J Grant Collins

Australian Defence Force Academy, Canberra, Australian Capital Territory, Australia

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Publications (59)171.44 Total impact

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    ABSTRACT: A series of dinuclear ruthenium(II) complexes that contain labile chlorido ligands, [{Ru(tpy)Cl}2{μ-bbn}]2+ {designated Cl-Rubbn; tpy = 2,2′:6′,2′′-terpyridine, bbn = bis[4(4′-methyl-2,2′-bipyridyl)]-1,n-alkane (n = 7, 10, 12, 14 or 16)} and derivatives containing nitro substituents on the tpy ligand and/or secondary amines within the bbn linking chain have been synthesised and their potential as anticancer agents examined. Some of the Cl-Rubbn species showed good anticancer activity against MCF-7 and MDA-MB-231 breast cancer cell lines, with the Cl-Rubb12 complex being four-times more active than cisplatin. Inclusion of nitro substituents on the tpy ligands of Cl-Rubb12 resulted in significantly decreased anticancer activity. The incorporation of amine groups into the linking ligand did not increase the anticancer activity of the Cl-Rubbn complexes. The Cl-Rubbn complexes and those containing amine groups in the linking chain aquated at approximately the same rate, with 50% aquation within 120 minutes. By comparison, the complexes containing nitro substituents on the tpy ligand aquated extremely slowly, with 60% of the chlorido complex remaining 24 hours after they were dissolved in water. Cyclic voltammetry with the model mononuclear complex [Ru{(NO2)3tpy}(Me2bpy)Cl]+ {(NO2)3tpy = 4,4′,4′′-trinitro-2,2′:6′,2′′-terpyridine} showed that the nitro substituents exerted a strong effect on the ruthenium centre, with the anodic peak corresponding to the Ru(III/II) couple shifted positively by 300 mV compared to that from the non-nitrated parent complex [Ru(tpy)(Me2bpy)Cl]+. 1H NMR studies of the reaction of the Cl-Rubbn complexes with GMP indicated that the ruthenium complexes covalently bound the nucleotide slowly, with 33% bound in 24 hours. However, the results of this study suggest that the cytotoxicity of the dinuclear ruthenium complexes is a combination of covalent and reversible binding with DNA.
    New Journal of Chemistry 06/2014; · 2.97 Impact Factor
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    ABSTRACT: To determine the energy dependency of and the contribution of the membrane potential to the cellular accumulation of the dinuclear complexes [{Ru(phen)2}2{μ-bbn}](4+) (Rubbn) and the mononuclear complexes [Ru(Me4phen)3](2+) and [Ru(phen)2(bb7)](2+) in Staphylococcus aureus and Escherichia coli, and to examine their effect on the bacterial membrane. The accumulation of the ruthenium complexes in bacteria was determined using flow cytometry at a range of temperatures. The cellular accumulation of the ruthenium complexes was also determined in cells that had been incubated with the metal complexes in the presence or absence of metabolic stimulators or inhibitors and/or commercial dyes to determine the membrane potential or membrane permeability. The accumulation of ruthenium complexes in the two bacterial strains was shown to increase with increasing incubation temperature, with the relative increase in accumulation greater with E. coli, particularly for Rubb12 and Rubb16. No decrease in accumulation was observed for Rubb12 in ATP-inhibited cells. While carbonyl cyanide m-chlorophenyl hydrazone (CCCP) did depolarize the cell membrane, no reduction in the accumulation of Rubb12 was observed; however, all ruthenium complexes, when incubated with S. aureus at concentrations twice their MIC, depolarized the membrane to a similar extent to CCCP. Except for the mononuclear complex [Ru(Me4phen)3](2+), incubation of any of the other ruthenium complexes allowed a greater quantity of the membrane-impermeable dye TO-PRO-3 to be taken up by S. aureus. The results indicate that the potential new antimicrobial Rubbn complexes enter the cell in an energy-independent manner, depolarize the cell membrane and significantly permeabilize the cellular membrane.
    Journal of Antimicrobial Chemotherapy 07/2013; · 5.34 Impact Factor
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    ABSTRACT: The effect of human serum on the minimum inhibitory/bactericidal concentrations of the potential antimicrobial agents ΔΔ-[{Ru(phen)2}2(μ-bbn)](4+) {ΔΔ-Rubbn; where phen = 1,10-phenanthroline, bbn = 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.
