137 results for Denny, William, Journal article

  • 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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  • 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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  • 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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  • 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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  • Tyrosine Kinase Inhibitors. 20. Optimization of Substituted Quinazoline and Pyrido[3,4- d ]pyrimidine Derivatives as Orally Active, Irreversible Inhibitors of the Epidermal Growth Factor Receptor Family

    Smaill, Jeffrey; Gonzales, AJ; Spicer, Julie; Lee, H; Reed, JE; Sexton, K; Althaus, IW; Zhu, T; Black, Shannon; Blaser, Adrian; Denny, William; Ellis, PA; Fakhoury, S; Harvey, PJ; Hook, K; McCarthy, FOJ; Palmer, Brian; Rivault, F; Schlosser, K; Ellis, T; Thompson, Andrew; Trachet, E; Winters, RT; Tecle, H; Bridges, A (2016-09-08)

    Journal article
    The University of Auckland Library

    Structure???activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition. Optimum 4- and 6-substituents with known 7-substituents provided preferred irreversible inhibitors for pharmacodynamic testing in vivo. Quinazoline 54 and pyrido[3,4-d]pyrimidine 71 were identified as clearly superior to canertinib. Both compounds possess a piperidinyl crotonamide Michael acceptor and a 3-chloro-4-fluoroaniline, indicating these as optimized 6- and 4-substituents, respectively. Pharmacokinetic comparison of compounds 54 and 71 across three species selected compound 54 as the preferred candidate. Compound 54 (PF-00299804) has been assigned the nomenclature of dacomitinib and is currently under clinical evaluation.

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  • 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel antitubercular agents lead to a new preclinical candidate for visceral leishmaniasis

    Thompson, Andrew; O'Connor, PD; Marshall, AJ; Yardley, V; Maes, L; Gupta, S; Launay, D; Braillard, S; Chatelain, E; Franzblau, SG; Wan, B; Wang, Y; Ma, Z; Cooper, CB; Denny, William (2017-05)

    Journal article
    The University of Auckland Library

    Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety. Commencing with a biphenyl lead, bioisosteres formed by replacing one phenyl by pyridine or pyrimidine showed improved solubility and potency, whereas more hydrophilic side chains reduced VL activity. In a Leishmania donovani mouse model, two racemic phenylpyridines (71 and 93) were superior, with the former providing >99% inhibition at 12.5 mg/kg (b.i.d., orally) in the Leishmania infantum hamster model. Overall, the 7R enantiomer of 71 (79) displayed more optimal efficacy, pharmacokinetics, and safety, leading to its selection as the preferred development candidate.

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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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  • 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 ??H2AX 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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  • 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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  • 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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  • 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 ??mol/kg, highlighting their potential for development as novel NSAIDs.

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  • Synthesis and in vitro evaluation of analogues of avocado-produced toxin (+)-(R)-persin in human breast cancer cells.

    Brooke, Darby; Shelley, EJ; Roberts, CG; Denny, William; Sutherland, RL; Butt, AJ (2011-12)

    Journal article
    The University of Auckland Library

    A structure-activity study of several new synthetic analogues of the avocado-produced toxin persin has been conducted, with compounds being evaluated for their cytostatic and pro-apoptotic effects in human breast cancer cells. A 4-pyridinyl derivative demonstrated activity comparable to that of the natural product, suggesting future directions for exploration of structure-activity relationships.

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  • Synthesis and structure-activity relationships of soluble 8-substituted 4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of the Wee1 and Chk1 checkpoint kinases

    Smaill, Jeffrey; Lee, Ho; Palmer, Brian; Thompson, Andrew; Squire, Christopher; Baker, Edward; Booth, RJ; Kraker, AJ; Hook, K; Denny, William (2008)

    Journal article
    The University of Auckland Library

    Pyrrolo[3,4-c]carbazoles bearing solubilising basic side chains at the 8-position retain potent Wee1 and Chk1 inhibitory properties in isolated enzyme assays, and evidence of G2/M checkpoint abrogation in several cellular assays. Co-crystal structure studies confirm that the primary binding to the Wee1 enzyme is as described previously, with the C-8 side chains residing in an area of bulk tolerance.

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

    Kendall, Jackie; Rewcastle, Gordon; Fr??d??rick, Rapha??l; 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 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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