137 results for Denny, William, Journal article

  • Hypoxia-Activated Prodrugs: Substituent Effects on the Properties of Nitro seco-1,2,9,9a-Tetrahydrocyclopropa[c]benz[e]indol-4-one (nitroCBI) Prodrugs of DNA Minor Groove Alkylating Agents

    Tercel, Moana; Atwell, Graham; Yang, S; Stevenson, Ralph; Botting, KJ; Boyd, Maruta; Smith, E; Anderson, Robert; Denny, William; Wilson, William; Pruijn, Frederik (2009)

    Journal article
    The University of Auckland Library

    Nitrochloromethylbenzindolines (nitroCBIs) are a new class of hypoxia-activated prodrugs for antitumor therapy. The recently reported prototypes undergo hypoxia-selective metabolism to form potent DNA minor groove alkylating agents and are selectively toxic to some but not all hypoxic tumor cell lines. Here we report a series of 31 analogues that bear an extra electron-withdrawing substituent that serves to raise the one-electron reduction potential of the nitroCBI. We identify a subset of compounds, those with a basic side chain and sulfonamide or carboxamide substituent, that have consistently high hypoxic selectivity. The best of these, with a 7-sulfonamide substituent, displays hypoxic cytotoxicity ratios of 275 and 330 in Skov3 and HT29 human tumor cell lines, respectively. This compound (28) is efficiently and selectively metabolized to the corresponding aminoCBI, is selectively cytotoxic under hypoxia in all 11 cell lines examined, and demonstrates activity against hypoxic tumor cells in a human tumor xenograft in vivo.

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  • Aromatic lithiation directed by the carboxylic acid groups. Synthesis of 9-substituted dibenzodioxin-1-carboxylic acids and 6-substituted phenoxathiin-4-carboxylic acids

    Palmer, Brian; Boyd, Maruta; Denny, William (1990)

    Journal article
    The University of Auckland Library

    An efficient procedure has been developed for the regiospecific synthesis of 9-substituted dibenzo[ 1,4]diox- in-1-carboxylic acid derivatives. Lithiation of dibenzo[ 1,4]dioxin-l-carboxylic acid forms the lithium carboxylate, which directs subsequent metalation exclusively to the 9-position. Conditions for the controlled mono- and dilithiation of dibenzo[ 1,4]dioxin itself, leading to the direct synthesis of the corresponding mono- and isomeric dimethyl esters, are also described.

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  • Potential antitumor agents. 64. Synthesis and antitumor evaluation of dibenzo[1,4]dioxin-1-carboxamides: A new class of weakly binding DNA- intercalating agents

    Lee, Ho; Palmer, Brian; Boyd, Maruta; Baguley, Bruce; Denny, William (1992)

    Journal article
    The University of Auckland Library

    A series of substituted dibenzo[l,4]dioxin-l-carboxamides has been synthesized and evaluated for in vitro and in vivo antitumor activity. The required substituted dibenzo[ 1,4]dioxin-l-carboxylic acids were prepared by a variety of methods. No regiospecific syntheaea were available for many of these, and separation of the mixtures of regioisomers obtained was sometimes difficult. The dibenzo[l,4]dioxin-l-carboxamides are active against wild-type P388 leukemia in vitro and in vivo, with structureactivity relationships resembling those for both the acridine-4-carboxamide and phenazine-1-carboxamide series of DNA-intercalating antitumor agents. In all three series, substituents placed peri to the carboxamide sidechain (the 5-position in the acridines, and the 9-position in the phenazines and dibenzo- [ 1,4]dioxins) enhance activity and potency. The 9-chlorodibenzodioxin-1-carboxamide was also curative against the remotely sited Lewis lung carcinoma. Several of the compounds showed much lower levels of cross-resistance to the P388/AMSA line than classical DNA-intercalating agents, which suggests that their primary mechanism of action may not be via interference with topoisomerase IIa. This is of interest with regard to the development of drugs to combat resistance mechanisms which arise by the expression of the top0 IIj3 isozyme.

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  • Pyrazole analogues of the bispyrrolecarboxamide anti-tumour antibiotics: synthesis, DNA binding and anti-tumour properties.

