117 results for Denny, William, Journal article

  • 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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  • 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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  • Novel pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors: Exploring the benzenesulfonohydrazide SAR

    Kendall, Jackie; Giddens, Anna; Tsang, KY; Frederick, R; Marshall, ES; Singh, R; Lill, CL; Lee, Woo Jeong; Kolekar, Sharada; Chao, M; Malik, Alisha; Yu, S; Chaussade, C; Buchanan, Christina; Rewcastle, GW; Baguley, BC; Flanagan, Jack; Jamieson, Stephen; Denny, William; Shepherd, Peter (2012-01-01)

    Journal article
    The University of Auckland Library

    Structure–activity relationship studies of the pyrazolo[1,5-a]pyridine class of PI3 kinase inhibitors show that substitution off the hydrazone nitrogen and replacement of the sulfonyl both gave a loss of p110a selectivity, with the exception of an N-hydroxyethyl analogue. Limited substitutions were tolerated around the phenyl ring; in particular the 2,5-substitution pattern was important for PI3 kinase activity. The N-hydroxyethyl compound also showed good inhibition of cell proliferation and inhibition of phosphorylation of Akt/PKB, a downstream marker of PI3 kinase activity. It had suitable pharmacokinetics for evaluation in vivo, and showed tumour growth inhibition in two human tumour cell lines in xenograft studies. This work has provided suggestions for the design of more soluble analogues.

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  • Syntheses of 8-quinolinolatocobalt(III) complexes containing cyclen based auxiliary ligands as models for hypoxia-activated prodrugs

    Chang, JYC; Stevenson, Ralph; Lu, Guo-Liang; Brothers, Penelope; Clark, George; Denny, William; Ware, David (2010-12)

    Journal article
    The University of Auckland Library

    New ligands H2L2–H2L6 comprise the cyclen macrocycle which is N,N′-dialkylated at the 1,7-nitrogen atoms by three- and four-carbon alkyl chains bearing terminal sulfonic (C3 H2L2), phosphonic (C3 H2L3, C4 H2L4) or carboxylic acid (C3 H2L5, C4 H2L6) groups, and HL7 is N-monoalkylated by a four-carbon sulfonic acid group. The ligands were prepared by alkylation of a bridged bisaminal intermediate. The syntheses of cobalt(III) complexes containing a tetradentate cyclen, N,N′-1,7-Me2cyclen, cyclam or L2–L7 ligand together with the bidentate 8-quinolinato (8QO−) ligand, of interest as it is a model for a more potent cytotoxic analogue, were investigated. Coordination of ligands (L) cyclen, N,N′-1,7-Me2cyclen or cyclam to cobalt(III) was achieved using Na3[Co(NO6)] to form [Co(L)(NO2)2]+. HOTf (trifluoromethansulfonic acid) was used to prepare the triflato complexes [Co(L)(OTf)2]+, followed by substitution of the labile triflato ligands to yield [Co(L)(8QO)](ClO4)2 isolated as the perchlorate salts. One further example containing cyclam and the 5-hydroxymethyl-8-quinolinato ligand was also prepared by this method. Complexes containing the pendant arm ligands L2–L6 were prepared from the cobalt precursor trans-[Co(py)4Cl2]+. Reaction of this complex with H2L2·4HCl and 8QOH produced [Co(L2)(8QO)] in one step and contains two deprotonated sulfonato pendant arms. The reaction of H2L3·4HBr with [Co(py)4Cl2]+ gave [Co(L3)]Cl in which L3 acts as a hexadenate ligand with the three-carbon phosphonato side chains coordinated to cobalt. H2L5·4HCl bearing three-carbon carboxylic acid pendant arms gave a similar result. The four-carbon ligands were coordinated to cobalt by reaction of [Co(py)4Cl2]+ with H2L4·4HBr or H2L6·4HCl to give [Co(HL4)Cl2] or [Co(H2L6)Cl2]Cl, which in turn with 8QOH gave the 8QO− complexes [Co(L4)(8QO)] bearing anionic phosphate pendant arms or [Co(H2L6)(8QO)]Cl2 containing neutral carboxylic acid side chains. The reaction of Na3[Co(CO3)3] with the mono-N-alkylated ligand HL7·4HCl and then HOTf gave [Co(L7)(CO3)] and then in turn [Co(L7)(OTf)2]. The carbonato complex [Co(L7)(CO3)] with [8QO]2[SO4] produced [Co(L7)(CO3)]. All complexes containing L7 bear an anionic sulfonato group on the side chain. The synthesis and characterisation of the six new ligands based on N-alkylated cylen ligand and the cobalt complexes outlined above are described, along with cyclic voltammograms of the 8QO− complexes and the molecular structures determined by X-ray crystallography of [Co(cyclen)(H2O)2](OTf)3 (formed by aquation of the triflato complex), [Co(cyclen)(8QO)](ClO4)2, Co(L2)(8QO)·2H2O, Co(L4)(8QO)·6H2O and [Co(H2L6)Cl2]Cl·H2O. These demonstrate the coordination of the cyclen ligand in the folded anti-O,syn-N configuration with the N-alkylated nitrogens occupying apical positions.

