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https://hdl.handle.net/2440/94889
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Type: | Journal article |
Title: | An approach to therapeutic agents through selective targeting of destabilised nucleic acid duplex sequences |
Author: | Li, F. Weber, D. Morgan, J. Collins, J. Keene, F. |
Citation: | Dalton Transactions: an international journal of inorganic chemistry, 2012; 41(21):6528-6535 |
Publisher: | Royal Society of Chemistry |
Issue Date: | 2012 |
ISSN: | 1477-9226 1477-9234 |
Statement of Responsibility: | Fangfei Li, Daniel K. Weber, Joy L. Morgan, J. Grant Collins and F. Richard Keene |
Abstract: | The binding of ΔΔ/ΛΛ-[{Ru(phen)(2)}(2)(μ-bb(n))](4+) {where phen = 1,10-phenanthroline, bb(n) = 1,n-bis[4(4'-methyl-2,2'-bipyridyl)]-alkane (ΔΔ/ΛΛ-Rubb(n))} to the non-self complementary oligonucleotide 5'-d(CGCGATAAGCCGC·5'-GCGGCATTACGCG) (3-DB) has been examined using a 4',6-diamidino-2-phenylindole dihydrochloride (DAPI) displacement assay. The 3-DB oligonucleotide contains two single adenine bulge nucleotides that are separated by three base pairs. (1)H NMR spectroscopy data demonstrated that the adenine bases are intra-helical and that the segment containing the two bulge nucleotides and the three A·T base pairs between the bulges forms a destabilised segment within the stable duplex oligonucleotide. The DAPI displacement assay demonstrated that ΔΔ-Rubb(7)-bound 3-DB with higher affinity than the other members of the ΔΔ/ΛΛ-Rubb(n) series. Molecular models suggested that the seven-carbon chain length in ΔΔ-Rubb(7) was ideal to span the distance between the two bulge sites. The binding of ΔΔ-Rubb(7) to 3-DB was also studied by (1)H NMR spectroscopy and molecular modelling. The selective changes in chemical shifts for the resonances from 3-DB upon addition of ΔΔ-Rubb(7) suggested that the metal complex specifically bound at the destabilised segment between A(5) and A(19). Observation in NOESY spectra of NOE cross peaks between 3-DB and ΔΔ-Rubb(7) confirmed that one of the ruthenium centres bound at the A(5) bulge site, with the other metal centre positioned at the A(19) bulge. In addition, ΔΔ-Rubb(7) was found to bind chromosomal DNA extracted from a suspension of Staphylococcus aureus that had been incubated with the ruthenium(ii) complex. As inert dinuclear ruthenium(ii) complexes are capable of being transported into a bacterial cell and bind chromosomal DNA, it is possible that they could be developed into anti-microbial agents that specifically target destabilised segments of DNA that are recognised by essential DNA-binding proteins. |
Keywords: | Chromosomes, bacterial |
Rights: | Copyright the authors |
DOI: | 10.1039/c2dt12146h |
Published version: | http://dx.doi.org/10.1039/c2dt12146h |
Appears in Collections: | Aurora harvest 3 Chemistry publications |
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