期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 16, 期 19, 页码 5744-5754出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.200903078
关键词
arenes; calorimetry; DNA; DNA recognition; ruthenium
资金
- Ministry of Education of the Czech Republic [MSMT LC06030, 6198959216, ME08017, ME10066, OC08003, 0009018]
- Academy of Sciences of the Czech Republic [KAN200200651, M200040901, AV0Z50040507, AV0Z500040702]
- Grant Agency of the Academy of Sciences of the Czech Republic [IAA400040803]
- Grant Agency of the Czech Republic [301/09/H004, P301/10/0598]
- EU
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 orrho-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 I. 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 Run arene complexes belong to a class of anticancer agents for which structure pharmacological relationships might be correlated with their DNA-binding modes.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据