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  • A phase I trial of PR-104, a nitrogen mustard prodrug activated by both hypoxia and aldo-keto reductase 1C3, in patients with solid tumors

    Jameson, Michael; Rischin, D; Pegram, M; Gutheil, J; Patterson, Adam; Denny, William; Wilson, William (2010-03)

    Journal article
    The University of Auckland Library

    PURPOSE: PR-104 is a "pre-prodrug" designed to be activated to a dinitrobenzamide nitrogen mustard cytotoxin by nitroreduction in hypoxic regions of tumors. This study was conducted to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and pharmacokinetics (PK) of PR-104 in patients with advanced solid tumors. METHODS: Patients with solid tumors refractory or not amenable to conventional treatment were evaluated in a dose-escalation trial of PR-104 administered as a 1-h intravenous (IV) infusion every 3 weeks. The plasma PK of PR-104 and its primary metabolite, PR-104A, were evaluated. RESULTS: Twenty-seven patients received a median of two cycles of PR-104 in doses ranging from 135 to 1,400 mg/m(2). The MTD of PR-104 as a single-dose infusion every 3 weeks was established as 1,100 mg/m(2). One of six patients treated at 1,100 mg/m(2) experienced DLT of grade 3 fatigue. Above the MTD, the DLTs at 1,400 mg/m(2) were febrile neutropenia and infection with normal absolute neutrophil count. No objective responses were observed, although reductions in tumor size were observed in patients treated at doses > or = 550 mg/m(2). The plasma PK of PR-104 demonstrated rapid conversion to PR-104A, with approximately dose-linear PK of both species. CONCLUSIONS: PR-104 was well tolerated at a dose of 1,100 mg/m(2) administered as an IV infusion every 3 weeks. The area under the PR-104A plasma concentration-time curve at this dose exceeded that required for activity in human tumor cell cultures and xenograft models. The recommended dose of PR-104 as a single agent for phase II trials is 1,100 mg/m(2) and further trials are underway

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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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  • Genotoxicity of non-covalent interactions: DNA intercalators

    Ferguson, Lynnette; Denny, William (2007)

    Journal article
    The University of Auckland Library

    This review provides an update on the mutagenicity of intercalating chemicals, as carried out over the last 17 years. The most extensively studied DNA intercalating agents are acridine and its derivatives, that bind reversibly but non-covalently to DNA. These are frameshift mutagens, especially in bacteria and bacteriophage, but do not otherwise show a wide range of mutagenic properties. Di-acridines or di-quinolines may be either mono- or bis-intercalators, depending upon the length of the alkyl chain separating the chromophores. Those which monointercalate appear as either weak frameshift mutagens in bacteria, or as non-mutagens. However, some of the bisintercalators act as “petite” mutagens in Saccharomyces cerevisiae, suggesting that they may be more likely to target mitochondrial as compared with nuclear DNA. Some of the new methodologies for detecting intercalation suggest this may be a property of a wider range of chemicals than previously recognised. For example, quite a number of flavonoids appear to intercalate into DNA. However, their mutagenic properties may be dominated by the fact that many of them are also able to inhibit topoisomerase II enzymes, and this property implies that they will be potent recombinogens and clastogens. DNA intercalation may serve to position other, chemically reactive molecules, in specific ways on the DNA, leading to a distinctive (and wider) range of mutagenic properties, and possible carcinogenic potential.