    Lee, Ho; Boyd, Maruta; Gravatt, GL; Denny, William (1991-11)

    Journal article
    The University of Auckland Library

    Four bispyrazole compounds have been prepared as potentially more stable analogues of the DNA minor groove binding polypyrrole compounds netropsin and distamycin, which are susceptible to oxidative breakdown. These compounds bind less strongly to DNA, and show much lower specificity for binding to AT-rich DNA sequences in comparison with distamycin. N.m.r. studies show that two of these compounds cause a downfield shift of the DNA imino proton resonances on interaction with the oligonucleotide d(ATATATATAT)2, suggesting that these isomers can adopt low-energy conformations similar to that shown by distamycin in its DNA minor groove binding site. The benzoic acid mustard analogue of one of the minor groove binding bispyrazoles was prepared, and showed in vitro cytotoxicity comparable with that of the previously-reported distamycin mustard, but only a low level of activity in vivo.

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  • Novel pyrazolo[1,5-a]pyridines as p110??-selective PI3 kinase inhibitors: Exploring the benzenesulfonohydrazide SAR

    Kendall, Jackie; Giddens, Anna; Tsang, KY; Frederick, R; Marshall, ES; Singh, R; Lill, CL; Lee, Woo Jeong; Kolekar, Sharada; Chao, M; Malik, Alisha; Yu, S; Chaussade, C; Buchanan, Christina; Rewcastle, GW; Baguley, BC; Flanagan, Jack; Jamieson, Stephen; Denny, William; Shepherd, Peter (2012-01-01)

    Journal article
    The University of Auckland Library

    Structure???activity relationship studies of the pyrazolo[1,5-a]pyridine class of PI3 kinase inhibitors show that substitution off the hydrazone nitrogen and replacement of the sulfonyl both gave a loss of p110a selectivity, with the exception of an N-hydroxyethyl analogue. Limited substitutions were tolerated around the phenyl ring; in particular the 2,5-substitution pattern was important for PI3 kinase activity. The N-hydroxyethyl compound also showed good inhibition of cell proliferation and inhibition of phosphorylation of Akt/PKB, a downstream marker of PI3 kinase activity. It had suitable pharmacokinetics for evaluation in vivo, and showed tumour growth inhibition in two human tumour cell lines in xenograft studies. This work has provided suggestions for the design of more soluble analogues.

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  • Structure-activity relationships for amide-, carbamate-, and urea-linked analogues of the tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)

    Blaser, Adrian; Palmer, Brian; Sutherland, Hamish; Kmentova, I; Franzblau, SG; Wan, B; Wang, Y; Ma, Z; Thompson, Andrew; Denny, William (2012)

    Journal article
    The University of Auckland Library

    Analogues of clinical tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824), in which the OCH(2) linkage was replaced with amide, carbamate, and urea functionality, were investigated as an alternative approach to address oxidative metabolism, reduce lipophilicity, and improve aqueous solubility. Several soluble monoaryl examples displayed moderately improved (???2- to 4-fold) potencies against replicating Mycobacterium tuberculosis but were generally inferior inhibitors under anaerobic (nonreplicating) conditions. More lipophilic biaryl derivatives mostly displayed similar or reduced potencies to these in contrast to the parent biaryl series. The leading biaryl carbamate demonstrated exceptional metabolic stability and a 5-fold better efficacy than the parent drug in a mouse model of acute M. tuberculosis infection but was poorly soluble. Bioisosteric replacement of this biaryl moiety by arylpiperazine resulted in a soluble, orally bioavailable carbamate analogue providing identical activity in the acute model, comparable efficacy to OPC-67683 in a chronic infection model, favorable pharmacokinetic profiles across several species, and enhanced safety.

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  • The effect of sulfonate leaving groups on the hypoxia-selective toxicity of nitro analogs of the duocarmycins.

    Ashoorzadeh, Amir; Atwell, Graham; Pruijn, Frederik; Wilson, William; Tercel, Moana; Denny, William; Stevenson, Ralph (2011-08-15)

    Journal article
    The University of Auckland Library

    A series of 3-substituted (5-nitro-2,3-dihydro-1H-benzo[e]indol-1-yl)methyl sulfonate (nitroCBI) prodrugs containing sulfonate leaving groups undergo hypoxia-selective metabolism to form potent DNA minor groove alkylating agents. They were evaluated (along with chloride leaving group analogs for comparison) for their cytotoxicity against cultures of SKOV3 and HT29 human tumor cell lines under both aerobic and hypoxic conditions. Sulfonates with neutral side chains (e.g., 5,6,7-trimethoxyindole; TMI) show consistently higher hypoxic cytotoxicity ratios (HCRs) (34-246) than the corresponding chloro analogs (2.8-3.1) in SKOV3 cells, but these trends do not hold for compounds with cationic or polar neutral side chains.

