31 results on '"Gillard JW"'
Search Results
2. Alkaloids of Darlingia ferruginea
- Author
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Bick, IRC, Gillard, JW, and Leow, H
- Abstract
Darlingia ferruginea J. F. Bailey contains the new tropane alkaloids ferrugine (2) and 3α-benzoyloxy-2α-hydroxybenzyltropane (4) as well as darlingine (1) and ferruginine (3), which also occur in D. darlingiana. more...
- Published
- 1979
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Catalog
3. Alkaloids of Darlingia darlingiana
- Author
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Bick, IRC, Gillard, JW, and Leow, H
- Abstract
The structures of eleven alkaloids isolated from Darlingia darlingiana (F. Muell.) L. A. S. Johnson, a Queensland proteaceous tree, have been determined. They comprise a tropene, two pyranotropanes, and eight pyrrolidine alkaloids. more...
- Published
- 1979
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4. Alkaloids of Bellendena montana
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Bick, IRC, Gillard, JW, and Leow, H
- Abstract
Fourteen alkaloids have been isolated from Bellendena montana, a monotypic proteaceous plant endemic in Tasmania. The structures of ten of these, bellendine (1), isobellendine (2), darlingine (3),5,ll-dihydroisobellendine (5), 2,3-dihydrobellendine (6), 2,3-epidihydrobellendine (7), 2,3-dihydrodarlingine(8), 3α-acetoxy-6β-isobutoxytropane (9), 6β-acetoxy-3α-isobutoxytropane (10) and 3α-acetoxy-6β-hydroxytropane (11), have been established. more...
- Published
- 1979
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5. Alkaloids of Anthocercis tasmanica (Solanaceae).
- Author
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Bick, IRC, Bremner, JB, Gillard, JW, and Winzenberg, KN
- Abstract
The major alkaloids of Anthocercis tasmanica are shown to be hyoscine and nicotine.
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- 1974
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6. Alkaloids of Agastachys odorata
- Author
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Bick, IRC, primary, Gillard, JW, additional, Leow, HM, additional, and Preston, NW, additional
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- 1979
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7. Effects of Two Soluble ACE2-Fc Variants on Blood Pressure and Albuminuria in Hypertensive Mice: Research Letter.
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Trentin-Sonoda M, Zimpelmann J, Tailor K, Gillard JW, Yoganathan N, Sulea T, and Burns KD
- Abstract
Background: Angiotensin-converting enzyme 2 (ACE2) hydrolyzes angiotensin (Ang) II to Ang-(1-7), promoting vasodilatation, and inhibiting oxidative stress and inflammation. Plasma membrane ACE2 is the receptor for all known SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) viral variants. In COVID-19 infection, soluble ACE2 variants may act as decoys to bind and neutralize the coronavirus, reducing its tissue infectivity. Furthermore, soluble ACE2 variants have been proposed as potential therapeutics for kidney disease and hypertensive disorders., Objective: Soluble ACE2 variants conjugated to human Fc domains and selected for high-potency viral SARS-CoV-2 neutralization were prepared and evaluated for ACE2 activity in vitro. Lead candidates were then tested for systemic ACE2 activity, stability, and effects on blood pressure and albuminuria in mice with Ang II-induced hypertension., Methods: ACE2 activity of 10 soluble ACE2 variants was first assessed in cell-free conditions using a fluorogenic substrate, or by Ang II hydrolysis to Ang-(1-7). Hypertension was induced in male or female mice by implantation of osmotic minipumps containing Ang II. Two lead ACE2 variants were injected intravenously (i.v.) into hypertensive mice, followed by measurements of blood pressure (tail-cuff plethysmography), albuminuria, and tissue ACE2 activity and protein (immunoblots)., Results: Soluble ACE2-Fc variants demonstrated significant ACE2 enzymatic activity, with kinetics comparable with human recombinant ACE2. In hypertensive mice, single dose i.v. injection of ACE2-Fc variant K (10 mg/kg) significantly decreased systolic blood pressure at 24 hours, with partial lowering sustained to 48 hours, and tendency to reduce albuminuria at 72 hours. By contrast, ACE2-Fc variant I had no effect on blood pressure or albuminuria in hypertensive mice; ACE2-Fc variant K was detected by immunoblotting in plasma, kidney, heart, lung, liver, and spleen lysates 72 hours after injection, associated with significantly increased ACE2 activity in all tissues except kidney and spleen. Angiotensin-converting enzyme 2-Fc variant I had no effect on plasma ACE2 activity., Conclusions: Soluble ACE2-Fc variant K reduces blood pressure and tends to lower albuminuria in hypertensive mice. Furthermore, soluble ACE2-Fc variant K has prolonged tissue retention, associated with increased tissue ACE2 activity. The results support further studies directed at the therapeutic potential of soluble ACE2-Fc variant K for cardiovascular and kidney protection., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.) more...
