An approach to therapeutic agents through selective targeting of destabilised nucleic acid duplex sequences
Date
2012
Authors
Li, F.
Weber, D.
Morgan, J.
Collins, J.
Keene, F.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Dalton Transactions, 2012; 41(21):6528-6535
Statement of Responsibility
Fangfei Li, Daniel K. Weber, Joy L. Morgan, J. Grant Collins and F. Richard Keene
Conference Name
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.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
Copyright the authors