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  • Morpholylureas are a new class of potent and selective inhibitors of the type 5 17-??-hydroxysteroid dehydrogenase (AKR1C3)

    Flanagan, Jack; Atwell, GJ; Heinrich, DM; Brooke, DG; Silva, S; Rigoreau, LJM; Trivier, E; Turnbull, AP; Raynham, T; Jamieson, Stephen; Denny, William (2014-02-01)

    Journal article
    The University of Auckland Library

    Inhibitors of the aldo-keto reductase enzyme AKR1C3 are of interest as potential drugs for leukemia and hormone-related cancers. A series of non-carboxylate morpholino(phenylpiperazin-1-yl)methanones were prepared by palladium-catalysed coupling of substituted phenyl or pyridyl bromides with the known morpholino(piperazin-1-yl)methanone, and shown to be potent (IC50???100nM) and very isoform-selective inhibitors of AKR1C3. Lipophilic electron-withdrawing substituents on the phenyl ring were positive for activity, as was an H-bond acceptor on the other terminal ring, and the ketone moiety (as a urea) was essential. These structure-activity relationships are consistent with an X-ray structure of a representative compound bound in the AKR1C3 active site, which showed H-bonding between the carbonyl oxygen of the drug and Tyr55 and His117 in the 'oxyanion hole' of the enzyme, with the piperazine bridging unit providing the correct twist to allow the terminal benzene ring to occupy the lipophilic pocket and align with Phe311.

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  • Synthesis, DNA interactions and biological activity of DNA minor groove targeted polybenzamide-linked nitrogen mustards

    Atwell, Graham; Yaghi, BM; Turner, PR; Boyd, Maruta; O'Connor, Charmian; Ferguson, Lynnette; Baguley, Bruce; Denny, William (1995)

    Journal article
    The University of Auckland Library

    A series of polybenzamide DNA minor groove binding ligands bearing either one or two monofunctional mustards have been synthesised, and their cytotoxicities and interactions with DNA have been studied. Analogues with two alkylating functions (e.g. compounds 7 and 14) are the most cytotoxic, with 7 being 1000-fold more potent than the clinical mustard chlorambucil against P388 leukemia in culture, as well as being more potent in vivo. Monofunctional analogues were also significantly more cytotoxic than chlorambucil, despite bearing much less reactive mustard species. These results support the concept that targeting nitrogen mustard alkylating agents to DNA by attachment to DNA-affinic carriers can greatly enhance cytotoxicity due to alkylation, and that even for such DNA-targeted mustards, crosslinking is a more toxic event than monoalkylation. Close analogues of 7 differing only in their radius of curvature, appear to alkylate and crosslink DNA in similar fashion, yet have widely differing cytotoxicities. The most cytotoxic compound (7) possesses a geometry most complementary to that of duplex DNA, suggesting that the most toxic lesions are those which result in least DNA distortion, thus being less easily recognised by DNA repair systems.

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  • Structure-activity relationships for 1-phenylbenzimidazoles as selective ATP site inhibitors of the platelet-derived growth factor receptor.

    Palmer, Brian; Smaill, Jeffrey; Boyd, Maruta; Boschelli, DH; Doherty, AM; Hamby, JM; Khatana, SS; Kramer, JB; Kraker, AJ; Panek, RL; Lu, GH; Dahring, TK; Winters, RT; Showalter, HD; Denny, William (1998)

    Journal article
    The University of Auckland Library

    1-Phenylbenzimidazoles are shown to be a new class of ATP-site inhibitors of the platelet-derived growth factor receptor (PDGFR). Structure???activity relationships (SARs) are narrow, with closely related heterocycles being inactive. A systematic study of substituted 1-phenylbenzimidazoles showed clear SARs. Substituents at the 4???- and 3???-positions of the phenyl ring are tolerated but do not significantly improve activity, while substituents at the 2???-position abolish it. Substituents in the 2-, 4-, and 7-positions of the benzimidazole ring (with the exception of 4-OH) also abolish activity. Most substituents at the 5- and 6-positions maintain or increase activity, with the 5-OH, 5-OMe, 5-COMe, and 5-CO2Me analogues being >10-fold more potent than the parent 1-phenylbenzimidazole. The 5-OMe analogue was both the most potent inhibitor, and showed the highest selectivity (50-fold) between PDGFR and FGFR isolated enzymes, and also a moderately effective inhibitor (IC50 = 1.9 ??M) of PDGF-stimulated PDGFR autophosphorylation in rat aorta smooth muscle cells.

