13,024 results for Journal article, ResearchSpace@Auckland

  • Acute action of rotenone on nigral dopaminergic neurons - involvement of reactive oxygen species and disruption of Ca2+homeostasis

    Freestone, Peter; Chung, Kenny; Guatteo, E; Mercuri, NB; Nicholson, Louise; Lipski, Janusz (2009)

    Journal article
    The University of Auckland Library

    Rotenone is a toxin used to generate animal models of Parkinson's disease; however, the mechanisms of toxicity in substantia nigra pars compacta (SNc) neurons have not been well characterized. We have investigated rotenone (0.05-1 mu m) effects on SNc neurons in acute rat midbrain slices, using whole-cell patch-clamp recording combined with microfluorometry. Rotenone evoked a tolbutamide-sensitive outward current (94 +/- 15 pA) associated with increases in intracellular [Ca2+] ([Ca2+](i)) (73.8 +/- 7.7 nm) and intracellular [Na+] (3.1 +/- 0.6 mm) (all with 1 mu m). The outward current was not affected by a high ATP level (10 mm) in the patch pipette but was decreased by Trolox. The [Ca2+](i) rise was abolished by removing extracellular Ca2+, and attenuated by Trolox and a transient receptor potential M2 (TRPM2) channel blocker, N-(p-amylcinnamoyl) anthranilic acid. Other effects included mitochondrial depolarization (rhodamine-123) and increased mitochondrial reactive oxygen species (ROS) production (MitoSox), which was also abolished by Trolox. A low concentration of rotenone (5 nm) that, by itself, did not evoke a [Ca2+](i) rise resulted in a large (46.6 +/- 25.3 nm) Ca2+ response when baseline [Ca2+](i) was increased by a 'priming' protocol that activated voltage-gated Ca2+ channels. There was also a positive correlation between 'naturally' occurring variations in baseline [Ca2+](i) and the rotenone-induced [Ca2+](i) rise. This correlation was not seen in non-dopaminergic neurons of the substantia nigra pars reticulata (SNr). Our results show that mitochondrial ROS production is a key element in the effect of rotenone on ATP-gated K+ channels and TRPM2-like channels in SNc neurons, and demonstrate, in these neurons (but not in the SNr), a large potentiation of rotenone-induced [Ca2+](i) rise by a small increase in baseline [Ca2+](i).

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  • The distribution of the growth factors FGF-2 and VEGF, and their receptors, in growing red deer antler

    Lai, AK; Hou, Weilin; Verdon, DJ; Nicholson, Louise; Barling, Peter (2007)

    Journal article
    The University of Auckland Library

    The cellular distributions of the growth factors FGF-2 and VEGF, and their receptors FGFR1, FGFR2 and FGFR3, and VEGFR-2 respectively, were visualized by immunohistochemistry and light microscopy in sections of growing red deer antler. Both of these signalling systems were widely expressed in the integument and osteocartilaginous compartments. FGF-2 was found in the same cells as all three FGFRs, indicating that FGF signalling may be principally autocrine. The patterns of labelling for VEGF and its receptor were similar to those seen for FGF-2 and FGFR-3, in both compartments. Our data are consistent with the findings of others in suggesting that FGF-2 induces expression of VEGF, to stimulate and maintain high rates of neovascularisation and angiogenesis, thereby providing nutrients to both velvet and bone as they rapidly grow and develop. The presence of FGF and VEGF and their receptors in epithelial cells suggests that these signalling systems play a role in skin development, raising the possibility that one or both may be involved in the close coupling of the coordinated growth of the integument and osteocartilage of antler, a process which is poorly understood at present.

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  • Phosphoinositide-3-kinases (PI3Ks): Combined comparative modeling and 3D-QSAR to rationalize the inhibition of p110±.

    Frederick, R; Denny, William (2008)

    Journal article
    The University of Auckland Library

    The p110α isoform of the class IA PI3Ks was recently genetically validated as a promising target for anticancer therapy. However, up to now, only one compound (PIK75 = 1) has been reported as a very potent and selective inhibitor of this isoform. The lack of a 3D structure for this enzyme has clearly hindered the discovery of new p110α selective compounds. In view of this, we combined target-based (homology modeling) and ligand-based (3D-QSAR) approaches in an attempt to define an integrated interaction model for p110α inhibition. Twenty-five analogues of 1 were docked within the putative p110α binding site, and the molecular alignment generated was subsequently used to derive QSAR models based on scoring function, free energy of binding, CoMFA. and CoMSIA. The predictive power of these models was then analyzed using a challenging test set of 5 compounds. CoMSIA, and particularly CoMFA, models were found to outperform the other methods, predicting accurately the potency of 100% of the compounds in the test set, thereby validating our p110α homology model for use in further drug development.

