title: Protein binding by dinuclear polypyridyl ruthenium(II) complexes and the effect of cucurbit[10]uril encapsulation.
abstract: The effect of human serum on the minimum inhibitory/bactericidal concentrations of the potential antimicrobial agents ΔΔ-[{Ru(phen)2}2(μ-bb(n))](4+) {ΔΔ-Rubb(n); where phen = 1,10-phenanthroline, bb(n) = 1,n-bis[4(4'-methyl-2,2'-bipyridyl)]-alkane for n = 12 and 16} against four strains of bacteria--Gram positive Staphylococcus aureus and methicillin-resistant S. aureus (MRSA), and Gram negative Escherichia coli and Pseudomonas aeruginosa--has been determined. The results demonstrated that the ruthenium(ii) complexes have significantly decreased in vitro activity in serum. Fluorescence spectroscopy was used to confirm that the decrease in antimicrobial activity was due to the strong binding of the ruthenium complexes with the serum proteins human serum albumin (HSA) and transferrin. A series of ruthenium complexes showed stronger binding to HSA than apo-transferrin but comparable or less than with holo-transferrin, with the binding affinity to all three proteins decreasing in the order trinuclear > dinuclear > mononuclear. The dinuclear complex ΔΔ-Rubb12 displaced warfarin from HSA, tentatively suggesting that the ruthenium complexes bind at or near the warfarin-binding site, Sudlow's site 1. The binding of ΔΔ-Rubb12 and ΔΔ-Rubb16 to the macrocyclic host molecule cucurbit[10]uril (Q[10]) was examined by NMR spectroscopy. The large upfield (1)H NMR chemical shift changes observed for the methylene protons in the bridging ligands upon addition of Q[10], coupled with the observation of a range of intermolecular ROEs in ROESY spectra, indicated that the dinuclear complexes bound Q[10] with the bridging ligand within the cavity and the metal centres positioned outside the portals. NMR and fluorescence spectroscopy demonstrated that the Q[10]-encapsulated ruthenium complexes directly bound HSA, and with similar affinity to the corresponding free metal complexes.
authors: School of Physical, Environmental and Mathematical Sciences, University of New South Wales, Australian Defence Force Academy, Canberra, ACT 2600, Australia.
authors: Fangfei
authors: F
authors: Li
authors: Marshall
authors: M
authors: Feterl
authors: Jeffrey M
authors: JM
authors: Warner
authors: Anthony I
authors: AI
authors: Day
authors: F Richard
authors: FR
authors: Keene
authors: J Grant
authors: JG
authors: Collins
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D004318:Doxycycline / Q000737:chemistry; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D055624:Methicillin-Resistant Staphylococcus aureus / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D008968:Molecular Conformation; D011485:Protein Binding / Q000187:drug effects; D011550:Pseudomonas aeruginosa / Q000378:metabolism; D012428:Ruthenium / Q000737:chemistry*; D012709:Serum Albumin / Q000378:metabolism; D013050:Spectrometry, Fluorescence / Q000379:methods; D013211:Staphylococcus aureus / Q000378:metabolism; D014168:Transferrin / Q000737:chemistry / Q000378:metabolism; D014859:Warfarin / Q000737:chemistry; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils
chemical_list: D000890:Anti-Infective Agents; D001952:Bridged-Ring Compounds; D004318:Doxycycline; D007093:Imidazoles; D012428:Ruthenium; D012709:Serum Albumin; D014168:Transferrin; D014859:Warfarin; C507827:cucurbit(10)uril; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils