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Biomedical subjects

Trevor W Hambley

Publications and source records attributed to Trevor W Hambley.

At least 19 recordsLinked to original sources
PubMed2005

DNA adducts of the enantiomers of the Pt(II) complexes of the ahaz ligand (ahaz=3-aminohexahydroazepine) and recognition of these adducts by HMG domain proteins.

The bending, unwinding, and structural changes in DNA caused by the binding of each of the enantiomers of the platinum(II) complexes of the ahaz ligand (R- and S-[PtCl(2)(ahaz)], ahaz=3-aminohexahydroazepine) have been studied using 20-23 bp oligonucleotides containing TGGT and CGGA-binding sites as has the recognition of the adducts by HMG domain proteins. The domain A of HMGB1 (HMGB1a protein) binds to the adduct formed by the R enantiomer at the CGGA sequence with a similar high affinity as it does to the adduct of antitumor cisplatin, and to the adduct formed by the S enantiomer with a slightly lower affinity. In contrast, HMGB1a binds much more weakly to the ahaz adducts than to the cisplatin adducts formed at the TGGT sequence, with the binding to the adduct formed by the R enantiomer being weakest. Each enantiomer and cisplatin cause unwinding of both sequences that is in the narrow range, 19-22 degrees. There are modest but significant differences in the degree of bending induced, with the S enantiomer causing the least bending, cisplatin intermediate, and the R enantiomer the most. Molecular modeling of the {Pt(ahaz)}/GG adducts in 8-bp models reveals significant differences in the local distortion at the GG-binding sites depending on the flanking bases and shows that interactions between the thymine methyl groups and the ahaz ligand are likely to inhibit bending of the TGGT sequence.

Animals↗
PubMed2005

Structural measures of element-oxygen bond covalency from the changes to the delocalisation of the carboxylate ligand.

The data set of more than 40,000 crystal structures containing the carboxylate group that have been deposited in the CSD has been used to examine the structural changes that occur in the carboxylate C-O bond lengths upon binding to different elemental centres. We report here quantifiable structural changes that are dependent on the elemental centre with which the group is interacting. For the main-group elements the trends are entirely periodic and follow those traditionally associated with covalency; elements exhibiting electronegativity closest to that of oxygen exhibit the largest structural change. In addition, we find the measure is extendable to both the transition metals and the lanthanoids and actinoids. Amongst the transition metals the trends of Pauling neutrality are not only maintained, but are quantifiable. The difference between the two C-O bond lengths increases with oxidation state and decreases with an increase in coordination number. All of the lanthanoids exhibit covalency within error of each other and the bonds to the actinoids are found to be more covalent than those to the lanthanoids. From the data analysis we are able to derive a correlation between the lengths of the two carboxylate arms that allows us to quantify percentage covalent character defined in terms of the resonance contributions to the carboxylate group.

Journal Article↗
PubMed2005

Nuclear magnetic resonance analysis of indomethacin-induced gastric ulcers.

Acetonitrile extracts of ulcerated and control rat stomachs were studied by various NMR techniques in an attempt to understand how indomethacin, a common and powerful nonsteroidal antiinflammatory drug (NSAID), induces ulcers in the stomach. One- (1D) and two-dimensional (2D) NMR spectra of extracts of ulcerated and control stomachs revealed that glycolytic and Krebs cycle enzymes were partially inhibited in the ulcerated stomach as shown by the lactate/glucose ratio. The (total choline)/lactate ratio was also higher in the extract from the control stomach than in the ulcerated stomach. Glycerophosphoethanolamine and glycerophosphocholine concentrations were higher in the ulcerated stomach extract as compared with the control stomach extract. These results explain the gastrointestinal protective effect of D-glucose and Krebs cycle intermediates on NSAID-induced ulceration.

Animals↗
PubMed2004

Studies on pyridazine azide cyclisation reactions.

