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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
PubMed2007

Studies of a cobalt(III) complex of the MMP inhibitor marimastat: a potential hypoxia-activated prodrug.

We report a potential means of selectively delivering matrix metalloproteinase (MMP) inhibitors to target tumour sites by use of a bioreductively activated Co(III) carrier system. The carrier, comprising a Co(III) complex of the tripodal ligand tris(methylpyridyl)amine (tpa), was investigated with the antimetastatic MMP inhibitor marimastat (mmstH(2)). The X-ray crystal structure of [Co(mmst)(tpa)]ClO(4) x 4H(2)O was determined and two-dimensional NMR revealed the existence of two isomeric forms of the complex in solution. Electrochemical analysis showed that the reduction potential of the complex is suitable for it to be bioreductively activated at hypoxic tumour sites. In vitro assays confirmed the stability of the prodrug in solution prior to reduction and revealed very low cytotoxicity against A2780 cells. In vivo testing in mice showed a higher level of tumour-growth inhibition by the complex than by free marimastat. Both free marimastat and and its Co(III) complex increased metastasis in the model used, with the complex significantly more active.

Amines↗
PubMed2006

Towards bioreductively activated prodrugs: Fe(III) complexes of hydroxamic acids and the MMP inhibitor marimastat.

Fe(III)-salen (N,N-bis(salicylidene)-ethane-1,2-diimine) complexes of simple hydroxamic acids and the MMP (matrix metalloproteinase) inhibitor marimastat have been evaluated as hypoxia activated drug carriers. The aceto- (aha), propion- (pha), benzohydroxamato (bha), and marimastat complexes were prepared and characterised by single crystal X-ray diffraction and electrochemical analysis. The hydroxamato ligands form a bidentate chelate to Fe(III) with the remaining octahedral coordination sites occupied by the tetradentate salen ligand. Bonding of the hydroxamato ligands is in the typical motif of the majority of Fe(III) complexes in the literature. The reduction potentials of the complexes are of the order of -1300 mV (vs ferrocene/ferrocenium) and show partial reversibility in the re-oxidation waveforms of the cyclic voltammetry scans. This suggests that the Fe-salen carrier system would provide a suitably redox inert framework yet would release the ligands at hypoxic tumour sites upon reduction to the more labile Fe(II) oxidation state. Furthermore, biological testing of the marimastat complex established that these carriers are stable in non-reducing biological environments and would serve to deliver MMP inhibitors to tumour sites intact.

Antineoplastic Agents↗
PubMed2006

DNA-binding and molecular mechanics modelling studies of the bulky chiral platinum(II) complex [PtCl(2)(mepyrr)] (mepyrr=N-methyl-2-aminomethylpyrrolidine).

Detailed studies were carried out on the binding of the enantiomers of [PtCl(2)(mepyrr)] (mepyrr=N-methyl-2-aminomethylpyrrolidine) to dG, d(GpG) and a 52-mer oligonucleotide. The pyrrolidine ligand structure was found to be neither sufficiently rigid nor bulky to enforce a single chirality at the exocyclic amine site in this complex, resulting in the presence of diastereomers that complicated the binding studies. Reaction of the (GpG) dinucleotide with R- and S-[PtCl(2)(mepyrr)] resulted in formation of four [Pt{d(GpG)}(mepyrr)] isomers for each enantiomer as a consequence of the existence of two orientational isomers and two diastereomers. These isomers formed in different amounts most likely as a consequence of the unequal formation of the diastereomers together with stereoselectivity induced by interactions between the dinucleotide and the mepyrr ligand. The [PtCl(2)(mepyrr)] complexes displayed stereoselectivity and enantioselectivity in their reactions with a 52-mer duplex designed to allow formation of only GpG intrastrand adducts. All four bifunctional adducts formed for each enantiomer, providing further evidence of the lack of directing ability of the ligand in formation of the 1,2-intrastrand adduct. Significant amounts of monofunctional species remained in these assays suggesting that the introduction of the methyl substituent to the exocyclic amine inhibited ring-closure to the bifunctional adduct. This was not sufficient to achieve enantiospecificity, but in the case of the R-enantiomer, one of the bifunctional adducts formed in only small amounts.

Base Sequence↗
PubMed2006

Platinum(IV) analogues of AMD473 (cis-[PtCl2(NH3)(2-picoline)]): preparative, structural, and electrochemical studies.

