4 research outputs found
Cytotoxicity, cellular uptake, glutathione and DNA interactions of an antitumor large-ring PtII chelate complex incorporating the cis-1,4-diaminocyclohexane carrier ligand
No full textInternational audienceEarlier studies have described promising antitumor activity of a large-ring chelate complex [PtCl(-1,4-DACH)] (DACH = diaminocyclohexane). Encouraging antitumor activity of this analogue of cisplatin prompted us to perform studies focused on the mechanistic basis of pharmacological effects of this complex. Four early steps in the mechanism of biological activity of cisplatin have been delineated: cell entry, reactions with sulfur-containing compounds, platinum–DNA binding along with processing platinated DNA by proteins (enzymes) and DNA repair. Here, we describe comparative experiments (involving also cisplatin) revealing: (i) improved cytotoxicity (3.4 – 5.4-fold) of [PtCl(-1,4-DACH)] in human tumor ovarian cell lines; (ii) enhanced cellular uptake (∼1.5-fold) of [PtCl(-1,4-DACH)]; (iii) somewhat enhanced rate of reactions of [PtCl(-1,4-DACH)] with glutathione (∼1.5-fold), but a similar rate of reactions with metallothionenin-2; (iv) enhanced rate of DNA binding of [PtCl(-1,4-DACH)] in cell-free media (∼2-fold); (v) similar sequence preference of DNA binding of [PtCl(-1,4-DACH)] in cell-free media; (vi) identical DNA interstrand crosslinking efficiency (6%); (vii) similar bending (32 °) and enhanced local unwinding (∼1.5-fold) induced in DNA by the major 1,2-GG-intrastrand crosslink; (viii) markedly enhanced inhibiting effects of DNA adducts of [PtCl(-1,4-DACH)] on processivity of DNA polymerase; and (ix) a slightly lower efficiency of DNA repair systems to remove the adducts of [PtCl(-1,4-DACH)] from DNA
Cytotoxicity, mutagenicity, cellular uptake, DNA and glutathione interactions of lipophilic trans-platinum complexes tethered to 1-adamantylamine
No full textCytotoxicity, cellular uptake, and DNA interactions of new monodentate ruthenium(II) complexes containing terphenyl arenes
No full textWe have compared the cancer cell cytotoxicity, cell uptake., and DNA binding properties of the isomeric terphenyl complexes [(eta(6)-arene)Ru(en)Cl](+), where the arene is ortho- (2), meta- (3), or para-terphenyl (1) (o-, m-, or p-terp). Complex 1, the X-ray crystal structure of which confirms that it has the classical "piano-stool" geometry, has a similar potency to cisplatin but is not cross-resistant and has a much higher activity than 2 or 3. The extent of Ru uptake into A2780 or A2780cis cells does not correlate with potency. Complex I binds to DNA rapidly and quantitatively, preferentially to guanine residues, and causes significant DNA unwinding. Circular and linear dichroism, competitive binding experiments with ethidium bromide, DNA melting, and surface-enhanced Raman spectroscopic data are consistent with combined intercalative and monofunctional (coordination) binding mode of complex 1. This unusual DNA binding mode may therefore make a major contribution to the high potency of complex 1
Unusual DNA binding modes for metal anticancer complexes
No full textDNA is believed to be the primary target for many metal-based drugs. For example, platinum-based anticancer drugs can form specific lesions on DNA that induce apoptosis. New platinum drugs can be designed that have novel modes of interaction with DNA, such as the trinuclear platinum complex BBR3464. Also it is possible to design inert platinum(IV) pro-drugs which are non-toxic in the dark, but lethal when irradiated with certain wavelengths of light. This gives rise to novel DNA lesions which are not as readily repaired as those induced by cisplatin, and provides the basis for a new type of photoactivated chemotherapy. Finally, newly emerging ruthenium(II) organometallic complexes not only bind to DNA coordinatively, but also by H-bonding and hydrophobic interactions triggered by the introduction of extended arene rings into their versatile structures. Intriguingly osmium (the heavier congener of ruthenium) reacts differently with DNA but can also give rise to highly cytotoxic organometallic complexes