Reaction of sodium azide with 4-methyl-3,5,6-tribromopyridazine results in the formation of 3,5,6-triazide intermediate which could cyclise to give two possible bicyclic products while ab initio calculations show that the formation of a tricyclic compound is extremely energetically unfavourable. However, experimentally, only one major product is isolated. The structure of this unstable product has been conclusively established by X-ray crystallography as 3,5-diazido-4-methyl[1,5-b]tetrazolopyridazine confirming theoretical predictions.

Journal Article↗
PubMed2004

NMR spectroscopic characterization of copper(II) and zinc(II) complexes of indomethacin.

Molecular diffusion constants were studied by NMR spectroscopy to provide information about the solution structures of a variety of Cu(II) and Zn(II) monomeric and dimeric complexes of indomethacin (IndoH). These studies showed that monomeric Zn(II)-Indo complexes substantially dimerize in DMF-d7 and DMSO-d6 solutions at room temperature, whereas the Cu(II) and Zn(II) dinuclear complexes remain largely intact in these solutions. There is evidence of an equilibrium between monomers and dimers for the Zn(II) complexes in solution, as shown by a reduced diffusion constant and lower average radius compared to the Cu(II) dimer. Such an equilibrium between monomers and dimers for the Zn(II) complexes is also consistent with previous results obtained from XAFS analysis of DMF solutions of such complexes. The greater lability and lower thermodynamic stability of the Zn(II) dimer complex compared to the Cu(II) analogue, as determined from the NMR experiments, is likely to result in the more ready release of free Indo in the GI tract. This is consistent with the previously observed higher GI toxicities of the Zn-Indo pharmaceutical preparations compared to the Cu(II)-Indo counterparts.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

X-ray absorption spectroscopic studies of chromium(V/IV/III)- 2-ethyl-2-hydroxybutanoato(2-/1-) complexes.

Structures of the complexes [Cr(V)O(ehba)(2)](-), [Cr(IV)O(ehbaH)(2)](0), and [Cr(III)(ehbaH)(2)(OH(2))(2)](+) (ehbaH(2) = 2-ethyl-2-hydroxybutanoic acid) in frozen aqueous solutions (10 K, [Cr] = 10 mM, 1.0 M ehbaH(2)/ehbaH, pH 3.5) have been determined by single- and multiple-scattering fitting of X-ray absorption fine structure (XAFS) data. An optimal set of fitting parameters has been determined from the XAFS calculations for a compound with known crystal structure, Na[Cr(V)O(ehba)(2)] (solid, 10 K). The structure of the Cr(V) complex [Cr(V)O(ehba)(2)](-) does not change in solution in the presence of excess ligand. Contrary to the earlier suggestions made from the kinetic data (Ghosh, M. C.; Gould, E. S. J. Chem. Soc., Chem. Commun. 1992, 195-196), the structure of the Cr(IV) complex (generated by the Cr(VI) + As(III) + ehbaH(2) reaction) is close to that of the Cr(V) complex (five-coordinate, distorted trigonal bipyramidal) and different from that of the Cr(III) complex (six-coordinate, octahedral). For both Cr(V) and Cr(IV) complexes, some disorder in the position of the oxo group is observed, which is consistent with but not definitive for the presence of geometric isomers. The structure of the Cr(IV) complex differs from that of Cr(V) by protonation of alcoholato groups of the ligands, which leads to significant elongation of the corresponding Cr-O bonds (2.0 vs 1.8 A). This is reflected in the different chemical properties reported previously for the Cr(IV) and Cr(V) complexes, including their reactivities toward DNA and other biomolecules in relation to Cr-induced carcinogenicity.

Chromium↗
PubMed2004

Comparative efficacy of novel platinum(IV) compounds with established chemotherapeutic drugs in solid tumour models.

