149 results for The University of Auckland Library, Denny, William

  • Deoxyribonucleic Acid Topoisomerase Inhibitors

    Denny, William (2007)

    Book item
    The University of Auckland Library

    Drugs that inhibit the action of topoisomerase enzymes (regulatory enzymes that catalyze the breakage and religation of DNA) are an important class of anticancer drugs. The drugs bind reversibly to form ternary drug/DNA/enzyme complexes that result in cytotoxic DNA breaks, primarily by preventing the relegation step. The drugs are usually classified by their spectrum of inhibition, as inhibitors of topo I, topo II, or of both enzymes (dual topo I/II inhibitors). The majority of the topo II and dual topo I/II inhibitors are DNA intercalators, where a flat polyaromatic drug chromophore intercalates between the base pairs, driven primarily by stacking and electrostatic interactions. There is also a substantial and diverse class of drugs with little direct DNA affinity but which nevertheless form ternary complexes. Inhibitors of topo I are primarily of the latter type, most being analogues of the natural product camptothecin. The major deficiencies of this class are the instability of the essential E ring lactone and the susceptibility of the drugs to cell efflux mechanisms, and the majority of the new analogues attempt to improve these. Inhibitors of topo II are mostly DNA intercalators, with the major deficiencies being cardiotoxicity and, again, susceptibility to cell efflux pumps. While the cardiotoxicity issue has been quite well addressed, many topo II drugs are still susceptible to transport-mediated resistance. There is evidence that some of the newer topo II inhibitors may act by additional mechanisms. Finally, the dual topo I/II inhibitors represent the newest class of topoisomerase-active drugs. While it is still not clear if such dual inhibition is an advantage, the class has considerable structural diversity, with some members inhibiting topoisomerase in a novel manner, and others suspected of working primarily by non-topoisomerase mechanisms.

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  • Pyrazolo[1,5-a]pyridines: alpha-isoform-selective inhibitors of phosphatidylinositol-3-kinase (PI3K)

    Denny, William; Kendall, JD; Flanagan, JU; Rewcastle, GW; Gamage, SA; Shepherd, PR; Baguley, BC; Kestell, P; Giddens, A; Tsang, S; Marshall, A (2009)

    Conference item
    The University of Auckland Library

    The Class 1A phosphatidylinositol 3-kinases (PI 3-kinases) operate downstream of receptor tyrosine kinases. By catalyzing the phosphorylation of PIP2 to PIP3 they recruit Akt to the membrane, where it is activated through phosphorylation at Thr308 by PDK1. They are comprised of a common p85 regulatory subunit and one of three catalytic subunits (p110??, -?? or -??). The p110?? and p110?? isoforms are ubiquitous, whereas the ?? isoform is predominantly expressed in leucocytes. The p110?? isoform is often over-expressed and/or mutated in tumors, making it a prime target for inhibitory drugs. A wide range of chemotypes have been shown as ATP site inhibitors of the class 1A PI 3-kinases, but the majority of these show little or only modest selectivity towards the p110?? isoform. This is also reflected by the initial series of PI 3-kinase inhibitors selected for clinical trial. In a search for more p110??-selective inhibitors, we explored structure-activity relationships around the known class of imidazo[1,2-a]pyridines, exemplified by the compound PIK-75 [(E)-N'-((6-bromoimidazo[1,2-a]pyridin-3-yl)methylene)-N,2-dimethyl-5-nitrobenzenesulfonohydrazide], which showed high potency for p110?? (IC50 12 nM) and good selectivity for p110?? over the other isoforms (25-fold over p110?? and 80-fold over p110??). An initial study of the heterocyclic unit showed generally tight structure-activity relationships (SAR), but discovered the superiority of the pyrazolo[1,5-a]pyridine chromophore. Studies of analogues of this demonstrated the desirability of small electron-withdrawing substituents at the 5-position for retaining both potency and selectivity. Replacements for the hydrogen bond accepting nitro group on the appended phenyl ring were also sought, with cyano and bromo proving most suitable. More soluble analogues could be prepared by placing weakly basic groups on either the sulfonohydrazide nitrogen or at the 2-position of the appended benzene ring. These compounds broadly retained potency against, and selectivity for, the p110?? isoform. Modelling studies showed that the key interactions stabilizing the compounds are H-bonds between the drug N-1 nitrogen atom and the backbone NH of Val-882, and between the nitro group on the arylsulfonyl moiety and the backbone NH of Asp-884 and Ala-885. The high selectivity for the p110?? isoform was explained using a p110?? homology model derived from the p110?? structure, which identified a hydrogen bond interaction between one of the oxygen atoms of the sulfonyl group and the NH of a histidine (His855) that is unique to the ?? isoform. Selected compounds were screened in a panel of established (OVCAR3 ovarian, HCT116 colon, H460 lung) and early-passage human melanoma cell lines, typed for PI 3-kinase E545K and H1047R mutations and PTEN, p53 and BRAF expression. Cell lines with similar genetic backgrounds showed broadly similar sensitivities to the compounds. The pyrazolo[1,5-a]pyridines showed good stability in human plasma, but varying microsomal stabilities. Results from current work focused on improving stability, and from efficacy studies in human tumour xenografts, will be reported.

