Document Detail

Mechanism of interstrand migration of organoruthenium anticancer complexes within a DNA duplex.
MedLine Citation:
PMID:  22262368     Owner:  NLM     Status:  Publisher    
Organometallic ruthenium(ii) anticancer complexes [(η(6)-arene)Ru(en)Cl][PF(6)] (e.g. arene = biphenyl (bip, 1), indane (ind, 2); en = ethylenediamine) bind to N7 of guanine (G) in DNA selectively. The fragment {(η(6)-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'-CTCTCTTG(8)TCTTCTC-3' (I) contained a single guanine (G(8)). 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 G(8)-bound adducts I-G(8)-1' and I-G(8)-2' (2' = {(η(6)-ind)Ru(en)}(2+)) as the rate-controlling step, and secondly the coordination of the dissociated 1' and 2' to guanine bases (G(21) for 1', either G(21) or G(18) 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 G(8)-bound 1' and 2' due to the competition of cytosine in II with the en-NH(2) groups in 1' and 2' for H-bonding with C6O of guanine. Complex 2 (t(1/2) = 18 h) containing a mono-ringed arene ligand dissociates more readily from the initially binding site G(8) than complex 1 (t(1/2) = 23 h). The extended biphenyl arene ligand which is intercalated into DNA stabilizes the adduct I-G(8)-1'. 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.
Kui Wu; Qun Luo; Wenbing Hu; Xianchan Li; Fuyi Wang; Shaoxiang Xiong; Peter J Sadler
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-1-20
Journal Detail:
Title:  Metallomics : integrated biometal science     Volume:  -     ISSN:  1756-591X     ISO Abbreviation:  -     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-1-20     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101478346     Medline TA:  Metallomics     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, PR China.
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