138 results for Denny, William, Journal article

  • Crystallographic and oxygen-17 NMR studies of nitro group torsion angles in a series of 4-alkylaminonitroquinolines designed as hypoxia-selective cytotoxins

    Boyd, Maruta; Boyd, Peter; Atwell, Graham; Wilson, William; Denny, William (1992)

    Journal article
    The University of Auckland Library

    Nitro group torsion angles have been determined by 17O NMR spectroscopy for a series of 4-(alkyl-amino)nitroquinolines and their ortho-methyl-substituted analogues. Crystal structures were determined for two pairs of compounds, to further evaluate the validity of Boykin's equation. The crystallographic torsion angles were used to calculate a modified version of the equation, relating 17O chemical shift values (??) and nitro group torsion angles (??), applicable to N-heterocyclic systems, as follows: ??= 1.18(??0.13)????? 661. This equation was then used to compute nitro group torsion angles for the nitroquinolines. Unhindered nitro groups were close to coplanar with the aromatic ring as expected, while addition of one ortho methyl group increased the torsion angle to ca. 30??. The 5-nitro derivative had a nitro group torsion angle of ca. 80??, due to peri interactions with the 4-aminoalkyl sidechain. The 8-nitroquinoline derivative is the first example of a nitroaromatic with a peri aromatic nitrogen substituent, and the torsion angle of 70???78??(measured by both NMR spectroscopy and X-ray crystallography) indicates the substantial steric effect of the nitrogen lone pair. Addition of a 7-methyl group in the other nitro ortho position of this compound results in the nitro group being virtually at right angles to the ring (torsion angle 86??). A comparison was made between the measured torsion angles and those calculated using the AM1 and PM3 methods. The former underestimates the nitro torsion angles in these systems, while the PM3 method significantly overestimates them. Overall, no simple relationship exists in the nitroquinolines between nitro group torsion angles and the reduction potentials of the compounds.

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  • A 2D hydrogen-bonded network constructed from large organic dications

    Holmes, RJ; Abrahams, BF; Murray, V; Denny, William; McFadyen, WD (2010-06-30)

    Journal article
    The University of Auckland Library

    The crystal structure determination of N,N???-Bis-(2-aminoethyl)-phenazine-1,6-dicarboxamide dihydrochloride dihydrate reveals an essentially planar dication. A pair of ammonium groups tethered to the phenazine group in the 1 and 6 positions through alkyl amide links, act as hydrogen-bond donors to amide oxygen atoms of symmetry-related neighbouring dications. With each dication molecule having two hydrogen-bond donors and acceptors, an undulating 2D network is formed. The chloride ions, lying within the network voids, associate with the ammonium groups and pairs of water molecules. The network topology appears to be largely governed by cation???cation hydrogen-bonds, ionic associations involving the chloride ions and ???????-stacking interactions.

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  • Inhibition of the cellular function of perforin by 1-amino-2,4- dicyanopyrido[1,2-a]benzimidazoles

    Lyons, DM; Huttunen, KM; Browne, KA; Ciccone, A; Trapani, JA; Denny, William; Spicer, JA (2011)

    Journal article
    The University of Auckland Library

    A high throughput screen showed the ability of a 1-amino-2,4-dicyanopyrido[1,2-a]benzimidazole analogue to directly inhibit the lytic activity of the pore-forming protein perforin. A series of analogues were prepared to study structure???activity relationships (SAR) for the this activity, either directly added to cells or released in situ by KHYG-1 NK cells, at non-toxic concentrations. These studies showed that the pyridobenzimidazole moiety was required for effective activity, with strongly basic centres disfavoured. This class of compounds was relatively unaffected by the addition of serum, which was not the case for a previous class of direct inhibitors.

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  • Inhibitors of phosphatidylinositol 3-kinases; the next wave of anti-cancer drugs?