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  • Hypoxia-Selective 3-Alkyl 1,2,4-Benzotriazine 1,4-Dioxides: The Influence of Hydrogen Bond Donors on Extravascular Transport and Antitumor Activity

    Hay, Michael; Pchalek, Karin; Pruijn, Frederik; Hicks, Kevin; Siim, Bronwyn; Anderson, Robert; Shinde, Sujata; Phillips, Victoria; Denny, William; Wilson, William (2007)

    Journal article
    The University of Auckland Library

    Tirapazamine (TPZ) and related 1,2,4-benzotriazine 1,4 dioxides (BTOs) are selectively toxic under hypoxia, but their ability to kill hypoxic cells in tumors is generally limited by their poor extravascular transport. Here we show that removing hydrogen bond donors by replacing the 3-NH2 group of TPZ with simple alkyl groups increased their tissue diffusion coefficients as measured in multicellular layer cultures. This advantage was largely retained using solubilizing 3-alkylaminoalkyl substituents provided these were sufficiently lipophilic at pH 7.4. The high reduction potentials of such compounds resulted in rates of metabolism too high for optimal penetration into hypoxic tissue, but electron-donating 6- and 7-substituents moderated metabolism. Pharmacokinetic/pharmacodynamic model-guided screening was used to select BTOs with optimal extravascular transport and hypoxic cytotoxicity properties for evaluation against HT29 human tumor xenografts in combination with radiation. This identified four novel 3-alkyl BTOs providing greater clonogenic killing of hypoxic cells than TPZ at equivalent host toxicity, with the 6-morpholinopropyloxyBTO 22 being 3-fold more active.

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  • Synthesis and structure-activity relationships of varied ether linker analogues of the antitubercular drug (6 S)-2-nitro-6-{[4-(trifluoromethoxy) benzyl]oxy}-6,7-dihydro-5 H -imidazo[2,1- b ][1,3]oxazine (PA-824)

    Thompson, Andrew; Sutherland, Hamish; Palmer, Brian; Kmentova, I; Blaser, Adrian; Franzblau, SG; Wan, B; Wang, Y; Ma, Z; Denny, William (2011)

    Journal article
    The University of Auckland Library

    New analogues of antitubercular drug PA-824 were synthesized, featuring alternative side chain ether linkers of varying size and flexibility, seeking drug candidates with enhanced metabolic stability and high efficacy. Both α-methyl substitution and removal of the benzylic methylene were broadly tolerated in vitro, with a biaryl example of the latter class exhibiting an 8-fold better efficacy than the parent drug in a mouse model of acute Mycobacterium tuberculosis infection and negligible fragmentation to an alcohol metabolite in liver microsomes. Extended linkers (notably propenyloxy, propynyloxy, and pentynyloxy) provided greater potencies against replicating M. tb (monoaryl analogues), with propynyl ethers being most effective under anaerobic (nonreplicating) conditions (mono/biaryl analogues). For benzyloxybenzyl and biaryl derivatives, aerobic activity was maximal with the original (OCH(2)) linker. One propynyloxy-linked compound displayed an 89-fold higher efficacy than the parent drug in the acute model, and it was slightly superior to antitubercular drug OPC-67683 in a chronic infection model.

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  • Gemcitabine sensitization by Chk1 inhibition correlates with inhibition of a Rad51 DNA damage response in pancreatic cancer cells

    Parsels, LA; Morgan, MA; Tanska, DM; Parsels, JD; Palmer, Brian; Booth, RJ; Denny, William; Canman, CE; Kraker, AJ; Lawrence, TS; Maybaum, J (2009)

    Journal article
    The University of Auckland Library

    The protein kinase checkpoint kinase 1 (Chk1) has been implicated as a key regulator of cell cycle progression and DNA repair, and inhibitors of Chk1 (e.g., UCN-01 and EXEL-9844) potentiate the cytotoxic actions of chemotherapeutic drugs in tumor cells. We have examined the ability of PD-321852, a small-molecule Chk1 inhibitor, to potentiate gemcitabine-induced clonogenic death in a panel of pancreatic cancer cell lines and evaluated the relationship between endpoints associated with Chk1 inhibition and chemosensitization. Gemcitabine chemosensitization by minimally toxic concentrations of PD- 321852 ranged from minimal (30-fold in MiaPaCa2 cells. PD-321852 inhibited Chk1 in all cell lines as evidenced by stabilization of Cdc25A; in combination with gemcitabine, a synergistic loss of Chk1 protein was observed in the more sensitized cell lines. Gemcitabine chemosensitization, however, did not correlate with abrogation of the S-M or G2-M checkpoint; PD-321852 did not induce premature mitotic entry in gemcitabine-treated BxPC3or M-Panc96