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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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  • A model for the cyclic behaviour of steel under earthquake conditions

    Seal, CK; Hodgson, Michael; Ferguson, William (2011)

    Journal article
    The University of Auckland Library

    During the mid 1990s earthquakes in Northridge, California, and Kobe, Japan, illustrated a lack of understanding of the behaviour of structural steels exposed to seismic loads. Under this type of load regime, structural steel members are subjected to fully plastic load cycles and unexpectedly brittle failures resulted. This paper presents a simple, yet powerful, method for predicting the accumulation of damage in a steel element, based on its toughness. In addition the damage parameter chosen provides an accurate prediction of when failure of the element can be expected to occur. The damage accumulation model developed allows for the deconvolution of complex load histories, such as could be expected to occur during a seismic event, in a systematic, stepwise manner. This approach is ideally suited to automation and could readily be implemented into a finite element model.

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  • Effect of low mg(2+) and bicuculline on cell survival in hippocampal slice cultures

    Yoon, Jinny; Green, CR; Bai, Jizhong; Lipski, Janusz; Nicholson, Louise (2010)

    Journal article
    The University of Auckland Library

    A reliable model system of epileptiform insult would facilitate investigation into the underlying biological mechanisms. Epileptiform insult was induced in hippocampal slice cultures by lowering extracellular Mg(2+), (+)-bicuculline, or (-)-bicuculline methochloride, a stable salt form of bicuculline (both forms block GABA(A) receptors). Cell death was assessed by propidium iodide uptake. Low Mg(2+) or (+)-bicuculline did not produce cell death regardless of dose or incubation period. Exposure to 100 microM (-)-bicuculline methochloride for 48 hr resulted in prominent CA1 cell death. These findings demonstrate that not all pro-epileptic drugs/ion changes used routinely for electrophysiological recording of seizure activity lead to cell death in hippocampal slice cultures and that treatment with bicuculline methochloride can be used as a reliable model for epileptiform insult.

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  • Policy Entrepreneurship and Policy Change

    Mintrom, Michael; Norman, Phillipa (2009)

    Journal article
    The University of Auckland Library

    This article reviews the concept of policy entrepreneurship and its use in explaining policy change. Although the activities of policy entrepreneurs have received close attention in several studies, the concept of policy entrepreneurship is yet to be broadly integrated within analyses of policy change. To facilitate more integration of the concept, we here show how policy entrepreneurship can be understood within more encompassing theorizations of policy change: incrementalism, policy streams, institutionalism, punctuated equilibrium, and advocacy coalitions. Recent applications of policy entrepreneurship as a key explanation of policy change are presented as models for future work. Room exists for further conceptual development and empirical testing concerning policy entrepreneurship. Such work could be undertaken in studies of contemporary and historical policy change.

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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 specificity. ...

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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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  • Mechanism of Action and Preclinical Antitumor Activity of the Novel Hypoxia-Activated DNA Cross-Linking Agent PR-104

    Patterson, Adam; Ferry, DM; Edmunds, SJ; Gu, Yongchuan; Singleton, DC; Patel, K; Pullen, Susan; Valentine, SP; Atwell, Graham; Yang, SY; Denny, William; Wilson, William (2007)