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  • 1,2,4-benzotriazine-1,4-dioxides

    Denny, William; Hay, Michael; Hicks, Kevin; Pruijn, Frederik; Wilson, William; Pchalek, Karin (2010)

    Patent
    The University of Auckland Library

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  • Pteridinones as kinase inhibitors

    Denny, William; Rewcastle, Gordon; Dobrusin, EM; Kramer, JB; McNamara, DJ; Showalter, HD; Toogood, PL (2007)

    Patent
    The University of Auckland Library

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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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  • Syntheses and structural studies of platinum(II) complexes of O-methylselenomethionine and related ligands.

    Carland, M; Abrahams, BF; Rede, T; Stephenson, J; Murray, V; Denny, William; McFadyen, WD (2006)

    Journal article
    The University of Auckland Library

    The complexes dichloro[2-(phenylselanyl)ethanamine]platinum(II), dichloro[2-(benzylselanyl)ethanamine]platinum(II) and dichloro(O-methylselenomethionine)platinum(II) have been prepared and the structure of dichloro(O-methylselenomethionine)platinum(II) has been determined by single crystal X-ray diffraction. The Pt(II) is in a square planar environment and is coordinated by two cis chloride ligands and a chelating O-methylselenomethionine ligand. The cytotoxicities of the compounds have been assessed in the human cell lines HeLa and K562 and they are at least threefold less toxic than cisplatin in both cell lines.

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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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  • 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 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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  • Preclinical characterization of PWT33597, a dual inhibitor of PI3-kinase alpha and mTOR.

    Matthews, DJ; O???Farrell, M; James, J; Giddens, Anna; Rewcastle, Gordon; Denny, William (2011-04-05)

    Conference poster
    The University of Auckland Library

    4485: Phosphoinositide-3-kinase (PI3K) is an important mediator of tumor cell growth, survival and proliferation. In particular, PI3K alpha is important for signaling downstream of receptor tyrosine kinases and is also frequently amplified or mutationally activated in tumors, suggesting that selective inhibitors of this isoform may have therapeutic utility in the treatment of cancer. Downstream of PI3K, the mTOR kinase also plays a critical role in cellular growth and metabolism, and inhibitors of mTOR have demonstrated clinical benefit in several tumor types. We report here the discovery and characterization of PWT33597, a dual inhibitor of PI3K alpha and mTOR. PWT33597 inhibits PI3K alpha and mTOR in biochemical assays with IC50 values of 19 and 14 nM respectively, and is approximately 10-fold selective with respect to PI3K gamma and PI3K delta. Profiling of PWT33597 against 442 protein kinases (Ambit Kinomescan) revealed little or no cross-reactivity with either serine/threonine or tyrosine kinases, and there was little cross-reactivity with an additional panel of 64 pharmacologically relevant targets. In NCI-H460 and HCT116 tumor cells with mutationally activated PI3K alpha, PWT33597 inhibits phosphorylation of PI3K and mTOR pathway proteins with cellular IC50 values similar to its biochemical IC50 values. PWT33597 has good pharmacokinetic properties in multiple preclinical species, is not extensively metabolized in vivo and shows little potential for interaction with cytochrome P450 enzymes. Following a single oral dose in vivo, PWT33597 shows durable inhibition of PI3K and mTOR pathway signaling in xenograft tumors. High compound distribution into tumors and potent anti-tumor activity has been observed in multiple tumor xenograft models with activated PI3K/mTOR pathways. Also, administration of PWT33597 in mice is associated with transient increases in plasma insulin, consistent with an effect on PI3K/AKT signaling. A robust PK/PD relationship has been defined, which will guide interpretation of the planned phase I clinical study. IND-enabling studies with PWT33597 are currently in progress.

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  • 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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  • Long-chain triazolyl acids as inhibitors of osteoclastogenesis

    Marshall, Andrew; Lin, Jian; Grey, Andrew; Reid, Ian; Cornish, Jillian; Denny, William (2013-07-15)

    Journal article
    The University of Auckland Library

    Saturated fatty acids (e.g., palmitic acid) are known to moderately inhibit the development of osteoclasts in vitro. In pursuit of more effective inhibitors of osteoclastogenesis we explored two new classes of palmitic acid analogues containing either an ether or triazolyl group at various positions along the chain. The compounds were evaluated for their ability to inhibit the formation of osteoclasts in primary mouse bone marrow cultures. The oxyacids were generally prepared by condensation of the appropriate alkyl halides and diols, followed by Jones oxidation. The triazolyl acids were prepared by copper-catalysed click chemistry between alkyl azides and acetylenic acids, or with the appropriately-protected azides and alkynes, followed by deprotection and oxidation. The oxyacids were little more effective than palmitic acid, but the triazolyl analogues were much more effective osteoclastogenesis inhibitors, especially when the triazole was distant from the acid unit.

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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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  • 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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  • 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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