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  • Hypoxia-activated prodrugs in cancer therapy: progress to the clinic

    Denny, William (2010-03)

    Journal article
    The University of Auckland Library

    The hypoxic cells common in solid tumors (because of their inefficient blood supply) limit the effectiveness of radiotherapy and many cytotoxic drugs. Nontoxic prodrugs that generate active species in hypoxic tissue by selective bioreduction have long been explored, and the first examples, representing a variety of different chemistries, have now reached advanced clinical trials. In the process, a great deal has been learnt about the properties that such drugs require to be successful, notably, efficient extravascular diffusion, appropriate reduction chemistry and kinetics, and an effective biological profile of the activated species, including a good bystander effect. The critical importance of prodrug diffusion and techniques to quantify this have assisted the development of models to predict the killing of tumor cells, which promises to help accelerate new drug evaluation. A cell cycleindependent mechanism of killing by the released cytotoxin is also a potential advantage, although it is likely that much of the killing will be when out-of-cycle hypoxic cells reoxygenate and resume division.

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  • Mass spectrometry studies of the binding of the minor groove-directed alkylating agent Alkamin to AT-tract oligonucleotides

    Abdul Majid, AM; Smythe, G; Denny, William; Wakelin, LP (2009)

    Journal article
    The University of Auckland Library

    Minor groove binding alkylating agents, which have potential as cancer drugs, generate cytotoxic DNA adducts that are relatively resistant to repair as a consequence of locating covalent attachment at purine N3 nitrogen atoms. Recently, we used electrospray and matrix-assisted laser desorption ionization mass spectrometry to study the binding of the minor groove-directed polybenzamide bis-half-mustard alkamin, and its monofunctional analogue alkamini, to the oligonucleotide d(CGCGAATTCGCG)2, identifying a number of inter- and intrastrand alkamin cross-links involving the GAATTC sequence [Abdul Majid, A. M. S., Smythe, G., Denny, W. A., and Wakelin, L. P. G. (2007) Mol. Pharmacol.71, 1165−1178]. Here, we extend these studies to d(CGCAAATTTGCG)2, A3T3, and d(CGCAAAAAAGCG)·d(CGCTTTTTTGCG), A6/T6, in which the opportunity for both inter- and intrastrand cross-linking is enhanced. We find that both ligands alkylate all adenines in the longer AT-tracts, as well as the abutting guanines, whether they are in the same strand as the adenines or not, in a manner consistent with covalent attack on purine N3 atoms from the minor groove. Alkamin forms intrastrand cross-links involving A4 and A6 and A6 and G10 in A3T3 and all of the purines in the A6/T6 purine tract, including G10. In addition, it forms interstrand cross-links between A4, A5, A6 and A4′, A5′, A6′, between G10 and the latter adenines in A3T3, and between G22 and adenines A5 and A6 in A6/T6. The reactivity of the abutting guanines provides unexpected opportunities for both inter- and intrastrand cross-linking by alkamin, such as the interstrand cross-link in the CAAAAAAG sequence. We conclude that positioning monofunctional mustard groups on either end of a minor groove-directed polybenzamide has the capacity to enhance interstrand cross-links at all manner of AT-tracts, including most in which the adenines are all in one strand.

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  • Pharmacokinetic/pharmacodynamic modeling identifies SN30000 and SN29751 as tirapazamine analogues with improved tissue penetration and hypoxic cell killing in tumors.

    Hicks, Kevin; Siim, BG; Jaiswal, Jagdish; Pruijn, Frederik; Fraser, AM; Patel, R; Hogg, A; Liyanage, HD; Dorie, MJ; Brown, JM; Denny, William; Hay, Michael; Wilson, William (2010-10)

    Journal article
    The University of Auckland Library

    Tirapazamine (TPZ) has attractive features for targeting hypoxic cells in tumors but has limited clinical activity, in part because of poor extravascular penetration. Here, we identify improved TPZ analogues by using a spatially resolved pharmacokinetic/pharmacodynamic (SR-PKPD) model that considers tissue penetration explicitly during lead optimization.