    Rewcastle, Gordon; Denny, William (2009)

    Journal article
    The University of Auckland Library

    Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinase enzymes, which catalyse the phosphorylation of the 3???-hydroxyl position of the inositol ring of phosphatidylinositol 4,5-diphosphate (PIP 2 ) to give the messenger molecule phosphatidylinositol 3,4,5-triphosphate (PIP 3 ) (Scheme 1). This then participates in a variety of physiological processes, including cell growth and differentiation. 1 The PI3Ks are divided into three classes (I-III) based on their structure, mode of regulation, and substrate speci???city. ...

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  • Frameshift mutations induced by four isomeric nitroacridines and their des-nitro counterpart in the lacZ reversion assay in Escherichia coli

    Hoffmann, GR; Yin, CR; Terry, CE; Ferguson, LR; Denny, William (2006)

    Journal article
    The University of Auckland Library

    Acridines are well-known as compounds that intercalate noncovalently between DNA base pairs and induce ??1 frameshift mutations at sites of monotonous repeats of a single base. Reactive derivatives of acridines, including acridine mustards and nitroacridines, form covalent adducts in DNA and exhibit mutagenic properties different from the simple intercalators. We compared the frameshift mutagenicity of the cancer chemotherapy drug nitracrine (1-nitro-9-(3???-dimethylaminopropylamino)-acridine), its des-nitro counterpart 9-(3???-dimethylaminopropylamino)-acridine (DAPA), and its 2-, 3-, and 4-nitro isomers (2-, 3-, and 4-nitro-DAPA) in the lacZ reversion assay in Escherichia coli. DAPA is a simple intercalator, much like the widely studied 9-aminoacridine. It most strongly induced ??1 frameshift mutations in runs of guanine residues and more weakly induced ???1 frameshifts in a run of adenine residues. A nitro group in the 1, 3, or 4 position of DAPA reduced the yield of ??1 frameshift mutations. DAPA weakly induced ???2 frameshifts in an alternating CG sequence. In contrast, nitracrine and its 3-nitro isomer resembled the 3-nitroacridine Entozon in effectively inducing ???2 frameshift mutations. The 2- and 4-nitro isomers were less effective than the 1- and 3-nitro compounds in ???2 frameshift mutagenesis. The results are interpreted with respect to intercalation, steric interactions, effects of base strength on DNA binding, enzymatic processing, and a slipped mispairing model of frameshift mutagenesis.

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  • Therapeutic reactivation of mutant p53 protein by quinazoline derivatives

    Sutherland, Hamish; Hwang, IY; Marshall, ES; Lindsay, BS; Denny, William; Gilchrist, Catherine; Joseph, Wayne; Greenhalgh, D; Richardson, E; Kestell, P; Ding, A; Baguley, Bruce (2011)

    Journal article
    The University of Auckland Library

    Purpose The human tumour suppressor protein p53 is mutated in nearly half of human tumours and most mutant proteins have single amino acid changes. Several drugs including the quinazoline derivative 1 (CP-31398) have been reported to restore p53 activity in mutant cells. The side chain of 1 contains a styryl linkage that compromises its stability and we wished to explore the activity of analogues containing more stable side chains. Methods Reactivation of p53 function was measured by flow cytometry as the ability to potentiate radiation-induced G1-phase cell cycle arrest and by western blotting to determine expression of p21WAF1. DNA binding was measured by competition with ethidium and preliminary pharmacological and xenograft studies were carried out. Results Screening of analogues for potentiation of radiation-induced G1-phase cell cycle arrest using NZOV11, an ovarian tumour cell line containing a p53R248Q mutation, demonstrated that the (2-benzofuranyl)-quinazoline derivative 5 was among the most active of the analogues. Compound 5 showed similar effects in several other p53 mutant human tumour cell lines but not in a p53 null cell line. 5 also potentiated p21WAF1 expression induced by radiation. DNA binding affinity was measured and found to correlate with p53 reactivation activity. Plasma concentrations of 5 in mice were sufficient to suggest in vivo activity and a small induced tumour growth delay (7 days) of NZM4 melanoma xenografts was observed. Conclusion Compound 5 restores p53-like function to a human tumour cells lines expressing a variety of mutant p53 proteins, thus providing a basis for the design of further new drugs.