    Journal article
    The University of Auckland Library

    Purpose: Hypoxia is a characteristic of solid tumors and a potentially important therapeutic target. Here, we characterize the mechanism of action and preclinical antitumor activity of a novel hypoxia-activated prodrug, the 3,5-dinitrobenzamide nitrogen mustard PR-104, which has recently entered clinical trials. Experimental Design: Cytotoxicity in vitro was evaluated using 10 human tumor cell lines. SiHa cells were used to characterize metabolism under hypoxia, by liquid chromatography-mass spectrometry, and DNA damage by comet assay and γH2AX formation. Antitumor activity was evaluated in multiple xenograft models (PR-104 ± radiation or chemotherapy) by clonogenic assay 18 h after treatment or by tumor growth delay. Results: The phosphate ester “pre-prodrug” PR-104 was well tolerated in mice and converted rapidly to the corresponding prodrug PR-104A. The cytotoxicity of PR-104A was increased 10- to 100-fold by hypoxia in vitro. Reduction to the major intracellular metabolite, hydroxylamine PR-104H, resulted in DNA cross-linking selectively under hypoxia. Reaction of PR-104H with chloride ion gave lipophilic cytotoxic metabolites potentially able to provide bystander effects. In tumor excision assays, PR-104 provided greater killing of hypoxic (radioresistant) and aerobic cells in xenografts (HT29, SiHa, and H460) than tirapazamine or conventional mustards at equivalent host toxicity. PR-104 showed single-agent activity in six of eight xenograft models and greater than additive antitumor activity in combination with drugs likely to spare hypoxic cells (gemcitabine with Panc-01 pancreatic tumors and docetaxel with 22RV1 prostate tumors). Conclusions: PR-104 is a novel hypoxia-activated DNA cross-linking agent with marked activity against human tumor xenografts, both as monotherapy and combined with radiotherapy and chemotherapy.

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  • Effect of wet milling process on the solid state of Indomethacin and Simvastatin.

    Sharma, P; Denny, William; Garg, Sanjay (2009)

    Journal article
    The University of Auckland Library

    The aim of this study was to investigate the effect of wet milling on the solid state of indomethacin (IMC) and simvastatin (SIM). Wet milling was performed using high pressure homogenization (HPH). Polyvinylpyrrolidone-K25 (PVP) and poloxamer 407 (P407) were used as suspension stabilizers. Samples were characterized before and after wet milling using particle size analyzer, scanning electron microscopy (SEM), infrared (IR) spectroscopy and modulated temperature differential scanning calorimetry (MTDSC) techniques. After wet milling of IMC, physical appearance and IR spectra indicated surface amorphization; however, the solid state of SIM remained unaffected. MTDSC could not detect surface amorphization in IMC, suggesting that if present, it was only at very low levels. These results are in contradiction to the previous reports where dry milling of IMC and SIM resulted in amorphization of crystalline particles. Moreover, cryogrinding of IMC in the absence of water resulted in an amorphous form while presence of water using the same cryogrinding conditions resulted in a solid state similar to that obtained after wet milling. These results signify the role of water in inhibiting the amorphization during wet milling of crystalline drugs.

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  • Pharmacokinetic/pharmacodynamic model-guided identification of hypoxia-selective 1,2,4-benzotriazine 1,4-dioxides with antitumor activity: the role of extravascular transport

    Hay, Michael; Hicks, Kevin; Pruijn, Frederik; Pchalek, K; Siim, Bronwyn; Wilson, William; Denny, William (2007)

    Journal article
    The University of Auckland Library

    Pharmacokinetic/pharmacodynamic (PK/PD) modeling has shown the antitumor activity of tirapazamine (TPZ), a bioreductive hypoxia-selective cytotoxin, to be limited by poor penetration through hypoxic tumor tissue. We have prepared a series of 1,2,4-benzotriazine 1,4-dioxide (BTO) analogues of TPZ to improve activity against hypoxic cells by increasing extravascular transport. The 6 substituents modified lipophilicity and rates of hypoxic metabolism. 3-Alkylamino substituents increased aqueous solubility and also influenced lipophilicity and hypoxic metabolism. PK/PD model-guided screening was used to select six BTOs for evaluation against hypoxic cells in HT29 human tumor xenografts. All six BTOs were active in vivo, and two provided greater hypoxic cell killing than TPZ because of improved transport and/or plasma PK. This PK/PD model considers two causes of therapeutic failure (limited tumor penetration and poor plasma pharmacokinetics) often not addressed early in drug development and provides a general strategy for selecting candidates for in vivo evaluation during lead optimization.

