117 results for Denny, William, Journal article

  • 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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  • Minor groove binding of a bis-quaternary ammonium compound: the crystal structure of SN 7167 bound to d(CGCGAATTCGCG)2

    Squire, Christopher; Clark, George; Denny, William (1997-10)

    Journal article
    The University of Auckland Library

    The X-ray crystal structure of the complex between the synthetic antitumour and antiviral DNA binding ligand SN 7167 and the DNA oligonucleotide d(CGCGAATTCGCG)2 has been determined to an R factor of 18.3% at 2.6 Å resolution. The ligand is located within the minor groove and covers almost 6 bp with the 1-methylpyridinium ring extending as far as the C9-G16 base pair and the 1-methylquinolinium ring lying between the G4-C21 and A5-T20 base pairs. The ligand interacts only weakly with the DNA, as evidenced by long range contacts and shallow penetration into the groove. This structure is compared with that of the complex between the parent compound SN 6999 and the alkylated DNA sequence d(CGC[e6G]AATTCGCG)2. There are significant differences between the two structures in the extent of DNA bending, ligand conformation and groove binding.

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  • Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure-Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis

    Thompson, Andrew; O'Connor, Patrick; Blaser, Adrian; Yardley, V; Maes, L; Gupta, S; Launay, D; Martin, D; Franzblau, SG; Wan, B; Wang, Y; Ma, Z; Denny, William (2016-03)

    Journal article
    The University of Auckland Library

    6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivatives were initially studied for tuberculosis within a backup program for the clinical trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Additional work was then conducted to delineate its essential structural features, aiming to improve solubility and safety without compromising activity against VL. While the 4-nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well-tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of phenyl rings by pyridine. Several less lipophilic analogues displayed improved aqueous solubility, particularly at low pH, although stability toward liver microsomes was highly variable. Upon evaluation in a mouse model of acute Leishmania donovani infection, one phenylpyridine derivative (37) stood out, providing efficacy surpassing that of the original preclinical lead.

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  • Structure-activity relationships for ketamine esters as short-acting anaesthetics

    Jose, Jiney; Gamage, Swarnalatha; Harvey, MG; Voss, LJ; Sleigh, James; Denny, William (2013-09-01)

    Journal article
    The University of Auckland Library

    A series of aliphatic esters of the non-opioid anaesthetic/analgesic ketamine were prepared and their properties as shorter-acting analogues of ketamine itself were explored in an infused rat model, measuring the time after infusion to recover from both the anaesthetic (righting reflex) and analgesic (response to stimulus) effects. The potency of the esters as sedatives was not significantly related to chain length, but Me, Et and i-Pr esters were the more dose potent (up to twofold less than ketamine), whereas n-Pr esters were less potent (from 2- to 6-fold less than ketamine). For the Me, Et and i-Pr esters recovery from anaesthesia was 10-15-fold faster than from ketamine itself, and for the n-Pr esters it was 20-25-fold faster than from ketamine. A new dimethylamino ketamine derivative (homoketamine) had ketamine-like sedative effects but was slightly less potent than, but ester analogues of homoketamine had very weak sedative effects.

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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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  • Phosphoinositide-3-kinase (PI3K) inhibitors: Identification of new scaffolds using virtual screening

    Frederick, R; Mawson, C; Kendall, Jackie; Chaussade, C; Rewcastle, Gordon; Shepherd, Peter; Denny, William (2009-10-15)

    Journal article
    The University of Auckland Library

    In the present work, we used virtual screening (VS) of the ZINC database of 2.5 million compounds to seek new PI3K inhibitory scaffolds. The VS flowchart implemented various filters, including a 3D-database screen, and extensive docking studies, to derive 89 derivatives that were experimentally assayed against the four PI3K isoforms. Seven compounds showed inhibitory activities between 1 and 100 μM, with four being sufficiently potent to constitute potential new scaffolds. The binding conformations of these four were analyzed to provide a rationalization of their activity profile.