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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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  • Facile dimerisation of 3-benzylideneindoline-2-thiones

    Thompson, Andrew; Boyd, Maruta; Denny, William (1993)

    Journal article
    The University of Auckland Library

    3-Benzylideneindoline-2-thione, formed by the condensation of indoline-2-thione with benzaldehyde, undergoes an unexpectedly facile [4 + 2] cycloaddition in solution to yield an unsymmetrical dimer 7. The structure of this dimer, elucidated by NMR spectroscopy and confirmed by X-ray crystallography, is described, and the mechanism and stereospecificity of this reaction is discussed.

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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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  • 2-[Bis(2-bromoethyl)amino]-N-(2-hydroxyethyl)-3,5-dinitrobenzamide .

    Atwell, Graham; Boyd, Peter; Denny, William; Yang, S (2006)

    Journal article
    The University of Auckland Library

    The title compound, C13H16Br2N4O6, is a dinitrobenzamide dibromo mustard. The tetrasubstituted benzene ring is significantly distorted from both planarity and ideal hexagonal symmetry. The molecules assemble in the crystal structure via hydrogen-bonding interactions between the amide groups on adjacent molecules, and by O-HO(nitro) and O-HBr contacts. There are short BrBr contacts (3.388 ??) that are significantly less than the sum of the van der Waals radii of two Br atoms.

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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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  • A Novel and simple method of screening compounds for DNA-interaction: a validation study

    Garas, A; Webb, E; McPhee, D; Denny, William; Zeller, H; Pillay, V; Cotton, R (2009)

    Journal article
    The University of Auckland Library

    We report the development of a simple, cost-effective assay for detecting compounds that have the ability to interact with and modify DNA. Potential uses for the assay lie in the areas of early genotoxicity testing of drug candidates, anticancer and antibiotic drug discovery, environmental monitoring and testing in the food, beverage and cosmetics industries. At present the assay has been used to assess direct-acting compounds only and it is yet to be established whether the assay is compatible with bio-activation. The methodology is based on the oxidative reaction of potassium permanganate with pyrimidine bases, which have become perturbed and more reactive by the agent under test. Results are recorded by use of UV/vis spectroscopy. The adaptation to a multi-well plate format provides the capacity for high throughput utilizing small amounts of compounds. Over 100 compounds, comprising different classes of DNA-binding chemicals as well as non-binding controls, have been put through the assay and the results compared with existing genotoxicity testing data from other methods. The assay has shown to be predictive of the results of other genotoxicity testing methods. We have found that the method is overall predictive of 71% of Ames bacterial reverse-mutation test results (where data are given) encompassing both negative and positive results.

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  • In the footsteps of Adrien Albert: chemotherapeutic drug development "down under"

    Denny, William (2007)

    Journal article
    The University of Auckland Library

    Adrien Albert is one of the greatest medicinal chemists of the mid-20th century whose role in the development of acridine-based antimalarial and anti-bacterial drugs during World War II is a marked event in the history of drug development. A brief survey of the work in the Auckland Cancer Society Research Centre (ACSRC) on acridines and related compounds as DNA-binding cancer drugs illustrates the common conclusions drawn from Adrien Albert's achievements.

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  • 1,4-bis[4-(1-pyridinium)styryl]benzene ditosylate

    Clark, George; Denny, William; Squire, Christopher (1999)

    Journal article
    The University of Auckland Library

    The crystal structure of the title compound (alternative name: 1, 1'-[p-phenylenebis(4-styryl)] dipyridinium ditosylate), C32H26N22+. 2C(7)H(7)O(3)S(-), provides an energy-minimum conformation which can be related to its DNA-binding properties.

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  • The 3-N-phenyl amide of all-cis-cyclopentane-1,2,3,4-tetracarboxylic acid as a potential pH-sensitive amine-releasing prodrug; intervention of imide formation around neutral pH.

