Binuclear platinum (II)-terpyridine complexes. A new class of bifunctional DNA-intercalating agent

Abstract

A series of binuclear DNA-binding ligands was prepared by linking two (2,2':6',2"-terpyridine)platinum(II) moieties via alpha omega-dithiols of the type HS-[CH2]n-SH where n = 4-10. A monomeric analogue was also synthesized. Compounds were characterized by elemental analysis and electronic and n.m.r. spectroscopy. Viscometric measurements with sonicated rod-like DNA fragments and covalently closed circular DNA were performed to investigate the mode of binding of these agents. The ligands with n = 5 and 6 function as bis intercalators and form a single 'base-pair sandwich' in violation of neighbour-exclusion binding. Bifunctional reaction occurs for the ligand with n = 7, whereas the ligands with n = 8 and 10 show a preference for mixed monofunctional/bifunctional binding. The data do not permit definitive assignment of the binding mode of the ligands with n = 4 and 9. All compounds are growth-inhibitory against mouse leukaemia L1210 cells in culture with IC50 values in the range 2-14 microM.

The binding of binuclear platinum(II)-terpyridine complexes to DNA

“…Strong intermolecular aggregation of the dimeric ligands, as reflected in the dimerization constants, is also accompanied by intramolecular stacking of the terpyridine chromophores (McFadyen et al, 1986). Spectral data (McFadyen et al, 1986) (Crothers, 1968;Muller & Crothers, 1968McGhee & von Hippel, 1974 (Fig. 2a inset), in accord with polyelectrolyte theory as developed by Record et al (1978) and Friedman & Manning (1984 (Wakelin et al, 1984) for the structurally related cations hydroxyethylthiolato(terpyridine)platinum(II) (2.3x x03 M-1) and phenylthiolato(terpyridine)platinum(II) (1.7 x 103 M-1).…”

“…The outer (Wakelin et al, 1984) and for ethidium and proflavine (Quadrifoglio et al, 1974). Strong intermolecular aggregation of the dimeric ligands, as reflected in the dimerization constants, is also accompanied by intramolecular stacking of the terpyridine chromophores (McFadyen et al, 1986). Spectral data (McFadyen et al, 1986) (Crothers, 1968;Muller & Crothers, 1968McGhee & von Hippel, 1974 (Fig.…”

“…The platinum ligands were prepared as previously described (McFadyen et al, 1986 (Wakelin et al, 1984). Equilibrium dialysis Binding curves were derived from equilibrium-dialysis measurements made with an MSE Dianorm apparatus.…”

“…1). Among these ligands we found that those with n = 5, 6 and 7 function as bisintercalators whereas those with n = 8 and 10 bind in a mixed monofunctional/bifunctional mode (McFadyen et al, 1986). We were not able to assign unambiguously the binding mode of the homologues with n = 4 and 9.…”

“…Although several classes of heteroaromatic (Muller & Crothers, 1975) Grant & Lippard, 1979;Wakelin et al, 1984) are known to bind to G+C-rich regions of DNA selectively, the idea that their inclusion in polyfunctional agents may further enhance selectivity (Kosturko et al, 1979) has received little attention. However, this latter notion provided a principal motivation for our synthesis (McFadyen et al, 1986) of a model monomer and a series of binuclear ligands formed by linking two (2,2':6',2"-terpyridine)platinum(II) moieties via acw-dithioalkanes (see Fig. 1).…”