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  • NMR Studies of configuration and tautomeric equilibria in nitroacridine antitumor agents

    Boyd, Maruta; Denny, William (1990)

    Journal article
    The University of Auckland Library

    The solution configurations of the 1-nitroacridine nitracrine (a clinically used anticancer agent and experimental hypoxia-selective cytotoxin) and its nitro isomers were determined, as both free bases in CDC& and as monocations (chromophore free base) and dications in D20, by high-resolution proton magnetic resonance spectroscopy. The free bases of the 1-, 2-, and 3-nitro isomers exist in the aminoacridine configuration in CDCl,, while the 4-nitro isomer appears to exchange slowly between the aminoacridine and iminoacridan configurations. As cations at pH 2 in DzO, all four isomers exist in the aminoacridine configuration. When the pH is increased to 7-8 to form the free bases of the nitroacridine chromophores, the 2- and 3-nitro isomers retain the aminoacridine configuration, but the 1- and 4-nitro isomers convert to the iminoacridan configuration. These results are relevant to the ongoing discussion of aminoacridine-iminoacridan tautomerism of these acridine derivatives in solution.

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  • Relationships between nitro group reduction potentials and torsion angles in di-ortho-substituted nitrobenzenes; a crystallographic and oxygen-17 NMR study

    Boyd, Maruta; Lee, Ho; Anderson, Robert; Denny, William (1994)

    Journal article
    The University of Auckland Library

    A series of 3-nitro-4-alkylbenzamides has been prepared, and the effects of nitro group torsion angle on reduction potential studied. Nitro and carboxamide group torsion angles have been determined by 17O NMR spectroscopy and X-ray crystallography, and one-electron reduction potentials by pulse radiolysis. 17O Chemical shifts indicated similar amide torsion angles (from 35?? to 45??) as the alkyl group varied from hydrogen to tert-butyl, but widely differing nitro group torsion angles; from 36??(hydrogen) to 92??(tert-butyl). Crystal structures of the isopropyl and tert-butyl derivatives indicate amide group torsion angles (50?? and 64??) somewhat larger than those predicted by 17O NMR, and nitro group torsion angles (59?? and 65?? respectively) considerably smaller than those predicted by 17O NMR (75?? and 92?? respectively). These results support earlier data that 17O chemical shifts predict for erroneously large nitro group torsion angles in non-rigid but sterically crowded molecules, because of additional contributions to the shift from van der Waals repulsions. The drop in reduction potential of 90 mV between the unsubstituted and tert-butyl derivatives is too large to be accounted for by the electronic effects of the alkyl groups, and indicates that increasing the nitro group torsion angle significantly lowers reduction potential.

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  • Evaluation of a crystalline nanosuspension: polymorphism, process induced transformation and in vivo studies.

    Sharma, P; Zujovic, ZD; Bowmaker, Graham; Marshall, Andrew; Denny, William; Garg, Sanjay (2011-04-15)

    Journal article
    The University of Auckland Library

    The aim of this work was to evaluate a crystalline nanosuspension of an investigational anticancer compound, SN 30191. Solid forms of SN 30191 were prepared and characterized by thermal analysis, infrared spectroscopy, ????C CP/MAS SSNMR spectroscopy, SEM and powder XRD. Wet milling was performed using a high pressure homogenizer and process induced transformations were studied as a function of time and pressure using infrared spectroscopy. Dose-toxicity and pharmacokinetics (PK) of the nanocrystal formulation were evaluated in mice after intravenous administration. SN 30191 was found to exist in two polymorphic forms (I and II) and a hydrate with an equilibrium solubility < 0.1 ??g/ml (pH 1.3-11.0, 37 ??C). Wet milling resulted in solid state transformation as a function of pressure. Form II was found to transform into form I at intermediate pressures. A further increase in pressure resulted in formation of a hydrate. The final nanosuspension consisted of SN 30191 as a hydrate. The dose-toxicity studies revealed higher tolerance (~4 times) for the nanosuspension (10 mg/kg) when compared with a solution formulation (2.5 mg/kg). Compared with solution formulation, the nanosuspension allowed the delivery of a higher dose and rendered possible the performance of PK and tissue distribution studies in animals.