    Billett, MG; Phillis, AG; Main, L; Nicholson, BK; Denny, William; Hay, Michael (2006)

    Journal article
    The University of Auckland Library

    To assess the potential utility of the new amide [(1S,2R,3R,4R)-3-(phenylaminocarbonyl)cyclopentane-1,2,4-tricarboxylic acid] (10) as a pH-sensitive amine-releasing prodrug aimed at selective activation at the low extracellular pH of solid tumours, its reactivity in D2O was studied between pD 5 and 6.5. Neighbouring group catalysis of amide hydrolysis by unionised carboxylic acid groups was expected up to neutral pH, with this decreasing with increasing levels of ionisation. Rate measurements on 10 in D2O by UV at 27 o C gave k1 7.3 x 10 -5 s -1 (half-life ca 2.5 h) at pD 5.02 and 3.0 x 10 -5 s -1 (half-life ca 6.5 h) at pD 6.53. However, NMR monitoring of 10 in D2O showed that at pD 5 and above, formation of the 2,3- and 3,4-Nphenylimides of cyclopentane-1,2,3,4-tetracarboxylic acid (13 and 16) unexpectedly predominates over amide hydrolysis, thwarting the potential prodrug application. The rates together with variations in the product ratios with pD show that the rate of formation of 13 from 10 is only marginally reduced between pD 5 and 6.5 while the rates of formation of 16 and of hydrolysis products both decrease sharply. We report syntheses of 10 and the new imide 16, Xray crystal structure determinations of imides 13 and 16, as well as NMR data for their solutions in D2O at different levels of ionization.

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  • Synthesis of asymmetric halomesylate mustards with aziridineethanol/alkali metal halides: application to an improved synthesis of the hypoxia prodrug PR-104

    Yang, SJ; Atwell, Graham; Denny, William (2007)

    Journal article
    The University of Auckland Library

    Aromatic asymmetric halomesylate mustards are efficiently prepared by reaction of activated aromatic chlorides with aziridineethanol/alkali metal halides, followed by mesylation of the haloalcohol. The reaction conditions are sufficiently mild to be compatible with a range of different substituents and protecting groups, including carboxylate and phosphate esters, and have been used in an improved synthesis of the anticancer bromomesylate mustard PR-104, now in clinical trials.

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  • Synthesis of 3H- and 2H4-labelled versions of the hypoxia-activated pre-prodrug 2-[(2-bromoethyl)-2,4-dinitro-6-[[[2-(phosphonooxy)ethyl]amino]carbonyl anilino]ethyl methanesulfonate (PR-104).

    Atwell, Graham; Denny, William (2007)

    Journal article
    The University of Auckland Library

    3H- and 2H4-versions of the hypoxia-activated pre-prodrug PR-104 [2-[(2-bromoethyl)-2,4-dinitro-6-[[[2-(phosphonooxy)ethyl]amino]carbonyl]anilino]ethyl methanesulfonate], labelled in the ethylcarboxamide side chain, have been prepared, respectively, by [3H]NaBH4 reduction of a precursor late stage aldehyde, and by late stage incorporation of deuterium with 2-amino[1,1,2,2-2H4]ethanol.

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  • 2-(1,4-Dioxo-1,4-dihydro-2-naphthyl)-2-methylpropanoic acid

    Dempster-Rivett, KJ; Main, L; Nicholson, BK; Denny, William (2007-11)

    Journal article
    The University of Auckland Library

    The sterically crowded title compound, C14H12O4, crystallizes as centrosymmetric hydrogen-bonded dimers involving the carboxyl groups. The naphthoquinone ring system is folded by 11.5 (1)?? about a vector joining the 1,4-C atoms, and the quinone O atoms are displaced from the ring plane, presumably because of steric interactions with the bulky substituent.

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  • 9,9a-Diphenyl-1,3,4,6,7,9a-hexahydro-2H-pyrazino[1,2-a]pyrimidine at 130 K.

    White, J; McFadyen, WD; Carland, M; Denny, William; Murray, V (2006)

    Journal article
    The University of Auckland Library

    The stereochemistry of the title compound, C19H21N3, has been confirmed by a single-crystal X-ray analysis. The bicyclic ring system adopts a cis-decalin-like conformation, which presumably minimizes steric repulsion involving the bridgehead phenyl substituent. The conformation of the amino group appears to be dictated by a nitrogen anomeric effect.

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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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