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  • Epigenetic Regulation of Gene Expression as an Anticancer Drug Target

    Ferguson, Lynnette; Tatham, AL; Lin, Z; Denny, William (2011)

    Journal article
    The University of Auckland Library

    Epigenetic processes play a key regulatory role in cancer. Hypermethylation in the CpG islands of the promoter regions of many tumour suppressor genes leads to the recruitment of co-repressors, altered chromatin structure, and ultimately transcriptional silencing. Key components in the regulation of DNA methylation are DNA methyltransferases (DNMT1, 2, 3A and 3B) and methyl CpG-binding proteins, which recognize methyl cytosine residues and recruit transcriptional repressor complexes, including histone deacetylases (HDAC). DNMT1 is responsible for the maintenance of DNA methylation patterns during replication. Inhibitors of this enzyme may potentially lead to DNA hypomethylation, and re-expression of tumour suppressor genes. Several DNMT inhibitors are currently being evaluated in preclinical and clinical studies, include various analogues of adenosine, cytidine or deoxycytidine. However, such drugs have had limited clinical success, perhaps because of cytotoxicity associated with their incorporation into DNA. Non-nucleoside small molecule inhibitors of DNMTs can directly block DNMT activity, and may be able to circumvent this cytotoxicity. Post-translational modifications of histones play a key role, not only in regulating chromatin structure and gene expression, but also in genomic stability. Histone acetylation (HAT) and histone deacetylation (HDAC) affect chromatin condensation, with concomitant effects on gene transcription. A further range of compounds is being evaluated for clinical use as HDAC inhibitors, including hydroxamic acids such as Trichostatin A (TSA) and Suberoyl anilide bishydroxamide (SAHA). MicroRNAs are also found to play a key role in cancer development, and novel approaches to their regulation may provide a susceptible anticancer drug target. Because of the interdependence of epigenetic processes, combinations of these approaches may have maximum clinical efficacy.

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  • Phenazine-1-carboxamides: Structure-cytotoxicity relationships for 9-substituents and changes in the H-bonding pattern of the cationic side chain

    Gamage, Swarnalatha; Rewcastle, Gordon; Baguley, Bruce; Charlton, PA; Denny, William (2006)

    Journal article
    The University of Auckland Library

    A series of phenazine-1-carboxamides were prepared, including variations in both chromophore substituents and the nature of the cationic side chain. The novel side-chain analogues were prepared from the corresponding phenazine-1-carboxylic acids via Schmidt conversion to the 1-amines and from the corresponding 1-halides. Structure-cytotoxicity relationships for these compounds in a panel of tumor cell lines showed that there is very limited scope for variation of the structure of the 1-carboxamide side chain, consistent with the recent structural model of how tricyclic carboxamides bind to DNA. There was generally little difference in IC(50)s between parent and P-glycoprotein expressing cell lines, suggesting that most of the compounds are not affected by the presence of this efflux pump.

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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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  • 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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  • 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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  • Release of nitrite from the antitubercular nitroimidazole drug PA-824 and analogues upon one-electron reduction in protic, non-aqueous solvent

    Maroz, A; Shinde, Sujata; Franzblau, SG; Ma, ZK; Denny, William; Palmer, Brian; Anderson, Robert (2010)

    Journal article
    The University of Auckland Library

    The one-electron reduction chemistry of the antituberculosis drug PA-824, together with a series of closely related compounds, has been investigated in irradiated anaerobic propan-2-ol solution. The protic solvent, of low dielectric constant, was chosen to mimic the environment of a water-restricting active site of a model protein, which is capable of reducing the compounds. Radiolytic reduction of the compounds containing electron donating substituents in the 2-position of the imidazole ring released nitrite, with compounds that are highly active against Mycobacterium tuberculosis exhibiting high yields of nitrite. The release of cytotoxic reactive nitrogen species through a one-electron pathway, by as yet unidentified proteins, may play a role in the activity of this class of compounds against TB. The described radiolytic quantification of nitrite release may have utility as a preliminary screening test for nitroaromatic candidate drugs against the disease.

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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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  • Synthesis and anti-inflammatory structure-activity relationships of thiazine-quinoline-quinones: inhibitors of the neutrophil respiratory burst in a model of acute gouty arthritis.

    Chia, EW; Pearce, Allison; Berridge, MV; Larsen, L; Perry, NB; Sansom, CE; Godfrey, CA; Hanton, LR; Lu, Guo-Liang; Walton, M; Denny, William; Webb, VL; Copp, Brent; Harper, Jacquie (2008)

    Journal article
    The University of Auckland Library

    Sixteen new thiazine–quinoline–quinones have been synthesised, plus one bicyclic analogue. These compounds inhibited neutrophil superoxide production in vitro with IC50s as low 60 nM. Compounds with high in vitro anti-inflammatory activity were also tested in a mouse model of acute inflammation. The most active compounds inhibited both neutrophil infiltration and superoxide production at doses 2.5 μmol/kg, highlighting their potential for development as novel NSAIDs.

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