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- 2023
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8. Inhibition of carbonic anhydrase IX in glioblastoma multiforme.
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Amiri A, Le PU, Moquin A, Machkalyan G, Petrecca K, Gillard JW, Yoganathan N, and Maysinger D
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- Acetazolamide administration & dosage, Acetazolamide chemistry, Antineoplastic Agents administration & dosage, Brain Neoplasms enzymology, Carbonic Anhydrase Inhibitors administration & dosage, Caspase 3 metabolism, Cell Death, Cell Line, Tumor, Cell Proliferation drug effects, Combined Modality Therapy methods, Dacarbazine administration & dosage, Dacarbazine chemistry, Drug Carriers chemistry, Glioblastoma enzymology, Humans, Micelles, Spheroids, Cellular, Temozolomide, Time Factors, Tumor Cells, Cultured drug effects, Antineoplastic Agents chemistry, Brain Neoplasms pathology, Carbonic Anhydrase IX antagonists & inhibitors, Carbonic Anhydrase Inhibitors chemistry, Dacarbazine analogs & derivatives, Glioblastoma pathology
- Abstract
Carbonic anhydrase IX (CAIX) is a transmembrane enzyme upregulated in several types of tumors including glioblastoma multiforme (GBM). GBM is among the most aggressive tumors among gliomas. Temozolomide (TMZ) therapy combined with surgical or radiation approaches is the standard treatment but not effective in long term. In this study we tested the treatment with acetazolamide (ATZ), an inhibitor of CAIX, alone or combined with TMZ. The experiments were performed in 2D and 3D cultures (spheroids) using glioblastoma U251N and human brain tumor stem cells (BTSCs). Several proteins implicated in tumor cell death were also investigated. The key results from these studies suggest the following: (1) Cell death of human glioblastoma spheroids and BTSC is significantly increased with combined treatment after 7 days, and (2) the effectiveness of ATZ is significantly enhanced against BTSC and U251N when incorporated into nano-carriers. Collectively, these results point toward the usefulness of nano-delivery of CAIX inhibitors and their combination with chemotherapeutics for glioblastoma treatment., (Copyright © 2016 Elsevier B.V. All rights reserved.) more...
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- 2016
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9. Reliability and minimal detectable change of physical performance measures in individuals with pre-manifest and manifest Huntington disease.