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  • Genotoxicity of non-covalent interactions: DNA intercalators

    Ferguson, Lynnette; Denny, William (2007)

    Journal article
    The University of Auckland Library

    This review provides an update on the mutagenicity of intercalating chemicals, as carried out over the last 17 years. The most extensively studied DNA intercalating agents are acridine and its derivatives, that bind reversibly but non-covalently to DNA. These are frameshift mutagens, especially in bacteria and bacteriophage, but do not otherwise show a wide range of mutagenic properties. Di-acridines or di-quinolines may be either mono- or bis-intercalators, depending upon the length of the alkyl chain separating the chromophores. Those which monointercalate appear as either weak frameshift mutagens in bacteria, or as non-mutagens. However, some of the bisintercalators act as ???petite??? mutagens in Saccharomyces cerevisiae, suggesting that they may be more likely to target mitochondrial as compared with nuclear DNA. Some of the new methodologies for detecting intercalation suggest this may be a property of a wider range of chemicals than previously recognised. For example, quite a number of flavonoids appear to intercalate into DNA. However, their mutagenic properties may be dominated by the fact that many of them are also able to inhibit topoisomerase II enzymes, and this property implies that they will be potent recombinogens and clastogens. DNA intercalation may serve to position other, chemically reactive molecules, in specific ways on the DNA, leading to a distinctive (and wider) range of mutagenic properties, and possible carcinogenic potential.

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  • Hypoxia-Selective 3-Alkyl 1,2,4-Benzotriazine 1,4-Dioxides: The Influence of Hydrogen Bond Donors on Extravascular Transport and Antitumor Activity

    Hay, Michael; Pchalek, Karin; Pruijn, Frederik; Hicks, Kevin; Siim, Bronwyn; Anderson, Robert; Shinde, Sujata; Phillips, Victoria; Denny, William; Wilson, William (2007)

    Journal article
    The University of Auckland Library

    Tirapazamine (TPZ) and related 1,2,4-benzotriazine 1,4 dioxides (BTOs) are selectively toxic under hypoxia, but their ability to kill hypoxic cells in tumors is generally limited by their poor extravascular transport. Here we show that removing hydrogen bond donors by replacing the 3-NH2 group of TPZ with simple alkyl groups increased their tissue diffusion coef???cients as measured in multicellular layer cultures. This advantage was largely retained using solubilizing 3-alkylaminoalkyl substituents provided these were suf???ciently lipophilic at pH 7.4. The high reduction potentials of such compounds resulted in rates of metabolism too high for optimal penetration into hypoxic tissue, but electron-donating 6- and 7-substituents moderated metabolism. Pharmacokinetic/pharmacodynamic model-guided screening was used to select BTOs with optimal extravascular transport and hypoxic cytotoxicity properties for evaluation against HT29 human tumor xenografts in combination with radiation. This identi???ed four novel 3-alkyl BTOs providing greater clonogenic killing of hypoxic cells than TPZ at equivalent host toxicity, with the 6-morpholinopropyloxyBTO 22 being 3-fold more active.

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  • Pharmacokinetic/pharmacodynamic modeling identifies SN30000 and SN29751 as tirapazamine analogues with improved tissue penetration and hypoxic cell killing in tumors.

    Hicks, Kevin; Siim, BG; Jaiswal, Jagdish; Pruijn, Frederik; Fraser, AM; Patel, R; Hogg, A; Liyanage, HD; Dorie, MJ; Brown, JM; Denny, William; Hay, Michael; Wilson, William (2010-10)

    Journal article
    The University of Auckland Library

    Tirapazamine (TPZ) has attractive features for targeting hypoxic cells in tumors but has limited clinical activity, in part because of poor extravascular penetration. Here, we identify improved TPZ analogues by using a spatially resolved pharmacokinetic/pharmacodynamic (SR-PKPD) model that considers tissue penetration explicitly during lead optimization.

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  • Selective treatment of hypoxic tumor cells in vivo: phosphate pre-prodrugs of nitro analogues of the duocarmycins.