Platinum(II)-based anticancer drugs are associated with high reactivity and thus a poor biological stability. The platinum(IV)-complexes display potential advantages due to their greater stability and bioreductive activation, thereby allowing a greater proportion of the drug to arrive at the target intact. All compounds tested were able to produce cytotoxicity in monolayer cell cultures, however, the potencies of platinum(IV) drugs were lower than that observed for the platinum(II) compounds or established organic chemotherapeutic agents. There was no significant alteration in the potency of platinum(II) or (IV) compounds to produce cytotoxicity in multicellular tumour spheroids (MCTS) compared to monolayer cultures. All the organic and platinum-based cytotoxic agents produced, to varying degrees, either a retardation or reduction in MCTS growth. Proliferating cells were restricted to the outer two to three cellular layers in intermediate (d=350 microm) and large (d=600 microm) MCTS. Regardless of MCTS size, drug treatment produced a larger and more widely distributed proliferating cell population, consistent with the recruitment of quiescent cells to the proliferating pool following cytotoxic damage. Histology indicated that the predominant morphological change was that of apoptosis, although there was some drug-dependent effects such as the metaphase arrest produced by vinblastine and chromatin dispersal to the periphery of nuclei produced by doxorubicin. In summary, whilst the platinum(IV) derivatives were able to produce cytotoxicity via apoptosis, the introduction of a stable axial group significantly retarded the rate at which this occurred.

Antineoplastic Agents↗
PubMed2004

The mechanism of action of platinum(IV) complexes in ovarian cancer cell lines.

The reduction potentials, lipophilicities, cellular uptake and cytotoxicity have been examined for two series of platinum(IV) complexes that yield common platinum(II) complexes on reduction: cis-[PtCl(4)(NH(3))(2)], cis,trans,cis-[PtCl(2)(OAc)(2)(NH(3))(2)], cis,trans,cis-[PtCl(2)(OH)(2)(NH(3))(2)], [PtCl(4)(en)], cis,trans-[PtCl(2)(OAc)(2)(en)] and cis,trans-[PtCl(2)(OH)(2)(en)] (en=ethane-1,2-diamine, OAc=acetate). As previously reported, the reduction occurs most readily when the axial ligand is chloride and least readily when it is hydroxide. The en series of complexes are marginally more lipophilic than their ammine analogues. The presence of axial chloride or acetate ligands results in a slighter higher lipophilicity compared with the platinum(II) analogue whereas hydroxide ligands lead to a substantially lower lipophilicity. The cellular uptake is similar for the platinum(II) species and their analogous tetrachloro complexes, but is substantially lower for the acetato and hydroxo complexes, resulting in a correlation with the reduction potential. The activities are also correlated with the reduction potentials with the tetrachloro complexes being the most active of the platinum(IV) series and the hydroxo being the least active. These results are interpreted in terms of reduction, followed by aquation reducing the amount of efflux from the cells resulting in an increase in net uptake.

Cell Line, Tumor↗
PubMed2003

XAFS studies of anti-inflammatory dinuclear and mononuclear Zn(II) complexes of indomethacin.

Zinc K-edge X-ray absorption fine structure (XAFS) experiments were performed in the solid and solution states at low temperature (10 K), on dimeric and monomeric anti-inflammatory Zn(II) complexes of indomethacin [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid=IndoH] of the formula [Zn2(Indo)4L2] [L=pyridine (Py), N,N-dimethylacetamide (DMA)], [Zn(Indo)2L2] [L=ethanol (EtOH), methanol (MeOH)], and Zn(II) acetate dihydrate [Zn(OAc)2(OH2)2]. The bond distances and angles obtained from multiple-scattering fits to the XAFS data of the Zn(II) dimeric complexes in the solid and solution states exhibit excellent correspondence with those obtained from single crystal diffraction studies. The Zn...Zn separations of 2.97 and 2.96 A and carboxylate group O-C-O angles of 125 degrees for powdered [Zn2(Indo)4(Py)2] and [Zn2(Indo)4(DMA)2] agree well with the XRD values of 2.969(1) and 2.9686(6) A and 125.8(4) degrees and 126.1(2) degrees, respectively. The calculated Zn-O(RCOO) and Zn-L bond distances of 2.03 and 2.04 A, or 2.02 and 1.98 A for Py or DMA complexes, respectively, also agree well with crystallographic data. The X-ray powder diffraction data on samples of the monomers exhibited additional reflections apart from those due to the crystallographically characterized cis-[Zn(eta2-O,O'-Indo)2L2], but microanalyses were consistent with this formulation. Therefore, mixed models that contained the cis complex and a second component consisting of a trans-six-coordinate complex, a five-coordinate complex, or a four-coordinate complex were used to model the XAFS. The best fits to the XAFS data were obtained with a mixture of the cis-six-coordinate complex and a four-coordinate complex containing two monodentate Indo ligands. The bond lengths for the six-coordinate structure were consistent with those determined on a single crystal, and those for the four-coordinate complexes were consistent with related four-coordinate structures with two monodentate carboxylate ligands. Dissolution of the dimer (DMA adduct) in DMF resulted in a mixture of dimer and monomer species as shown by MS XAFS fitting. This is the first time that solution structures have been determined for anti-inflammatory Zn(II) complexes, and this is an important first step in understanding the pharmacology of the complexes.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2003