- Author
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Quinn L, Khalil H, Dawes H, Fritz NE, Kegelmeyer D, Kloos AD, Gillard JW, and Busse M
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- Disease Progression, Female, Humans, Male, Middle Aged, Motor Activity physiology, Prospective Studies, Reproducibility of Results, Severity of Illness Index, Surveys and Questionnaires, Disability Evaluation, Exercise Test, Huntington Disease physiopathology
- Abstract
Background: Clinical intervention trials in people with Huntington disease (HD) have been limited by a lack of reliable and appropriate outcome measures., Objective: The purpose of this study was to determine the reliability and minimal detectable change (MDC) of various outcome measures that are potentially suitable for evaluating physical functioning in individuals with HD., Design: This was a multicenter, prospective, observational study., Methods: Participants with pre-manifest and manifest HD (early, middle, and late stages) were recruited from 8 international sites to complete a battery of physical performance and functional measures at 2 assessments, separated by 1 week. Test-retest reliability (using intraclass correlation coefficients) and MDC values were calculated for all measures., Results: Seventy-five individuals with HD (mean age=52.12 years, SD=11.82) participated in the study. Test-retest reliability was very high (>.90) for participants with manifest HD for the Six-Minute Walk Test (6MWT), 10-Meter Walk Test, Timed "Up & Go" Test (TUG), Berg Balance Scale (BBS), Physical Performance Test (PPT), Barthel Index, Rivermead Mobility Index, and Tinetti Mobility Test (TMT). Many MDC values suggested a relatively high degree of inherent variability, particularly in the middle stage of HD. Minimum detectable change values for participants with manifest HD that were relatively low across disease stages were found for the BBS (5), PPT (5), and TUG (2.98). For individuals with pre-manifest HD (n=11), the 6MWT and Four Square Step Test had high reliability and low MDC values., Limitations: The sample size for the pre-manifest HD group was small., Conclusions: The BBS, PPT, and TUG appear most appropriate for clinical trials aimed at improving physical functioning in people with manifest HD. Further research in people with pre-manifest HD is necessary. more...
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- 2013
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10. Cytoprotective effects of IAPs revealed by a small molecule antagonist.
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Galbán S, Hwang C, Rumble JM, Oetjen KA, Wright CW, Boudreault A, Durkin J, Gillard JW, Jaquith JB, Morris SJ, and Duckett CS
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- Cell Line, Tumor, Cells, Cultured, Down-Regulation, HCT116 Cells, Humans, Inhibitor of Apoptosis Proteins genetics, Signal Transduction, X-Linked Inhibitor of Apoptosis Protein metabolism, bcl-2-Associated X Protein metabolism, bcl-X Protein metabolism, Alkynes pharmacology, Dipeptides pharmacology, Inhibitor of Apoptosis Proteins antagonists & inhibitors, Inhibitor of Apoptosis Proteins metabolism, TNF-Related Apoptosis-Inducing Ligand metabolism
- Abstract
Deregulated expression of members of the IAP (inhibitor of apoptosis) family has been identified in a wide variety of neoplastic cells, and synthetic IAP antagonists represent a promising novel class of chemotherapeutic agents. Early work focused on the ability of these compounds to block the caspase-inhibitory function of XIAP (X-linked IAP). However, recent studies have shown that IAP antagonists, although primarily designed to target XIAP, trigger ubiquitin-mediated degradation of two related proteins, c-IAP (cellular IAP) 1 and c-IAP2, and through this process potentiates the death of tumour cells via autocrine cellular-signalling pathways. In this context, the relative contribution of XIAP as a target of this class of compounds is unclear. In the present study, we examine the involvement of XIAP using a recently described synthetic IAP antagonist, AEG40730, and through comparison of a human XIAP-depleted tumour cell line with its isogenic wild-type control line. Treatment with nanomolar concentrations of AEG40730 resulted in the loss of both XIAP and c-IAP1 proteins, albeit with different kinetics. Although XIAP-deficient HCT116 cells retained some sensitivity to external apoptotic stimuli, the results suggest that IAP antagonists, such as AEG40730, exert their apoptosis-enhancing effects through XIAP in addition to the c-IAPs. These results indicate that IAP antagonists can target multiple IAPs to augment distinct pro-apoptotic signalling pathways, thereby revealing the potential for these compounds in cancer therapy and underscoring the promise of IAP-targeted therapies. more...
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- 2009
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11. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination.