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  • Substituted 9-aminoacridine-4-carboxamides tethered to platinum(II)diamine complexes: Chemistry, cytotoxicity and DNA sequence selectivity

    Carland, M; Grannas, MJ; Cairns, MJ; Roknic, VJ; Denny, William; McFadyen, WD; Murray, V (2010-08)

    Journal article
    The University of Auckland Library

    Three platinum complexes in which substituted (7-OMe, 9-NH2; 7-F, 9-NH2; and 7-H, 9-NH(CH2)2OH) 9-aminoacridine-4-carboxamides were tethered to a platinum(II)diamine moiety were synthesised and characterised at the chemical and biological level. These variants showed a decrease in cytotoxicity, as measured by IC50 values in HeLa cells, when compared with the parent 7-H, 9-NH2 compound. The 7-F and 9-NH(CH2)2OH substituents gave rise to a small decrease in cytotoxicity, and the 7-OMe substituent resulted in a larger decrease in cytotoxicity. Their binding to purified pUC19 plasmid DNA was investigated and it was found that the addition of 7-F, 9-NH(CH2)2OH and especially the 7-OMe substituents, resulted in reduced DNA binding. This correlated well with the IC50 cytotoxicity values. However, the DNA sequence selectivity was unaffected by the addition of these moieties.

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  • Synthesis and Structure-activity Relationships of Antitubercular 2-Nitroimidazooxazines Bearing Heterocyclic Side Chains

    Sutherland, Hamish; Blaser, Adrian; Kmentova, I; Franzblau, SG; Wan, BJ; Wang, YH; Ma, ZK; Palmer, Brian; Denny, William; Thompson, Andrew (2010-01)

    Journal article
    The University of Auckland Library

    Recently described biphenyl analogues of the antituberculosis drug PA-824 displayed improved potencies against M. tuberculosis but were poorly soluble. Heterobiaryl analogues of these, in which the first phenyl ring was replaced with various 5-membered ring heterocycles, were prepared with the aim of identifying potent new candidates with improved aqueous solubility. The compounds were constructed by coupling the chiral 2-nitroimidazooxazine alcohol with various halomethyl-substituted arylheterocycles, by cycloadditions to a propargyl ether derivative of this alcohol, or by Suzuki couplings on haloheterocyclic methyl ether derivatives. The arylheterocyclic compounds were all more hydrophilic than their corresponding biphenyl analogues, and several showed solubility improvements. 1-Methylpyrazole, 1,3-linked-pyrazole, 2,4-linked-triazole, and tetrazole analogues had 3- to 7-fold higher MIC potencies against replicating M. tb than predicted by their lipophilicities. Two pyrazole analogues were >10-fold more efficacious than the parent drug in a mouse model of acute M. tb infection, and one displayed a 2-fold higher solubility.

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  • Synthesis and Structure-Activity Relationships of Aza- and Diazabiphenyl Analogues of the Antitubercular Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824).

    Kmentova, I; Sutherland, Hamish; Palmer, Brian; Blaser, Adrian; Franzblau, SG; Wan, B; Wang, Y; Ma, Z; Denny, William; Thompson, Andrew (2010-11)

    Journal article
    The University of Auckland Library

    New heterocyclic analogues of the potent biphenyl class derived from antitubercular drug PA-824 were prepared, aiming to improve aqueous solubility but maintain high metabolic stability and efficacy. The strategy involved replacement of one or both phenyl groups by pyridine, pyridazine, pyrazine, or pyrimidine, in order to reduce lipophilicity. For para-linked biaryls, hydrophilicities (ClogP) correlated with measured solubilities, but highly soluble bipyridine analogues displayed weak antitubercular activities. A terminal pyridine or proximal heterocycle allowed retention of potency and provided solubility improvements, particularly at low pH, with examples from the latter classes displaying the better in vivo efficacies, high metabolic stabilities, and excellent pharmacokinetics. Five such compounds were >100-fold better than the parent drug in a mouse model of acute Mycobacterium tuberculosis infection, and two orally bioavailable pyridine analogues (3-4-fold more soluble than the parent at low pH) were superior to antitubercular drug OPC-67683 in a chronic infection model.

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  • Synthesis, reduction potentials and anti-tubercular activity of ring A/B analogues of the bioreductive drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824).