The cellular distribution and oxidation state of platinum(II) and platinum(IV) antitumour complexes in cancer cells.

The cellular distribution of platinum in A2780 ovarian cancer cells treated with cisplatin and platinum(IV) complexes with a range of reduction potentials has been examined using elemental analysis (synchrotron radiation-induced X-ray emission). The cellular distribution of platinum(IV) drugs after 24 h is similar to that of cisplatin, consistent with the majority of administered platinum(IV) drugs being reduced. Micro-X-ray absorption near-edge spectra of cells treated with cisplatin and platinum(IV) complexes confirmed the reduction of platinum(IV) to platinum(II). In cells treated, the most difficult to reduce complex, cis, trans, cis-[PtCl(2)(OH)(2)(NH(3))(2)], platinum(IV) was detected in the cells along with platinum(II). The observations are in accordance with the relative ease of reduction of the platinum(IV) complexes used and support the requirement of reduction for activation of platinum(IV) complexes.

Antineoplastic Agents↗
PubMed2003

XANES determination of the platinum oxidation state distribution in cancer cells treated with platinum(IV) anticancer agents.

Here we describe the use of X-ray absorption near edge spectroscopy (XANES) to provide information about the relative proportions of platinum(II) and platinum(IV) complexes by analyzing the XANES edge height. The intracellular reduction of platinum(IV) complexes in cancer cells has been observed directly, and the proportion of reduction after 2 h was found to correlate with the reduction potentials of the complexes.

Antineoplastic Agents↗
PubMed2003

Investigations into the interactions between DNA and conformationally constrained pyridylamineplatinum(II) analogues of AMD473.

The syntheses of [PtCl(2)(amp)] (amp = 2-pyridylmethylamine) and enantiomerically pure [PtCl(2)(R-pea)] and [PtCl(2)(S-pea)] (pea = 1-(2-pyridyl)ethylamine) and the crystal structure of [PtCl(2)(R-pea)] are reported. The reactions of [PtCl(2)(amp)] and of the enantiomers of [PtCl(2)(pea)] with d(GpG) and with a 52-base-pair oligonucleotide were investigated. Each of the reactions with d(GpG) resulted in the formation of three platinated bifunctional d(GpG) species in a ratio of 1:2:1. These species were shown to be a pair of isomers, one of which exists as a pair of slowly interconverting rotamers that can be separated by HPLC but reequilibrate after 5 days at 37 degrees C. The pyridyl moieties of the pyridylalkylamine ligands are constrained to lie in the coordination plane, and as a consequence, the rotation about the Pt-N7 bond of the adjacent guanine is highly restricted. 2D NMR investigations were carried out on the isomer of [Ptd(GpG)(amp)] that did not form separable rotamers and identified it as the isomer having the pyridine adjacent to the 5'-guanine of the d(GpG). The reaction of each of the three [PtCl(2)(py-R)] complexes (py-R = amp or pea) with a 52-base-pair oligonucleotide resulted in the formation of the same three bifunctional d(GpG) adducts in approximately the same ratios as the reactions with d(GpG), indicating that negligible stereoselectivity results from interactions between the complexes and duplex DNA.