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Bertrand MJ, Milutinovic S, Dickson KM, Ho WC, Boudreault A, Durkin J, Gillard JW, Jaquith JB, Morris SJ, and Barker PA
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- Baculoviral IAP Repeat-Containing 3 Protein, Caspase 8 metabolism, Cell Death drug effects, Cell Line, Tumor, Cell Survival drug effects, Enzyme Activation drug effects, Female, Humans, Ovarian Neoplasms, Sulfonamides pharmacology, Inhibitor of Apoptosis Proteins metabolism, Nuclear Pore Complex Proteins metabolism, RNA-Binding Proteins metabolism, Ubiquitin metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
The inhibitor of apoptosis (IAP) family of proteins enhances cell survival through mechanisms that remain uncertain. In this report, we show that cIAP1 and cIAP2 promote cancer cell survival by functioning as E3 ubiquitin ligases that maintain constitutive ubiquitination of the RIP1 adaptor protein. We demonstrate that AEG40730, a compound modeled on BIR-binding tetrapeptides, binds to cIAP1 and cIAP2, facilitates their autoubiquitination and proteosomal degradation, and causes a dramatic reduction in RIP1 ubiquitination. We show that cIAP1 and cIAP2 directly ubiquitinate RIP1 and induce constitutive RIP1 ubiquitination in cancer cells and demonstrate that constitutively ubiquitinated RIP1 associates with the prosurvival kinase TAK1. When deubiquitinated by AEG40730 treatment, RIP1 binds caspase-8 and induces apoptosis. These findings provide insights into the function of the IAPs and provide new therapeutic opportunities in the treatment of cancer. more...
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- 2008
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12. X-linked inhibitor of apoptosis regulates T cell effector function.
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Zehntner SP, Bourbonnière L, Moore CS, Morris SJ, Methot D, St Jean M, Lacasse E, Hebb AL, Robertson GS, Durkin J, Gillard JW, and Owens T
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- Animals, CD4-Positive T-Lymphocytes drug effects, Central Nervous System pathology, Encephalomyelitis, Autoimmune, Experimental chemically induced, Encephalomyelitis, Autoimmune, Experimental pathology, Female, Injections, Intraperitoneal, Mice, Mice, Inbred C57BL, Myelin Proteins, Myelin-Associated Glycoprotein, Myelin-Oligodendrocyte Glycoprotein, Oligonucleotides, Antisense administration & dosage, RNA, Messenger drug effects, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction, X-Linked Inhibitor of Apoptosis Protein drug effects, X-Linked Inhibitor of Apoptosis Protein genetics, Apoptosis immunology, CD4-Positive T-Lymphocytes immunology, Central Nervous System immunology, Encephalomyelitis, Autoimmune, Experimental immunology, X-Linked Inhibitor of Apoptosis Protein physiology
- Abstract
To understand how the balance between pro- and anti-apoptotic signals influences effector function in the immune system, we studied the X-linked inhibitor of apoptosis (XIAP), an endogenous regulator of cellular apoptosis. Real-time PCR showed increased XIAP expression in blood of mice with experimental autoimmune encephalomyelitis, correlating with disease severity. Daily administration (10 mg/kg/day i.p.) of a 19-mer antisense oligonucleotide specific for XIAP (ASO-XIAP) abolished disease-associated XIAP mRNA and protein expression, and given from day of onset, alleviated experimental autoimmune encephalomyelitis and prevented relapses. Prophylactic treatment also reduced XIAP expression and prevented disease. Random or 5-base mismatched ASO was not inhibitory, and ASO-XIAP did not affect T cell priming. In ASO-XIAP-treated animals, infiltrating cells and inflammatory foci were dramatically reduced within the CNS. Flow cytometry showed an 88-93% reduction in T cells. The proportion of TUNEL(+) apoptotic CD4(+) T cells in the CNS was increased from <1.6 to 26% in ASO-XIAP-treated mice, and the proportion of Annexin V-positive CD4(+) T cells in the CNS increased. Neurons and oligodendrocytes were not affected; neither did apoptosis increase in liver, where XIAP knockdown also occurred. ASO-XIAP increased susceptibility of T cells to activation-induced apoptosis in vitro. Our results identify XIAP as a critical controller of apoptotic susceptibility of effector T cell function. more...
- Published
- 2007
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13. Preclinical characterization of AEG35156/GEM 640, a second-generation antisense oligonucleotide targeting X-linked inhibitor of apoptosis.
