prerequisite for nicking.

Synthesis, Characterization, DNA Binding and Cytotoxic Studies of Platinum(II) and Palladium(II) Complexes of the 2,2'-Bipyridine and an Anion of 1,1-Cyclobutanedicarboxylic Acid.

“…26) In these experiments the wavelength of excitation was set at 546 nm and the wavelength of emission at 605 nm. 31) in which the slope that is K (association constant) remain constant while the intercept on the absissa that is n (the number of binding sites per nucleotide) decrease with increasing concentrations of metal complex. This suggests that the [Pt(bpy)(cbdca)] binds to DNA via nonintercalating mode.…”

Differentiation of DNA . Platinum Complexes by Fluorescence. The Use of an Intercalating Dye as a Probe

“…In the second step, this complex was exhaustively dialysed against 10 mM NaC104, to remove the chloride ions. The covalently bound chlorine atom was hydrolyzed at 30 "C for 24 h and the corresponding fluorescence decrease was 65% (rb = 0.20 During the preparation of this manuscript, a paper by Howe-Grant et al [41] appeared. The results presented are in good agreement with ours.…”

4‐Picoline‐2,2′:6′,2″‐terpyridine‐platinum(II) — A potent intercalator of DNA

“…The binding association constants with ct-DNA were between 0.23 and 2× 105 M -~, that of the hydroxyethanethiol complex 1 (R --SCH2CH2OH ) being 0.83 × 105 M -~. The chloro-platinum complex 1 (R = C1) had essentially the same binding constant but was shown slowly to form a covalent link to DNA [3]. Recently the hydroxy-platinum complex 1 (R = OH) has been shown to intercalate into DNA with a binding constant of approximately 7 x 104 M -1 and to slowly form a covalent bond with the DNA [4].…”