    Dalton Transactions 05/2013; · 3.81 Impact Factor
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    ABSTRACT: A series of polypyridyl-ruthenium(ii) and -iridium(iii) complexes that contain labile chlorido ligands, [{M(tpy)Cl}(2){μ-bb(n)}](2/4+) {Cl-Mbb(n); where M = Ru or Ir; tpy = 2,2':6',2''-terpyridine; and bb(n) = bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane (n = 7, 12 or 16)} have been synthesised and their potential as antimicrobial agents examined. The minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) of the series of metal complexes against four strains of bacteria - Gram positive Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA), and Gram negative Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa) - have been determined. All the ruthenium complexes were highly active and bactericidal. In particular, the Cl-Rubb(12) complex showed excellent activity against all bacterial cell lines with MIC values of 1 μg mL(-1) against the Gram positive bacteria and 2 and 8 μg mL(-1) against E. coli and P. aeruginosa, respectively. The corresponding iridium(iii) complexes also showed significant antimicrobial activity in terms of MIC values; however and surprisingly, the iridium complexes were bacteriostatic rather than bactericidal. The inert iridium(iii) complex, [{Ir(phen)(2)}(2){μ-bb(12)}](6+) {where phen = 1,10-phenanthroline) exhibited no antimicrobial activity, suggesting that it could not cross the bacterial membrane. The mononuclear model complex, [Ir(tpy)(Me(2)bpy)Cl]Cl(2) (where Me(2)bpy = 4,4'-dimethyl-2,2'-bipyridine), was found to aquate very rapidly, with the pK(a) of the iridium-bound water in the corresponding aqua complex determined to be 6.0. This suggests the dinuclear complexes [Ir(tpy)Cl}(2){μ-bb(n)}](4+) aquate and deprotonate rapidly and enter the bacterial cells as 4+ charged hydroxo species.
    Dalton Transactions 01/2013; · 3.81 Impact Factor
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    ABSTRACT: To determine the in vitro susceptibility and cellular uptake for a series of dinuclear ruthenium(II) complexes [{Ru(phen)(2)}(2){μ-bb(n)}](4+) (Rubb(n)), and the mononuclear complexes [Ru(Me(4)phen)(3)](2+) and [Ru(phen)(2)(bb(7))](2+) against Staphylococcus aureus, methicillin-resistant S. aureus, Escherichia coli and Pseudomonas aeruginosa. The in vitro susceptibility was determined by MIC and MBC assays, and time-kill curve experiments, while the cellular uptake was evaluated by monitoring the fluorescence of the complexes remaining in the supernatant of the cultures after incubation for various periods of time, flow cytometry and confocal microscopy. Rubb(12) and Rubb(16) are highly active, with MIC and MBC values of 1-2 mg/L (0.5-1 μM) for the two Gram-positive strains and 2-4 mg/L for E. coli and 16-32 mg/L for P. aeruginosa. Rubb(16) showed equal or better activity (on a molar basis) to gentamicin and ampicillin for all strains apart from P. aeruginosa. The relative MBC to MIC values indicated that Rubb(12) and Rubb(16) are bactericidal, and from the time-kill curve experiments, the ruthenium complexes can kill the bacteria within 2-6 h. The cellular uptake studies demonstrated that the observed antimicrobial activity is correlated with the level of uptake of the ruthenium complexes. Confocal microscopy confirmed the cellular uptake of Rubb(16), and tentatively suggested that the ruthenium complex is localized in the bacteria. The inert dinuclear ruthenium(II) complexes Rubb(12) and Rubb(16) have potential as new antimicrobial agents. The structure of the dinuclear ruthenium complexes can be readily further modified in order to increase their selectivity for bacteria over human cells.
    Journal of Antimicrobial Chemotherapy 08/2012; 67(11):2686-95. · 5.34 Impact Factor
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    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.
    Dalton Transactions 02/2012; 41(21):6528-35. · 3.81 Impact Factor
  • Anthony Ivan Day, J. Grant Collins
    Supramolecular Chemistry from molecules to nanomaterials. 01/2012; 3:983-1000.
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    ABSTRACT: Solution NMR studies of the interaction between the hexanucleotide d(GTCGAC)(2), β-cyclodextrin and a boronated 2,2':6',2''-terpyridineplatinum(II) complex containing 1,12-dicarba-closo-dodecaborane(12) (1,12-closo-carborane) reveal the formation of a remarkable ternary supramolecular system in which the terpyridine ligand is intercalated between the C(3) and G(4) bases, whilst the closo-carborane moiety is encapsulated by the cyclic sugar.