- Author
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LaCasse EC, Cherton-Horvat GG, Hewitt KE, Jerome LJ, Morris SJ, Kandimalla ER, Yu D, Wang H, Wang W, Zhang R, Agrawal S, Gillard JW, and Durkin JP
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- Animals, Antineoplastic Agents therapeutic use, Apoptosis drug effects, Cell Line, Tumor, Disease Models, Animal, Docetaxel, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Drug Synergism, Gene Expression Profiling, Humans, Mice, Mice, Nude, RNA, Messenger drug effects, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction methods, Sensitivity and Specificity, Structure-Activity Relationship, TNF-Related Apoptosis-Inducing Ligand pharmacology, Taxoids therapeutic use, Transplantation, Heterologous, X-Linked Inhibitor of Apoptosis Protein genetics, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Neoplasms drug therapy, Oligodeoxyribonucleotides, Antisense pharmacology, Oligonucleotides pharmacology, X-Linked Inhibitor of Apoptosis Protein antagonists & inhibitors
- Abstract
Purpose: Cancer cells can use X-linked inhibitor of apoptosis (XIAP) to evade apoptotic cues, including chemotherapy. The antitumor potential of AEG35156, a novel second-generation antisense oligonucleotide directed toward XIAP, was assessed in human cancer models when given as a single agent and in combination with clinically relevant chemotherapeutics., Experimental Design: AEG35156 was characterized for its ability to cause dose-dependent reductions of XIAP mRNA and protein in vitro and in vivo, to sensitize cancer cell lines to death stimuli, and to exhibit antitumor activity in multiple human cancer xenograft models as a single agent or in combination with chemotherapy., Results: AEG35156 reduced XIAP mRNA levels with an EC50 of 8 to 32 nmol/L and decreased XIAP protein levels by >80%. Loss of XIAP protein correlated with increased sensitization to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in Panc-1 pancreatic carcinoma cells. AEG35156 exhibited potent antitumor activity relative to control oligonucleotides in three human cancer xenograft models (prostate, colon, and lung) and was capable of inducing complete tumor regression when combined with taxanes. Antitumor effects of AEG35156 correlated with suppression of tumor XIAP levels., Conclusions: AEG35156 reduces XIAP levels and sensitizes tumors to chemotherapy. AEG35156 is presently under clinical assessment in multiple phase I trials in cancer patients as a single agent and in combination with docetaxel in solid tumors or cytarabine/idarubicin in leukemia. more...
- Published
- 2006
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14. AEG3482 is an antiapoptotic compound that inhibits Jun kinase activity and cell death through induced expression of heat shock protein 70.
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Salehi AH, Morris SJ, Ho WC, Dickson KM, Doucet G, Milutinovic S, Durkin J, Gillard JW, and Barker PA
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- Animals, Antigens, Neoplasm physiology, Benzoquinones, Enzyme Activation, JNK Mitogen-Activated Protein Kinases metabolism, Lactams, Macrocyclic, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins physiology, Neurons cytology, Neurons drug effects, PC12 Cells, Phosphorylation, Quinones pharmacology, Rats, Receptor, Nerve Growth Factor antagonists & inhibitors, Receptor, Nerve Growth Factor physiology, Apoptosis drug effects, Enzyme Inhibitors pharmacology, HSP70 Heat-Shock Proteins biosynthesis, JNK Mitogen-Activated Protein Kinases antagonists & inhibitors, Sulfonamides pharmacology, Thiadiazoles pharmacology
- Abstract
We describe a group of small-molecule inhibitors of Jun kinase (JNK)-dependent apoptosis. AEG3482, the parental compound, was identified in a screening effort designed to detect compounds that reduce apoptosis of neonatal sympathetic neurons after NGF withdrawal. We show that AEG3482 blocks apoptosis induced by the p75 neurotrophin receptor (p75NTR) or its cytosolic interactor, NRAGE, and demonstrate that AEG3482 blocks proapoptotic JNK activity. We show that AEG3482 induces production of heat shock protein 70 (HSP70), an endogenous inhibitor of JNK, and establish that HSP70 accumulation is required for the AEG3482-induced JNK blockade. We show that AEG3482 binds HSP90 and induces HSF1-dependent HSP70 mRNA expression and find that AEG3482 facilitates HSP70 production while retaining HSP90 chaperone activity. These studies establish that AEG3482 inhibits JNK activation and apoptosis by a mechanism involving induced expression of HSP proteins. more...