Base Sequence↗
PubMed2003

Specificity in template syntheses of hexaaza-macrobicyclic cages: [Pt(Me5-tricosatrieneN6)]4+ and [Pt(Me5-tricosaneN6)]4+.

The racemic C3 hexadentate cage complex, [Pt(Me5-tricosatrieneN6)]Cl4 (1,5,9,13,20-pentamethyl-3,7,11,15,18,22-hexaazabicyclo[7.7.7]tricosa- 3,14,18-triene)platinum(IV) tetrachloride), was synthesised stereospecifically and regiospecifically from a reaction of the bis-triamine template [Pt(tamc)2]Cl4 (bis[1,1,1-tris(aminomethyl)ethane]- platinum(IV) tetrachloride) with formaldehyde and then propanal, in acetonitrile under basic conditions. Largely, one racemic diastereoisomer was obtained in a surprisingly high yield (approximately 50%), even though the molecule has seven chiral centres. The origins of the stereoselective synthesis are addressed. The crystal structure of [Pt(Me5-tricosatrieneN6)]-(ZnCl4)1.5Cl.2H2O showed that all three imines were attached to one tame fragment with a chiral amine site ([symbol: see text] SSS, delta RRR) and a chiral methine carbon site ([symbol: see text] RRR, delta SSS) on each ligand strand. The PtN6(4+) moiety had a slightly distorted octahedral configuration with the two types of Pt-N bonds related to the imine and the amine donors, 2.050(7) and 2.072(6) A, respectively. Treatment with sodium borohydride (15 s, 20 degrees C) at pH approximately 12.5 reduced the imine groups, but not the Pt(IV) ion, producing a C3 saturated ligand complex [Pt(Me5-tricosaneN6)]Cl4 ((1,5,9,13,20- pentamethyl-3,7,11,15,18,22- hexaazabicyclo[7.7.7]tricosane)platinum(IV)tetrachloride). X-ray crystallographic analysis showed that the average Pt-N bond distance in the cation increased upon imine reduction to 2.10 (av) A. The cyclic voltammograms of the two cage complexes displayed irreversible two-electron reduction waves in aqueous media and a approximately 0.3 V shift to more positive potentials compared to that of the smaller cavity sar (3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane) analogue. After reduction, net dissociation of one strand of the cage was also evident, to give unstable square planar Pt(II) macrocyclic products.

Journal Article↗
PubMed2003

Structural measure of metal-ligand covalency from the bonding in carboxylate ligands.

The data set of over 40 000 crystal structures containing the carboxylate group that has been reported to the CSD has been used to extract structural changes to the carboxylate group upon binding to different elemental centers. We find quantifiable structural changes to the carboxylate group depending on the elemental center it is interacting with. The trends follow those traditionally associated with covalency; elements exhibiting electronegativity closest to that of oxygen exhibit the largest structural change. In addition, we find the measure is extendable to transition metal systems where we observe the trends of Pauling neutrality not only are maintained but also are quantifiable; i.e., the structural change increases with oxidation state, i.e., II < III < IV, and decreases with an increase in coordination number, 4c > 5c > 6c. Further, the measure gives us a quantifiable measure of the difference between the covalencies of the long and short bonds of Cu(II) complexes. From the bond lengths of the bound carboxylate arm, we are able to derive bond orders and hence calculate the covalent character in the adjoining metal-carboxylate bonds. As such, we have a structurally derived quantification of metal-ligand covalency.

Journal Article↗
PubMed2003

Gastrointestinal toxicity, antiinflammatory activity, and superoxide dismutase activity of copper and zinc complexes of the antiinflammatory drug indomethacin.