    Chemical Communications 12/2011; 48(6):880-2. · 6.38 Impact Factor
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    ABSTRACT: The accumulation, uptake mechanism, cytotoxicity, cellular localisation of-and mode of cell death induced by-dinuclear ruthenium(II) complexes ΔΔ/ΛΛ-[{Ru(phen)(2) }(2) {μ-bb(n) }](4+) (Rubb(n)), where phen is 1,10-phenanthroline, bb(n) is bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane (n=2, 5, 7, 10, 12 or 16), and the corresponding mononuclear complexes containing the bb(n) ligands, were studied in L1210 murine leukaemia cells. Cytotoxicity increased with linker chain length, and the ΔΔ-Rubb(16) complex displayed the highest cytotoxicity of the series, with an IC(50) value of 5 μM, similar to that of carboplatin in the L1210 murine leukaemia cell line. Confocal microscopy and flow cytometry studies indicated that the complexes accumulate in the mitochondria of L1210 cells, with the magnitude of cellular uptake and accumulation increasing with linking chain length in the bb(n) bridge of the metal complex. ΔΔ-Rubb(16) entered the L1210 cells by passive diffusion (with a minor contribution from protein-mediated active transport), inducing cell death via apoptosis. Additionally, metal-complex uptake in leukaemia cells was approximately 16-times that observed in healthy B cells highlighting that the bb(n) series of complexes may have potential as selective anticancer drugs.
    ChemMedChem 04/2011; 6(5):848-58. · 2.84 Impact Factor
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    ABSTRACT: The minimum inhibitory concentrations (MIC) of a series of synthetic inert polypyridylruthenium(II) complexes against four strains of bacteria--Gram positive Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA), and Gram negative Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa)--have been determined. The results demonstrate that for the dinuclear ruthenium(II) complexes ΔΔ/ΛΛ-[{Ru(phen)(2)}(2){μ-bb(n)}](4+) {where phen = 1,10-phenanthroline; bb(n) = bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane (n = 2, 5, 7, 10, 12 or 16)} the complexes linked by the bb(12), bb(14) and bb(16) ligands are highly active, with MIC values of 1 μg mL(-1) against both S. aureus and MRSA, and 2-4 and 8-16 μg mL(-1) against E. coli and P. aeruginosa, respectively. The mononuclear complex [Ru(Me(4)phen)(3)](2+) showed equal activity (on a mole basis) against S. aureus compared with the Rubb(12), Rubb(14) and Rubb(16), but was considerably less active against MRSA and the two Gram negative bacteria. For the dinuclear Rubb(n) family of complexes, the antimicrobial activity was related to the octanol-water partition coefficient (logP). However, the highly lipophilic mononuclear complex Δ-[Ru(phen)(2)(bb(16))](2+) was significantly less active than Rubb(16), highlighting the importance of the dinuclear structure. Preliminary toxicity assays were also carried out for the ΔΔ isomers of Rubb(7), Rubb(10), Rubb(12) and Rubb(16) against two human cells lines, fresh red blood cells and THP-1 cells. The results showed that the dinuclear ruthenium complexes are significantly less toxic to human cells compared to bacterial cells, with the HC(50) and IC(50) values 100-fold higher than the MIC for the complex that showed the best potential--ΔΔ-Rubb(12).
    Dalton Transactions 03/2011; 40(18):5032-8. · 3.81 Impact Factor
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    ABSTRACT: The paper reports the synthesis and characterisation of a series of flexible di-bidentate bridging ligands in which two 4-methyl-2,2'-bipyridine groups are linked at the 4'-position by polymethylene (bb(n)), linear polyether (bbO(n)) or linear alkylamine (bbN(n)) chains of varying length (n). The enantiomers (ΔΔ/ΛΛ) of the rac forms of the ruthenium(ii) dinuclear complexes incorporating these ligands -i.e. [{Ru(phen)(2)}(2)(μ-BL)](4+) (phen = 1,10-phenanthroline; BL = bb(n), bbO(n) or bbN(n)) - have been isolated by reaction of Δ- or Λ-[Ru(phen)(2)(py)(2)](2+) (py = pyridine) with the respective bridging ligands. Mononuclear species - in which only one of the bidentate moieties of the bridging ligand is coordinated - have also been isolated, as well as trinuclear and tetranuclear species involving the bb(7) bridge. Fluorescence displacement studies of the DNA-binding of the dinuclear complexes containing the bbO(n) and bbN(n) bridges generally revealed a lower affinity than their bb(n) analogues for an oligonucleotide containing a single bulge site; the mononuclear complexes showed a lower affinity - and the trinuclear and tetranuclear complexes a higher affinity - than the dinuclear species, revealing an interesting interplay of lipophilicity, electrostatics and size in the complex/nucleic acid interaction. Cytotoxicity studies of these complexes against a murine leukaemia cell line revealed that the presence of the polyether or polyamine links in the chain lowered the cytotoxicity compared with their polymethylene analogues, and that the bb(7)-bridged trinuclear and tetranuclear complexes showed considerably enhanced cytotoxicity compared with the dinuclear Rubb(7) analogue.