- Published
- 2006
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15. Application of XIAP antisense to cancer and other proliferative disorders: development of AEG35156/ GEM640.
- Author
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Lacasse EC, Kandimalla ER, Winocour P, Sullivan T, Agrawal S, Gillard JW, and Durkin J
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- Animals, Antineoplastic Agents pharmacology, Apoptosis, Apoptosis Regulatory Proteins, Clinical Trials as Topic, Enzyme Inhibitors pharmacology, Humans, Neoplasms metabolism, Oligonucleotides pharmacology, Oligonucleotides, Antisense chemistry, RNA, Messenger metabolism, Gene Expression Regulation, Enzymologic, Neoplasms therapy, X-Linked Inhibitor of Apoptosis Protein genetics, X-Linked Inhibitor of Apoptosis Protein metabolism
- Abstract
Targeting apoptosis control provides a novel therapeutic approach to the treatment of cancer and other proliferative disorders. We summarize the evidence for apoptosis deregulation in cancer and describe the pivotal role of XIAP, the X-linked Inhibitor-of-APoptosis. XIAP is the predominant inhibitor of caspases 3, 7 and 9 in cells, which suppresses the programmed cell death effector capability of these proteases. Evidence is presented validating XIAP as a cancer target. The inhibition or downregulation of XIAP in cancer cells lowers the apoptotic threshold, thereby inducing cell death and/or enhancing the cytotoxic action of chemotherapeutic agents. We describe the development of AEG35156 (also named GEM640), a second generation antisense compound targeting XIAP, from concept to in vivo preclinical proof-of-principle studies, through formal toxicology, and to a phase 1 clinical trial in cancer patients. more...
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- 2005
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16. Naphthalenic lignan lactones as selective, nonredox 5-lipoxygenase inhibitors. Synthesis and biological activity of (methoxyalkyl)thiazole and methoxytetrahydropyran hybrids.
- Author
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Ducharme Y, Brideau C, Dubé D, Chan CC, Falgueyret JP, Gillard JW, Guay J, Hutchinson JH, McFarlane CS, and Riendeau D
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- Animals, Benzofurans chemistry, Humans, Lactones chemistry, Lipoxygenase metabolism, Lipoxygenase Inhibitors chemistry, Lipoxygenase Inhibitors pharmacology, Male, Naphthalenes chemistry, Neutrophils drug effects, Neutrophils enzymology, Pyrans chemistry, Rats, Rats, Sprague-Dawley, Saimiri, Structure-Activity Relationship, Thiazoles chemistry, Benzofurans chemical synthesis, Benzofurans pharmacology, Lactones chemical synthesis, Lactones pharmacology, Lipoxygenase Inhibitors chemical synthesis, Naphthalenes chemical synthesis, Naphthalenes pharmacology, Pyrans chemical synthesis, Pyrans pharmacology, Thiazoles chemical synthesis, Thiazoles pharmacology
- Abstract
Combinations of structural elements found in (methoxyalkyl)thiazole 1a and methoxytetrahydropyran 2a with a naphthalenic lignan lactone produce the potent 5-lipoxygenase (5-LO) inhibitors 3 and 4. While the nature of link Y-Z has a major effect on the in vitro activity of compounds 1 and 2, inhibitors 3 and 4 retain their potencies with either an oxymethylene (Y = O, Z = CH2) or a methyleneoxy (Y = CH2, Z = O) link. Compound 4b inhibits the oxidation of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid by 5-LO (IC50 = 14 nM) and the formation of leukotriene B4 in human polymorphonuclear leukocytes (IC50 = 1.5 nM) as well as in human whole blood (IC50 = 50 nM). Compound 4b is a selective 5-LO inhibitor showing no significant inhibition of human 15-lipoxygenase or porcine 12-lipoxygenase or binding to human 5-lipoxygenase-activating protein up to 10 microM and inhibits leukotriene biosynthesis by a direct, nonredox interaction with 5-LO. Compound 15, the open form of lactone 4b, is well absorbed in the rat and is transformed into the active species 4b. In addition, 15 is orally active in the rat pleurisy model (ED50 = 0.6 mg/kg) and in the functional model of antigen-induced bronchoconstriction in allergic squirrel monkeys (95% inhibition at 0.3 mg/kg). more...
