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Issue 2, 2012
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Mechanism of interstrand migration of organoruthenium anticancer complexes within a DNA duplex

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Abstract

Organometallic ruthenium(II) anticancer complexes [(η6-arene)Ru(en)Cl][PF6] (e.g.arene = biphenyl (bip, 1), indane (ind, 2); en = ethylenediamine) bind to N7 of guanine (G) in DNA selectively. The fragment {(η6-bip)Ru(en)}2+ (1′) bound to N7 of one guanine residue at a 14-mer duplex DNA migrates readily to other guanine residues in both the same strand and the complementary strand when the strands are hybridized at elevated temperature. In this work, by applying HPLC coupled to mass spectrometry, the mechanism of such intra- and interstrand migration was investigated using a 15-mer duplex, in which one strand 5′-CTCTCTTG8TCTTCTC-3′ (I) contained a single guanine (G8). The results show that the interstrand migration of complexes 1 and 2 within the duplex involves an SN1 pathway, firstly solvent-assisted dissociation of the initially G8-bound adducts I–G81′ and I–G82′ (2′ = {(η6-ind)Ru(en)}2+) as the rate-controlling step, and secondly the coordination of the dissociated 1′ and 2′ to guanine bases (G21 for 1′, either G21 or G18 for 2′) on strand II. The high temperature used to anneal the single strands was found to increase the migration rate. The formation of the duplex acts as a key driving force to promote the dissociation of G8-bound 1′ and 2′ due to the competition of cytosine in II with the en-NH2 groups in 1′ and 2′ for H-bonding with C6O of guanine. Complex 2 (t1/2 = 18 h) containing a mono-ringed arene ligand dissociates more readily from the initially binding site G8 than complex 1 (t1/2 = 23 h). The extended biphenyl arene ligand which is intercalated into DNA stabilizes the adduct I–G81′. These results provide new insight into this unusual metal migration, and are of significance for the design and development of more active organometallic ruthenium anticancer complexes.

Graphical abstract: Mechanism of interstrand migration of organoruthenium anticancer complexes within a DNA duplex

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Publication details

The article was received on 11 Oct 2011, accepted on 13 Dec 2011 and first published on 20 Jan 2012


Article type: Paper
DOI: 10.1039/C2MT00162D
Metallomics, 2012,4, 139-148

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    Mechanism of interstrand migration of organoruthenium anticancer complexes within a DNA duplex

    K. Wu, Q. Luo, W. Hu, X. Li, F. Wang, S. Xiong and P. J. Sadler, Metallomics, 2012, 4, 139
    DOI: 10.1039/C2MT00162D

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