    Dalton Transactions 02/2011; 40(7):1510-23. · 3.81 Impact Factor
  • Damian P. Buck, J. Grant Collins
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    ABSTRACT: The study of the interaction between inert transition metal complexes and nucleic acids has developed from the early work of Dwyer [1], Lippard [2], Nordén [3] and Barton [4] to the point that it is now a central theme in bio-inorganic chemistry. While there has been considerable interest in metal complexes that bind nucleic acids, the interaction of metallointercalators with DNA and RNA has received the most attention [5, 6]. Square-planar platinum(II) complexes have demonstrated significant anticancer activity [7], and octahedral ruthenium(II) and rhodium(III) complexes have been used as probes of nucleic acid structure and as a means to study electron transfer reactions mediated by the heteroaromatic bases [5, 6]. While a range of techniques is available to study the nucleic acid binding of metal complexes, NMR spectroscopy (particularly 1H NMR) has proven to be the most useful. NMR spectroscopy can provide a detailed, atom level resolution, picture of the metal complex binding, and if the quality of the data is sufficient, a threedimensional structure of the metal complex bound to the oligonucleotide can be determined. The strategies used to assign the 1H NMR spectrum of an oligonucleotide [8-10], the extension of these methods to study the interaction of metal complexes with DNA and the use of molecular modelling will be presented in this chapter.
    Metallointercalators. 01/2011;
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    ABSTRACT: The binding of the anticancer drug pixantrone (6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione dimaleate) to the octanucleotide duplexes d(ACGATCGT)(2) and the corresponding C-5 methylated cytosine ((5Me)C) analogue d(A(5Me)CGAT(5Me)CGT)(2) has been studied by NMR spectroscopy and molecular modelling. The large upfield shifts observed for the resonances from the aromatic protons of pixantrone upon addition to either d(ACGATCGT)(2) or the corresponding (5Me)C analogue is consistent with the drug binding the octanucleotides by intercalation. The selective reduction in the sequential NOEs between the C(2)-G(3) and C(6)-G(7) nucleotides in NOESY spectra of either octanucleotide with added pixantrone confirms the intercalative binding mechanism. Strong NOEs from the side-chain ethylene protons of pixantrone to the H5 protons and the 5-CH(3) protons of the C(2) and C(6) residues of d(ACGATCGT)(2) and d(A(5Me)CGAT(5Me)CGT)(2), respectively, indicate that pixantrone predominantly intercalates from the DNA major groove at the 5'-CG and 5'-(5Me)CG sites. Simple molecular models based on the conclusions from the NMR experiments indicated that the (5Me)C groups do not represent a steric barrier to intercalation from the major groove. However, the observation of weak NOEs from the ethylene protons of pixantrone to a variety of minor groove protons from either octanucleotide suggests that the drug can also associate in the minor groove.
    Organic & Biomolecular Chemistry 12/2010; 8(23):5359-66. · 3.57 Impact Factor
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    ABSTRACT: Mitoxantrone is an anticancer agent that acts as a topoisomerase II poison, however, it can also be activated by formaldehyde to form DNA adducts. Pixantrone, a 2-aza-anthracenedione with terminal primary amino groups in its side chains, forms formaldehyde-mediated adducts with DNA more efficiently than mitoxantrone. Molecular modeling studies indicated that extension of the "linker" region of anthracenedione side arms would allow the terminal primary amino greater flexibility and thus access to the guanine residues on the opposite DNA strand. New derivatives based on the pixantrone and mitoxantrone backbones were synthesized, and these incorporated primary amino groups as well as extended side chains. The stability of DNA adducts increased with increasing side chain length of the derivatives. A mitoxantrone derivative bearing extended side chains (7) formed the most stable adducts with ∼100-fold enhanced stability compared to mitoxantrone. This finding is of great interest because long-lived drug-DNA adducts are expected to perturb DNA-dependent functions at all stages of the cell cycle.