- Published
- 1994
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17. Discovery of inhibitors of the 5-lipoxygenase activating protein (flap).
- Author
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Young RN, Gillard JW, Hutchinson JH, Léger S, and Prasit P
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- 5-Lipoxygenase-Activating Proteins, Animals, Humans, Indoles chemistry, Indoles pharmacology, Leukotrienes biosynthesis, Lipoxygenase Inhibitors, Rats, Structure-Activity Relationship, Carrier Proteins antagonists & inhibitors, Membrane Proteins antagonists & inhibitors
- Published
- 1993
18. Pharmacology of MK-0591 (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-yl-methoxy)- indol-2-yl]-2,2-dimethyl propanoic acid), a potent, orally active leukotriene biosynthesis inhibitor.
- Author
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Brideau C, Chan C, Charleson S, Denis D, Evans JF, Ford-Hutchinson AW, Fortin R, Gillard JW, Guay J, and Guévremont D
- Subjects
- 5-Lipoxygenase-Activating Proteins, Administration, Oral, Animals, Antigens administration & dosage, Arachidonate 5-Lipoxygenase drug effects, Arachidonate 5-Lipoxygenase metabolism, Ascaris immunology, Bronchoconstriction drug effects, Carrier Proteins metabolism, Carrier Proteins pharmacology, Drug Interactions, Humans, Indoles blood, Leukotriene B4 blood, Lipoxygenase Inhibitors, Male, Membrane Proteins metabolism, Membrane Proteins pharmacology, Quinolines blood, Rats, Rats, Sprague-Dawley, Saimiri, Indoles pharmacology, Leukotriene B4 biosynthesis, Quinolines pharmacology
- Abstract
MK-0591 (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-yl-methoxy)- indol-2-yl]-2,2-dimethyl propanoic acid, previously L-686,708) is a potent inhibitor of leukotriene (LT) biosynthesis in intact human and elicited rat polymorphonuclear leukocytes (PMNLs) (IC50 values 3.1 and 6.1 nM, respectively) and in human, squirrel monkey, and rat whole blood (IC50 values 510, 69, and 9 nM, respectively). MK-0591 had no effect on rat 5-lipoxygenase. MK-0591 has a high affinity for 5-lipoxygenase activating protein (FLAP) as evidenced by an IC50 value of 1.6 nM in a FLAP binding assay and inhibition of the photoaffinity labelling of FLAP by two different photoaffinity ligands. Inhibition of activation of 5-lipoxygenase was shown through inhibition of the translocation of the enzyme from the cytosol to the membrane in human PMNLs. MK-0591 was a potent inhibitor of LT biosynthesis in vivo, first, following ex vivo challenge of blood obtained from treated rats and squirrel monkeys, second, in a rat pleurisy model, and, third, as monitored by inhibition of the urinary excretion of LTE4 in antigen-challenged allergic sheep. Inhibition of antigen-induced bronchoconstriction by MK-0591 was observed in inbred rats pretreated with methysergide, Ascaris-challenged squirrel monkeys, and Ascaris-challenged sheep (early and late phase response). These results indicate that MK-0591 is a potent inhibitor of LT biosynthesis both in vitro and in vivo indicating that the compound will be suitable for assessing the role of leukotrienes in pathological situations. more...
- Published
- 1992
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19. Characterization of a 5-lipoxygenase-activating protein binding assay: correlation of affinity for 5-lipoxygenase-activating protein with leukotriene synthesis inhibition.