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  • Quinazolines as novel anti-inflammatory histone deacetylase inhibitors

    Lin, ZG; Murray, PM; Ding, YY; Denny, William; Ferguson, Lynnette (2010-08-07)

    Journal article
    The University of Auckland Library

    Histone deacetylase (HDAC) inhibitors regulate many biological responses, including anti-inflammatory and anti-cancer effects. We sought to identify novel classes of HDAC inhibitors from in-house compound libraries. Initially, compounds from 26 different structural classes that showed anti-inflammatory effects in a pre-screen in HEK293T cells were tested in vitro for HDAC inhibition, using a commercial fluorescence assay. The known HDAC inhibitors suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA) were used as positive controls. Examples of three different structural classes (anilinoacridines, phenylpyrrolocarbazoles and benzofurylquinazolines) showed significant inhibition in the HDAC assay, and small subsets of these were also evaluated, seeking initial structure–activity relationships (SAR) for each class. Several of the most effective compounds from this HDAC screen were evaluated for their effects on the expression of the pro-inflammatory gene, IL1-α, and the cancer-related genes, p53, p21, E-cadherin and C-MYC. While the benzofurylquinazolines increased the expression level of the pro-inflammatory gene IL1-α as well as p21 and p53 in the PC3 cell line, a phenylpyrrolocarbazole had the converse effect on p53 expression. Several of the compounds showed in vitro HDAC inhibition ability in PC3, HCT116 and NIH-3T3 cell lines comparable to that of SAHA.

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  • Potential antitumor agents. 62. Structure-activity relationships for tricyclic compounds related to the colon tumor active drug 9-oxo-9H-xanthene-4-acetic acid

    Rewcastle, Gordon; Atwell, Graham; Palmer, Brian; Boyd, Peter; Baguley, Bruce; Denny, William (1991)

    Journal article
    The University of Auckland Library

    A series of tricyclic analogues of 9-oxo-9H-xanthene-4-acetic acid have been prepared and evaluated for their ability to cause hemorrhagic necrosis in subcutaneously implanted colon 38 tumors in mice, in an effort to extend the structure - activity relationships for this series. As was found previously with analogues of flavone-8-acetic acid (FAA) (Atwell et al. Anti-Cancer Drug Des. 1989, 4, 161), all electronic modifications of the XAA nucleus led to severe decreases or complete abolition of activity, suggesting narrow structure - activity relationships. Dipole moments for many of the compounds were computed, and the degree to which the molecular dipole moment lay out of the plane of the aromatic part of these molecules was found to be determined largely by the contributions from the acetic acid moiety relative to that from the tricyclic ring system. There did not appear to be any general relationship between the magnitude of the dipole moment and activity. However, for compounds containing the 9-carbonyl functionality, the orientation of the dipole vector may be of significance. In all compounds possessing an ether group peri to the acetic acid side chain, there was a close approach (ca. 2.4 Å) between this and the side chain OH.

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  • Synthesis, biological evaluation and molecular modelling of sulfonohydrazides as selective PI3K p110 alpha inhibitors

    Kendall, Jackie; Rewcastle, Gordon; Frédérick, Raphaël; Mawson, Claire; Denny, William; Marshall, Elaine; Baguley, Bruce; Chaussade, Claire; Jackson, SP; Shepherd, Peter (2007)

    Journal article
    The University of Auckland Library

    A series of 2-methyl-5-nitrobenzenesulfono-hydrazides were prepared and evaluated as inhibitors of PI3K. An isoquinoline derivative shows good selectivity for the p110a isoform over p110b and p110d, and also demonstrates good in vitro activity in a cell proliferation assay. Molecular modelling provides a rationalisation for the observed SAR.

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  • The effect of a bromide leaving group on the properties of nitro analogs of the duocarmycins as hypoxia-activated prodrugs and phosphate pre-prodrugs for antitumor therapy.

    Stevenson, Ralph; Denny, William; Ashoorzadeh, Amir; Pruijn, Frederik; van Leeuwen, WF; Tercel, Moana (2011-10-15)

    Journal article
    The University of Auckland Library

    Nitro seco analogs (nitroCBIs) of the antitumor antibiotic duocarmycins are a new class of hypoxia activated prodrugs. These compounds undergo hypoxia-selective metabolism to form potent DNA alkylating agents. A series of four nitroCBI alcohol prodrugs containing a bromide rather than chloride or sulfonate leaving group was synthesized. In assays for in vitro hypoxia-selective cytotoxicity against human tumor cell lines the two bromides with DNA minor groove binding basic side chains displayed hypoxic cytotoxicity ratios (HCRs) of 52-286 in HT29 cells and 41-43 in SiHa cells. These values compare well with a related previously reported chloride analog. The corresponding more water soluble phosphate pre-prodrugs of the bromides were synthesized and evaluated for in vivo antitumor activity against SiHa human tumor xenografts. All four phosphates, with both neutral and basic side chains, demonstrated activity providing statistically significant hypoxic log(10) cell kills of 0.87-2.80 at non-toxic doses, matching or proving superior to those of their chloride analogs.