    Tercel, Moana; Atwell, Graham; Yang, S; Ashoorzadeh, Amir; Stevenson, Ralph; Botting, KJ; Gu, Yongchuan; Mehta, Sunali; Denny, William; Wilson, William; Pruijn, Frederik (2011-03-07)

    Journal article
    The University of Auckland Library

    Hitting the hypoxic target: Combining a nitro prodrug with a water-soluble phosphate converts duocarmycin analogues from highly toxic DNA-alkylating agents to highly selective antitumor compounds. These prodrugs (see scheme) have outstanding activity against hypoxic tumor cells in???vivo, cells which are usually considered the most resistant to conventional therapy.

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  • Structure of 3-methoxycarbonyl-1-methyl-4-nitropyrazole-5-carboxylic acid monohydrate

    Boyd, Maruta; Atwell, Graham; Denny, William (1993-08-15)

    Journal article
    The University of Auckland Library

    C7H7N3O6.H2O, M(r) = 247.16, orthorhombic, Fdd2, a = 31.535 (8), b = 14,313 (5), c = 9.446 (3) angstrom, Z = 16, V = 4263.6 angstrom3, D(x) = 1.54 g cm-3, lambda(Mo Kalpha) = 0.71069 angstrom, mu = 1.31 cm-1 F(000) = 2048, room temperature, final R = 0.0368 for 1223 observed reflections. The pyrazole ring is planar. The methoxycarbonyl, nitro and acid groups make angles of 8.1, 74.5 and 16.7-degrees, respectively, with the pyrazole ring. The water of crystallization forms strong hydrogen bonds with the acid proton of one molecule and the unsubstituted pyrazole N atom of a symmetry-related molecule.

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  • Inhibition of the pore-forming protein perforin by a series of aryl-substituted isobenzofuran-1(3H)-ones

    Spicer, Julie; Huttunen, KM; Miller, Christian; Denny, William; Ciccone, A; Browne, KA; Trapani, JA (2011-12-22)

    Journal article
    The University of Auckland Library

    An aryl-substituted isobenzofuran-1(3H)-one lead compound was identified from a high throughput screen designed to find inhibitors of the lymphocyte pore-forming protein perforin. A series of analogs were then designed and prepared, exploring structure???activity relationships through variation of 2-thioxoimidazolidin-4-one and furan subunits on an isobenzofuranone core. The ability of the resulting compounds to inhibit the lytic activity of both isolated perforin protein and perforin delivered in situ by intact KHYG-1 natural killer effector cells was determined. Several compounds showed excellent activity at concentrations that were non-toxic to the killer cells. This series represents a significant improvement on previous classes of compounds, being substantially more potent and largely retaining activity in the presence of serum.

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  • Spin Trapping of Radicals Other Than the (OH)-O-center dot Radical upon Reduction of the Anticancer Agent Tirapazamine by Cytochrome P-450 Reductase

    Shinde, Sujata; Hay, Michael; Patterson, Adam; Denny, William; Anderson, Robert (2009-10-14)

    Journal article
    The University of Auckland Library

    The radical species produced following one-electron reduction of tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide, TPZ) by cytochrome P-450 reductase-enriched microsomes have been investigated using electron paramagnetic resonance (EPR) spectroscopy. Spin trapping with 5,5'-dimethylpyrroline 1-N-oxide (DMPO) gave a composite spectrum of a carbon-centered radical and the well-known DMPO-OH adduct. Using O-17-tabeted water resulted in a change in the EPR spectrum to that of DMPO-(OH)-O-17, indicating that this radical species is formed with solvent involvement and not from release of a (OH)-O-center dot radical from one-electron-reduced TPZ. Furthermore, using the closely related spin trap 5-diethoxyphosphoryl-5-methylpyrroline N-oxide (DEPMPO), which is less prone to oxidation than DMPO, gave only a carbon-centered radical spectrum without any involvement of a (OH)-O-center dot radical. Reduction of a more soluble analogue of TPZ, in redox: equilibrium with its 1-oxide derivative, led to spin trapping of both a carbon-centered radical and a nitrogen centered radical by N-tert-butyl-alpha-phenylnitrone (PBN). The multicentered nature of this nitrogen-centered radical spectrum provides support for the formation of a benzotriazinyl radical following one-electron reduction of this class of bioreductive drug.

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