Gastrointestinal (GI) toxicity is one of the major problems associated with antiinflammatory drugs. The complexation of the powerful antiinflammatory drug (IndoH) by metal ions, as a means of reducing GI toxicity, has been studied. The in vitro superoxide dismutase (SOD) activity, in vivo antiinflammatory activity, and gastrointestinal ulcerogenic properties of IndoH, [Cu2(Indo)4(DMF)2], and [Zn2(Indo)4(DMA)2] are reported. No SOD activity was observed for IndoH or [Zn2(Indo)4(DMA)2], but [Cu2(Indo)4(DMF)2] inhibited the reduction of nitroblue tetrazolium (NBT) at an IC50 value of 0.23 microM. All three compounds exhibited antiinflammatory activity in male Sprague-Dawley rats at an equivalent Indo dose of 10 mg/kg following oral administration of the drugs in 2% CMC solution. The severity of the toxicity (macroscopic ulcerations) in the stomach following oral dosing with [Zn2(Indo)4(DMF)2] was not significantly lower than that induced by IndoH (P = 0.78). Gastric ulcerations induced by [Cu2(Indo)4(DMF)2] were significantly lower than those induced by IndoH or [Zn2(Indo)4(DMA)2] (P = 0.0012 and P = 0.0175, respectively) but significantly greater than the control (P = 0.0013). The intestinal ulcerations induced by [Cu2(Indo)4(DMF)2] or [Zn2(Indo)4(DMA)2] were approximately 15 times lower than those of IndoH. A further indicator of gastrointestinal toxicity, caecal haemoglobin, increased in the following order: control < [Cu2(Indo)4(DMF)2] < [Zn2(Indo)4(DMA)2] < IndoH.[Cu2(Indo)4(DMF)2] exhibited the most promising results of the Indo complexes assayed, in that it exhibited SOD activity and the lowest gastrointestinal damage while also exhibiting antiinflammatory activity that was comparable to that for IndoH. Low-temperature EPR analyses also showed that the formulation used for [Cu2(Indo)4(DMF)2] administration was crucial to the integrity of the complex.

Animals↗
PubMed2002

Stereospecificity and enantioselectivity in the binding of the platinum(II) complex [PtCl2(tmdz)] (tmdz = 5,5,7-trimethyl-1,4-diazacycloheptane) to dinucleotides and oligonucleotides.

The two stereoisomers formed on reaction of each of the enantiomers of [PtCl2(tmdz)] with d(GpG) have been identified by using one- and two-dimensional 1H NMR spectroscopy. For both isomers formed with the R enantiomer the 3'-H8 shifts are downfield from those for the 5'-H8. For the S enantiomer the reverse is observed, showing that the bulky tmdz ligand determines the pattern of shifts. Models of these isomers generated by molecular mechanics show that the bulky tmdz ligand limits the rotation of the guanine bases and enforces right-handed (R2) canting for both isomers formed by the R enantiomer and left-handed (L1) canting for those formed by the S enantiomer. The pattern of H8 shifts is the opposite to that expected for these cantings; this suggests that other factors may play a role in determining these shifts. The interactions between the tmdz and d(GpG) ligands are also shown by molecular mechanics and the broadness of the H8 NMR signals to influence the tendency of the coordinated guanine bases to rotate about their Pt-N7 bonds. Reaction of each of the enantiomers with a 52 base-pair nucleotide, with a total of six GpG binding sites, resulted in the formation of only one of the stereoisomers in each case, the first reported case of complete stereoselectivity, or stereospecificity, in the reaction of Pt complexes with DNA. The observed stereoisomers were identified by comparison with the properties of the d(GpG) complexes. Molecular mechanics models of the adducts with duplex DNA show that the nonformation of one stereoisomer is consistent with the steric bulk of the tmdz ligand preventing closure from the monofunctional adduct to the bifunctional adduct. Enantioselectivity is also observed in that the R enantiomer forms more monofunctional adducts than bifunctional (59:41), whereas the S enantiomer forms more bifunctional adducts (27:73). The origins of this enantioselectivity must be at the level of monofunctional adduct formation and this has been investigated by molecular mechanics modelling.

Base Sequence↗