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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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  • 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 π–π-stacking interactions.

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  • A new short synthesis of 5,6-dimethylxanthenone-4-acetic acid (ASA404, DMXAA)

    Yang, S; Denny, William (2009)

    Journal article
    The University of Auckland Library

    A new short synthesis of 5,6-dimethylxanthenone-4-acetic acid (ASA404) is developed. The key steps of the synthesis are dibromination of 3,4-dimethylbenzoic acid, followed by regioselective coupling with 2-hydroxyphenylacetic acid and subsequent cyclodehydration.

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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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  • A roadmap for drug discovery and its translation to small molecule agents in clinical development for tuberculosis treatment.

    Showalter, HD; Denny, William (2008)

    Journal article
    The University of Auckland Library

    Summary Drug discovery and development, from an initial disease treatment concept to a new drug application (NDA), is a complex, lengthy and expensive process. In this review we discuss the key stages of drug discovery and early development, including target identification and validation, assay development and screening, confirmed hits to leads, lead optimization, and progressing development candidates to an investigational new drug (IND) filing. We also provide particular examples of how this process is beginning to assist in the development of small molecule treatments for tuberculosis, by summarizing the status of the clinical development of several newer classes of drugs. These include the fluoroquinolones, oxazolidinones, diarylquinolines, and nitroimidazo-oxazoles and -oxazines.

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  • Dihydrofuro[3,4-c]pyridinones as inhibitors of the cytolytic effects of the pore-forming glycoprotein perforin

    Lena, G; Trapani, JA; Sutton, VR; Ciccone, A; Browne, KA; Smyth, MJ; Denny, William; Spicer, Julie (2008-12-11)

    Journal article
    The University of Auckland Library

    Dihydrofuro[3,4-c]pyridinones are the first class of small molecules reported to inhibit the cytolytic effects of the lymphocyte toxin perforin. A lead structure was identified from a high throughput screen, and a series of analogues were designed and prepared to explore structure−activity relationships around the core bicyclic thioxofuropyridinone and pendant furan ring. This resulted in the identification of a submicromolar inhibitor of the perforin-induced lysis of Jurkat T-lymphoma cells.

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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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  • Palladium-Catalyzed Cross-Coupling in the Synthesis of Pyridinyl Boxazomycin C Analogues.

    Richardson, C; Rewcastle, Gordon; Hoyer, D; Denny, William (2005)

    Journal article
    The University of Auckland Library

    Palladium-catalyzed cross-coupling of 2-thiomethylbenzoxazoles with tri-alkylstannyl pyridines efficiently produces pyridinyl boxazomycin C analogues.

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  • The nitroimidazooxazines (PA-824 and analogs): structure-activity relationship and mechanistic studies.

    Denny, William; Palmer, Brian (2010-08)

    Journal article
    The University of Auckland Library

    PA-824 is an experimental anti-tubercular agent that has a novel mechanism of action. It is effective against both active and persistent forms of the disease and has recently shown early bactericidal activity in a Phase II clinical trial. This review summarizes recent studies on the mode of action of PA-824 and outlines successful efforts to prepare more effective second-generation analogs. PA-824 displays unusual chemistry following both enzymatic and radiolytic reduction, which is clearly related to its activity as an anti-tubercular agent. The nitroreductase enzyme deazaflavin-dependent nitroreductase, reduces PA-824 with loss of the nitro group, generating reactive nitrogen species such as nitric oxide, which appear important in mediating the activity of the drug. Bioreductive drugs such as PA-824 hold the promise of shorter treatment regimens.

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  • Cytotoxicity and DNA Interaction of the enantiomers of 6-amino-3-(chloromethyl)-1-[(5,6,7-trimethoxyindol-2-yl)-carbonyl]indoline (amino-seco-CI-TMI)

    Tercel, Moana; Gieseg, Michael; Milbank, JB; Boyd, Maruta; Fan, JY; Tan, Lee; Wilson, William; Denny, William (1999)

    Journal article
    The University of Auckland Library

    The enantiomers of the previously reported racemic 6-amino-3-(chloromethyl)-1-[(5,6,7-trimethoxyindol-2-yl)carbonyl]indoline (amino-seco-CI-TMI) were prepared via resolution of a precursor by chiral HPLC. The only detectable product isolated from rea

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