Novakova, Olga, Malina, J. (Jaroslav), Suchankova, Tereza, Kasparkova, Jana, Bugarcic, Tijana, Sadler, P. J. and Brabec, V. (Viktor) (2010) Energetics, conformation, and recognition of DNA duplexes modified by monodentate Ru-II complexes containing terphenyl arenes. Chemistry - A European Journal, Vol.16 (No.19). pp. 5744-5754. doi:10.1002/chem.200903078

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Abstract

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.

Item Type:	Journal Article
Subjects:	Q Science > QC Physics Q Science > QD Chemistry Q Science > QP Physiology
Divisions:	Faculty of Science > Chemistry
Library of Congress Subject Headings (LCSH):	Aromatic compounds -- Therapeutic use, Ruthenium compounds -- Therapeutic use, Calorimetry, Antineoplastic agents, DNA adducts, DNA-drug interactions
Journal or Publication Title:	Chemistry - A European Journal
Publisher:	Wiley - V C H Verlag GmbH & Co. KGaA
ISSN:	0947-6539
Official Date:	17 May 2010
Dates:	Date Event 17 May 2010 Published
Volume:	Vol.16
Number:	No.19
Number of Pages:	11
Page Range:	pp. 5744-5754
DOI:	10.1002/chem.200903078
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Czech Republic. Ministerstvo školství, mládeže a tělovýchovy [Czech Republic. Ministry of Education, Youth, and Sports], Akademie věd České republiky [Academy of Sciences of the Czech Republic] (ASCR), Grantová agentura České republiky [Grant Agency of the Czech Republic]
Grant number:	MSMT LC06030 (MSMT), 6198959216 (MSMT), ME08017 (MSMT), ME10066 (MSMT), OC08003 (MSMT), 0009018 (MSMT), KAN200200651 (ACSR), M200040901 (ACSR), AV0Z50040507 (ACSR), AV0Z500040702 (ACSR), IAA400040803 (ACSR), 301/09/H004 (GACR), P301/10/0598 (GACR)

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