    Journal of Medicinal Chemistry 10/2010; 53(19):6851-66. · 5.61 Impact Factor
  • Australian Journal of Chemistry 09/2010; 63(9):1365-1375. · 1.87 Impact Factor
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    ABSTRACT: The albendazole derivatives (2-methoxyethyl) 5-propylthio-1H-benzimidazole-2-yl carbamate (MEABZ), N1-(2-methoxyethoxycarbonyl)-2-amino-5-propylthiobenzimidazole and N1-(2-methoxyethoxycarbonyl)-2-amino-6-propylthiobenzimidazole (MEABZ isomers A and B) and (2-hydroxyethyl) 5-propylthio-1H-benzimidazole-2-yl carbamate (HEABZ) have been synthesised. The cytotoxicity of these compounds was evaluated against a human colorectal cancer cell line (HT-29) and a human prostate cancer cell line (PC-3). The results demonstrate MEABZ, a new benzimidazole, is up to ten times more cytotoxic than the parent drug albendazole, whereas the MEABZ isomers A and B and HEABZ show no activity. A comparison of the cytotoxicity of these compounds, relative to ABZ, provides structure-activity data for this important class of anticancer agents. The aqueous solubilities of MEABZ encapsulated in Q[n] have been determined by (1)H NMR spectroscopy. The aqueous solubility of MEABZ at a physiologically relevant pH increased by 1200-fold by encapsulation in Q[8], from 8 microM to 9.4 mM, while Q[6,7] encapsulation substantially increased the solubility to more than 2 mM. Encapsulation in Q[7] and Q[8] induced significant upfield shifts for the MEABZ propyl and benzimidazole resonances. The upfield shifts indicate that the propyl and benzimidazole protons are located within the Q[7] and Q[8] cavity upon encapsulation. By contrast, encapsulation in Q[6] induced large upfield shifts for the (1)H resonances from the carbamate functional group, indicating that MEABZ associates with Q[6] at its portals, with only the carbamate group binding within the cavity.
    Organic & Biomolecular Chemistry 07/2010; 8(14):3328-37. · 3.57 Impact Factor
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    ABSTRACT: The lipophilic ligand-bridged dinuclear cation Rubb₁₆ is significantly cytotoxic and preferentially accumulates in the mitochondria of the L1210 murine leukemia cancer cell line.
    Metallomics 06/2010; 2(6):393-6. · 4.10 Impact Factor
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    ABSTRACT: A simpler method for the purification of cucurbit[10]uril (Q[10]) from the Q[10].Q[5] inclusion complex is reported. 1,12-Diaminododecane was used to displace Q[5], as opposed to the synthetic melamine derivative currently used. The binding of trans-[{PtCl(NH(3))(2)}(2)(micro-NH(2)(CH(2))(8)NH(2))](2+) (CT008) and [{Ru(phen)(2)}(2)(micro-bb(5))](4+) {phen = 1,10-phenanthroline; bb(5) = 1,5-bis[4(4'-methyl-2,2'-bipyridyl)]pentane} (Rubb(5)) to Q[10] was studied by (1)H NMR and luminescence spectroscopy, cyclic voltammetry and molecular modelling. The (1)H NMR resonances of the methylene protons in the bridging ligands of CT008 and Rubb(5) exhibited large upfield chemical shift changes upon addition of Q[10]. These shifts are indicative of encapsulation of the bridging ligand within the Q[10] cavity, with the metal centres positioned outside the portals. (1)H NMR-based kinetics experiments with Rubb(5) show the presence of a portal-bound intermediate which progresses to a completely encapsulated inclusion complex only after many hours. The large metal centres of Rubb(5) provide a restriction to the movement of the complex in and out of the cavity and result in binding kinetics that are slow on both the (1)H NMR and biological timescales. This result was consistent with molecular modelling simulations. Cyclic voltammetry showed that the Ru(III/II) couple of free Rubb(5) appeared at +1.058 V (vs Ag/AgCl), with the first ligand reduction observed as a shoulder ( approximately -1.38 V) on the edge of the solvent (water) front. The Q[10]-bound complex exhibited an anodic shift of 48 mV compared to the free metal complex. Luminescence spectroscopy of the binding of Rubb(5) to Q[10] yielded an approximate binding constant of 1.9 x 10(9) M(-1). Although CT008 was encapsulated within Q[10], the inclusion complex was not soluble in several buffers at pH 7.0. These results indicate that Q[10] is not an effective delivery vehicle for dinuclear platinum(II) anti-cancer drugs; however, due to the strong binding affinity and slow exchange rates, Q[10] does show considerable promise as a delivery mechanism for controlled slow release of large dinuclear ruthenium(II) complexes.
