Energetics, conformation, and recognition of DNA duplexes modified by monodentate Ru(II) complexes containing terphenyl arenes
Language English Country Germany Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
Howard Hughes Medical Institute - United States
- MeSH
- DNA Adducts chemistry MeSH
- DNA chemistry drug effects MeSH
- Calorimetry MeSH
- Nucleic Acid Conformation MeSH
- Molecular Structure MeSH
- DNA Repair drug effects MeSH
- Organometallic Compounds chemistry pharmacology MeSH
- Antineoplastic Agents chemistry pharmacology MeSH
- Ruthenium chemistry MeSH
- Base Sequence MeSH
- Terphenyl Compounds chemistry pharmacology MeSH
- Protein Binding MeSH
- Hydrogen Bonding MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- DNA Adducts MeSH
- DNA MeSH
- Organometallic Compounds MeSH
- Antineoplastic Agents MeSH
- Ruthenium MeSH
- Terphenyl Compounds MeSH
We studied the thermodynamic properties, conformation, and recognition of DNA duplexes site-specifically modified by monofunctional adducts of Ru(II) complexes of the type [Ru(II)(eta(6)-arene)(Cl)(en)](+), in which arene=para-, meta-, or ortho-terphenyl (complexes 1, 2, and 3, respectively) and en=1,2-diaminoethane. It has been shown (J. Med. Chem. 2008, 51, 5310) that 1 exhibits promising cytotoxic effects in human tumor cells, whereas 2 and 3 are much less cytotoxic; concomitantly with the high cytotoxicity of 1, its DNA binding mode involves combined intercalative and monofunctional (coordination) binding modes, whereas less cytotoxic compounds 2 and 3 bind to DNA only through a monofunctional coordination to DNA bases. An analysis of conformational distortions induced in DNA by adducts of 1 and 2 revealed more extensive and stronger distortion and concomitantly greater thermodynamic destabilization of DNA by the adducts of nonintercalating 2. Moreover, affinity of replication protein A to the DNA duplex containing adduct of 1 was pronouncedly lower than to the adduct of 2. On the other hand, another damaged-DNA-binding protein, xeroderma pigmentosum protein A, did not recognize the DNA adduct of 1 or 2. Importantly, the adducts of 1 induced a considerably lower level of repair synthesis than the adducts of 2, which suggests enhanced persistence of the adducts of the more potent and intercalating 1 in comparison with the adducts of the less potent and nonintercalating 2. Also interestingly, the adducts of 1 inhibited DNA polymerization more efficiently than the adducts of 2, and they could also be bypassed by DNA polymerases with greater difficulty. Results of the present work along with those previously published support the view that monodentate Ru(II) arene complexes belong to a class of anticancer agents for which structure-pharmacological relationships might be correlated with their DNA-binding modes.
References provided by Crossref.org