The preparation and oxidation of the anticancer drug AMD473, cis-[PtCl2(NH3)(2-pic)] (2-pic = 2-methylpyridine), has been investigated. cis-[PtCl2(NH3)(2-pic)] is readily oxidized with peroxide to give the trans-dihydroxoplatinum(IV) complex cis,trans,cis-[PtCl2(OH)2(NH3)(2-pic)]. The crystal structure of this complex reveals that it is highly strained as a result of a steric clash between the methyl group of the 2-picoline ligand and an axial hydroxo ligand, with the Pt-N-C angle adjacent to this clash opened up to an unprecedented 138.6(6) degrees . Attempts at converting the dihydroxoplatinum(IV) complex to dichloro and diacetato analogues were unsuccessful with reaction with HCl leading to loss and protonation of the 2-picoline ligand to form the salt (2-picH)[PtCl5(NH3)] and the platinum(II) complex cis-[PtCl2(NH3)(2-pic)], both confirmed by crystallography. Electrochemical studies revealed that cis,trans,cis-[PtCl2(OH)2(NH3)(2-pic)] is reduced more readily (-714 mV vs Ag/AgCl) than its pyridine analogue cis,trans,cis-[PtCl2(OH)2(NH3)(pyridine)] (-770 mV vs Ag/AgCl) consistent with the steric clash in the former complex destabilizing the platinum(IV) oxidation state.

Electrochemistry↗
PubMed2006

The fate of platinum(II) and platinum(IV) anti-cancer agents in cancer cells and tumours.

SRIXE mapping has been used to gain insight into the fate of platinum(II) and platinum(IV) complexes in cells and tumours treated with anticancer active complexes to facilitate the development of improved drugs. SRIXE maps were collected of thin sections of human ovarian (A2780) cancer cells treated with bromine containing platinum complexes, cis-[PtCl(2)(3-Brpyr)(NH(3))] (3-Brpyr=3-bromopyridine) and cis,trans,cis-[PtCl(2)(OAcBr)(2)(NH(3))(2)] (OAcBr=bromoacetate), or a platinum complex with an intercalator attached cis-[PtCl(2)(2-[(3-aminopropyl)amino]-9,10-anthracenedione)(NH(3))]. After 24h the complexes appear to be localised in the cell nucleus with a lower concentration in the surrounding cytoplasm. In cells treated with cis-[PtCl(2)(3-Brpyr)(NH(3))] the concentration of bromine was substantially higher than in control cells and the bromine was co-localised with the platinum consistent with the 3-bromopyridine ligand remaining bound to the platinum. The cells treated with cis,trans,cis-[PtCl(2)(OAcBr)(2)(NH(3))(2)] also showed an increased level of bromine, but to a much lesser extent than for those treated with cis-[PtCl(2)(3-Brpyr)(NH(3))] suggestive of substantial reduction of the platinum(IV) complex. Maps were also collected from thin sections of a 4T1.2 neo 1 mammary tumour xenograft removed from a mouse 3h after treatment with cis,trans,cis-[PtCl(2)(OH)(2)(NH(3))(2)] and revealed selective uptake of platinum by one cell.

Animals↗
PubMed2006

XANES investigation of the Co oxidation state in solution and in cancer cells treated with Co(III) complexes.

XANES spectroscopy has been used to investigate whether it is possible to determine the oxidation state and coordination environment of Co complexes following treatment of cancer cells with Co(III) or Co(II) complexes. Our results show that the variation of the XANES with coordination geometry make it impossible to do this in a completely reliable way which is in contrast to the situation for platinum and chromium. It was established that the XANES spectrum obtained from cells treated with [Co(diNOsar)]Br(3) remained unchanged with respect to its XANES spectrum obtained in solution, demonstrating that the [Co(diNOsar)]Br(3) complex remained intact after 24h in cellular media (diNOsar=1,8-dinitro-3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane). In contrast, the XANES spectra obtained from cells treated with Na[Co(acac)(3)] and [Co(acac)(3)] differed from the XANES spectra of the respective complexes obtained in solution, indicating a change in co-ordination environment for both complexes upon uptake in cells. The similarity of these spectra suggests that appearance of this XANES can be used as an indication of loss of the carrier ligands, a useful indicator in the study of hypoxia selective complexes. The results obtained for Na[Co(acac)(3)] and [Co(acac)(3)] are consistent with the intracellular coordination of cobalt(III) to sulfur ligands upon cellular uptake.

Cobalt↗
PubMed2006

Models of hypoxia activated prodrugs: Co(III) complexes of hydroxamic acids.

Co(III) complexes of simple hydroxamic acids have been evaluated as models of hypoxia activated prodrugs containing MMP inhibitors. The complexes are based upon a proposed carrier system comprising the tripodal tetradentate ligand tris(2-methylpyridyl)amine (tpa) with the hydroxamate functionality occupying the remaining coordination sites of the Co centre. Acetohydroxamato (aha), propionhydroxamato (pha), and benzohydroxamato (bha) complexes were synthesised and characterised by single crystal X-ray diffraction. For aha and pha both the hydroxamato and hydroximato (deprotonated) forms were obtained and were readily interconverted by pH manipulation; for bha only the hydroximato complex was obtained as a stable species. Electrochemical analysis was used to probe the redox chemistry of the complexes and assess their ease of reduction. All of the complexes displayed irreversible reduction and had low cathodic peak potentials. This suggests that the Co-tpa carrier system would provide a suitably inert framework to deliver the drugs to target sites intact yet would release the ligands upon reduction to the more labile Co(II) oxidation state.

Cobalt↗
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↗