    Dalton Transactions 02/2010; 39(8):2078-86. · 3.81 Impact Factor
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    ABSTRACT: The platinum complexes trans-[{PtCl(NH3)2}2(micro-NH2(CH2)3NH2(CH2)3NH2)]3+ (CT033) and the corresponding N4-dimethyl linked analogue trans-[{PtCl(NH3)2}2(micro-NH2(CH2)3N(Me)2(CH2)3NH2)]3+ (CT233) have been synthesised, and their cytotoxicity, ability to bind cucurbit[7,8]uril (Q[7,8]) and reaction with cysteine studied. Both platinum complexes show good activity in the L1210 cell line and maintain their activity in the corresponding cisplatin L1210/DDP cell line. However, the N4-dimethyl analogue CT233 is approximately 50-times less active than the CT033 complex. This suggests that the insertion of a positive charge into the linking ligand may not, per se, be responsible for the higher cytotoxicity generally observed for dinuclear platinum complexes linked by polyamines. The upfield shifts of the resonances from the methylene protons in the linking triamine ligand observed in the 1H NMR spectra of either CT033 and CT233 upon addition of either Q[7] or Q[8] indicate that the cucurbituril is positioned over the linking ligand. However, the results show that the protonated secondary amine in CT033 acts as a barrier to encapsulation, with the Q[7,8] being positioned over only one propyl-arm at a time. Alternatively, the entire triamine linking ligand of CT233 is fully encapsulated within the Q[7,8] cavity. Encapsulation by Q[7,8] was found to reduce the rate of reaction of CT033 and CT233 with the thiol containing amino acid cysteine, with a greater rate reduction observed for CT233. These results are consistent with the NMR results of the Q[7,8] binding studies of the two platinum complexes. For CT033 encapsulated in Q[7,8], one of the two platinum centres is completely exposed to the solvent, whereas, for CT233 both platinum centres are simultaneously positioned within the portals of the cucurbit[n]uril, thereby, affording greater protection.
    Dalton Transactions 08/2009; · 3.81 Impact Factor
  • F. Richard Keene, Jayden A. Smith, J. Grant Collins
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    ABSTRACT: Concomitant with our increasing knowledge of the structure and biological role of nucleic acids is the interest in the development of small molecules that can regulate DNA and RNA function. While considerable effort has been devoted to synthesising compounds that can target specific DNA and RNA sequences, there is growing interest in developing agents that can recognise nucleic acid structural features. In particular, it has now been established that a variety of non-duplex structures – such as bulges, hairpins and junctions – play an important role in the regulation of DNA transcription and RNA translation. Metal complexes have great diversity in size and structure, as well as useful photophysical and electrochemical properties in many cases, and consequently they have become an important class of structure-selective binding agents for nucleic acids. The present review addresses the range and biological significance of non-duplex structures that are found in DNA and RNA, as well as the specific types of metal complexes that recognise these structural features. Particular attention is given to dinuclear ruthenium complexes that have been shown to bind duplex DNA and RNA weakly, but associate strongly with non-duplex structures.
    Coordination Chemistry Reviews. 08/2009;

Publication Stats

551 Citations
171.44 Total Impact Points

Institutions

  • 1992–2014
    • Australian Defence Force Academy
      Canberra, Australian Capital Territory, Australia
  • 2004–2011
    • James Cook University
      • • School of Pharmacy and Molecular Sciences
      • • Discipline of Chemistry
      Townsville, Queensland, Australia
  • 2009
    • University of Ioannina
      Yannina, Epirus, Greece
  • 2004–2007
    • University of Western Sydney
      Penrith, New South Wales, Australia
  • 2006
    • Queen's University Belfast
      • School of Chemistry and Chemical Engineering
      Belfast, NIR, United Kingdom
  • 2005
    • Australian Government, Department of Defence
      Canberra, Australian Capital Territory, Australia