    Thompson, Andrew; Blaser, Adrian; Anderson, Robert; Shinde, Sujata; Franzblau, SG; Ma, Z; Denny, William; Palmer, Brian (2009)

    Journal article
    The University of Auckland Library

    The nitroimidazooxazine S-1 (PA-824) is a new class of bioreductive drug for tuberculosis. A series of related bicyclic nitroheterocycles was synthesized, designed to have a wide range of one-electron reduction potentials E(1) (from −570 to −338 mV, compared with −534 mV for S-1). The observed E(1) values closely correlated with the σm values of the heteroatom at the 4/8-position of the adjacent six-membered ring. Although the compounds spanned a range of E(1) values around that of S-1, only the nitroimidazothiazines showed significant antitubercular activity (at a similar level of potency), suggesting that E(1) is not the main driver of efficacy. Furthermore, there was a correlation between activity and the formation of imidazole ring-reduced products at the two-electron level, pointing to the potential importance of this reduction pathway, which is determined by the nature of the substituent at the 2-position of the 4-nitroimidazole ring.

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  • Synthesis and structure-activity relationships of N-6 substituted analogues of 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of Wee1 and Chk1 checkpoint kinases

    Smaill, Jeffrey; Baker, Edward; Booth, RJ; Bridges, AJ; Dickson, James; Dobrusin, EM; Ivanovic, I; Kraker, AJ; Lee, Ho; Lunney, EA; Ortwine, DF; Palmer, Brian; quin, J; Squire, Christopher; Thompson, Andrew; Denny, William (2008)

    Journal article
    The University of Auckland Library

    A series of N-6 substituted 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones were prepared from N-substituted (5-methoxyphenyl)ethenylindoles. The target compounds were tested for their ability to inhibit the G2/M cell cycle checkpoint kinases, Wee1 and Chk1. Analogues with neutral or cationic N-6 side chains were potent dual inhibitors. Acidic side chains provided potent (average IC50 0.057 μM) and selective (average ratio 223-fold) Wee1 inhibition. Co-crystal structures of inhibitors bound to Wee1 show that the pyrrolo[3,4-c]carbazole scaffold binds in the ATP-binding site, with N-6 substituents involved in H-bonding to conserved water molecules. HT-29 cells treated with doxorubicin and then target compounds demonstrate an active Cdc2/cyclin B complex, inhibition of the doxorubicin-induced phosphorylation of tyrosine 15 of Cdc2 and abrogation of the G2 checkpoint.

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  • The DNA sequence selectivity of maltolato-containing cisplatin analogues in purified plasmid DNA and in intact human cells

    Cairns, MJ; Carland, M; McFadyen, DW; Denny, William; Murray, V (2009)

    Journal article
    The University of Auckland Library

    Cisplatin analogues with an attached DNA binding moiety have a higher affinity for DNA, but often suffer from poor aqueous solubility. In this study we examined the DNA sequence specificity of more soluble cisplatin analogues containing the maltolato leaving group in both purified DNA and in intact human cells. In both environments the DNA sequence specificity of these analogues was very similar to cisplatin. However, in purified DNA a higher concentration of the two maltolato-containing analogues was needed to achieve a similar level of DNA damage as cisplatin. This difference in reactivity was not observed in intact cells as the two maltolato-containing complexes were capable of producing a similar level of damage as cisplatin at comparable concentrations. This was consistent with the IC50 values obtained for both cisplatin and the maltolato compounds which were also similar. This study indicated that maltolato can be utilised as the leaving group to increase the aqueous solubility of cisplatin analogues without reducing their biological activity.

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  • Synthesis and Structure-Activity Studies of Biphenyl Analogues of the Tuberculosis Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)

    Palmer, Brian; Thompson, Andrew; Sutherland, Hamish; Blaser, Adrian; Kmentova, I; Franzblau, SG; Wan, BJ; Wang, YH; Ma, ZK; Denny, William (2010-01-14)

    Journal article
    The University of Auckland Library

    A series of biphenyl analogues of the new tuberculosis drug PA-824 was prepared, primarily by coupling the known (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ol with iodobenzyl halides, followed by Suzuki Coupling Of these iodides with appropriate arylboronic acids or by assembly of the complete biaryl side chain prior to coupling with the above alcohol. Antitubercular activity was determined under both replicating (MABA) and nonreplicating (LORA) conditions. para-Linked biaryls were the most active, followed by meta-linked and then ortho-linked analogues. A more detailed study of a larger group of para-linked analogues showed a significant correlation between potency (MABA) and both lipophilicity (CLOGP) and the electron-withdrawing properties of terminal ring substituents (Sigma sigma). Selected compounds Were evaluated for their efficacy in a mouse model of acute Mycobacterium tuberculosis infection. In vivo activity correlated well with the stability of compounds to microsomal metabolism. Three compounds bearing combinations of lipophilic, electron-withdrawing groups achieved >200-fold higher efficacies than the parent drug.

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