- Author
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Charleson S, Prasit P, Léger S, Gillard JW, Vickers PJ, Mancini JA, Charleson P, Guay J, Ford-Hutchinson AW, and Evans JF
- Subjects
- 5-Lipoxygenase-Activating Proteins, Binding, Competitive, Cell Membrane metabolism, Humans, Kinetics, Neutrophils metabolism, Protein Binding, Structure-Activity Relationship, Carrier Proteins metabolism, Indoles metabolism, Leukocytes metabolism, Lipoxygenase Inhibitors pharmacology, Membrane Proteins metabolism, Quinolines metabolism, SRS-A antagonists & inhibitors
- Abstract
A binding assay has been developed to measure the affinity of leukotriene synthesis inhibitors for 5-lipoxygenase-activating protein (FLAP), using human leukocyte membranes as the source of FLAP and a radioiodinated leukotriene synthesis inhibitor, 125I-L-691,831, as ligand. Linearity of specific binding of radiolabeled ligand was demonstrated with increasing protein and ligand concentrations. Saturation analysis of radioligand binding showed a Kd of 6 nM and a Bmax that, depending on the membrane preparation, varied between 8 and 53 pmol/mg of protein. An excellent correlation was shown between affinity for FLAP in the binding assay and inhibition of leukotriene synthesis in human polymorphonuclear leukocytes for compounds from two structurally distinct classes, namely indoles and quinolines. A large number of membrane-active compounds did not compete with 125I-L-691,831 binding to FLAP. In addition, direct 5-lipoxygenase inhibitors and a selection of eicosanoids were unable to compete for FLAP binding. This study validates a selective binding assay for leukotriene synthesis inhibitors whose protein target is FLAP. more...
- Published
- 1992
20. 5-Lipoxygenase-activating protein is the target of a novel hybrid of two classes of leukotriene biosynthesis inhibitors.
- Author
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Mancini JA, Prasit P, Coppolino MG, Charleson P, Leger S, Evans JF, Gillard JW, and Vickers PJ
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- 5-Lipoxygenase-Activating Proteins, Azides metabolism, Azides pharmacology, Binding, Competitive, Carrier Proteins drug effects, Cells, Cultured, Humans, Indoles pharmacology, Iodine Radioisotopes, Leukotriene Antagonists, Membrane Proteins drug effects, Neutrophils drug effects, Neutrophils metabolism, Quinolines pharmacology, Carrier Proteins metabolism, Indoles metabolism, Leukotrienes biosynthesis, Membrane Proteins metabolism, Quinolines metabolism
- Abstract
An 18-kDa leukocyte membrane protein, termed 5-lipoxygenase-activating protein (FLAP), has recently been shown to be the target of two structurally distinct classes of leukotriene biosynthesis inhibitors. These classes of inhibitors are based on indole and quinoline structures and are represented by MK-886 and L-674,573, respectively. A novel class of hybrid structure based on the indole and quinoline classes of inhibitors, termed quindoles, has recently been developed. These compounds, exemplified by L-689,037, are potent inhibitors of leukotriene biosynthesis, both in vitro and in vivo. In the present study, we have developed and characterized a potent radioiodinated photoaffinity analogue of L-689,037, termed [125I]L-691,678. This compound was used in immunoprecipitation studies with FLAP antisera to show that the quindole series of leukotriene biosynthesis inhibitors interact directly with FLAP. In addition, we show that MK-886, L-674,573, and L-689,037 specifically compete, in a concentration-dependent manner, with both [125I]L-691,678 and [125I]L-669,083, a photoaffinity analogue of MK-886, for binding to FLAP. These results suggest that these three classes of leukotriene biosynthesis inhibitors share a common binding site on FLAP, providing further evidence that FLAP represents a suitable target for structurally diverse classes of leukotriene biosynthesis inhibitors. more...
- Published
- 1992
21. Correlation between expression of 5-lipoxygenase-activating protein, 5-lipoxygenase, and cellular leukotriene synthesis.
- Author
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Reid GK, Kargman S, Vickers PJ, Mancini JA, Léveillé C, Ethier D, Miller DK, Gillard JW, Dixon RA, and Evans JF
- Subjects
- 5-Lipoxygenase-Activating Proteins, Affinity Labels, Animals, Arachidonate 5-Lipoxygenase physiology, Azides, Cell Differentiation drug effects, Dimethyl Sulfoxide pharmacology, Granulocytes metabolism, Humans, Immunoblotting, Indoles, Leukemia, Promyelocytic, Acute, Membrane Proteins physiology, Mice, Photochemistry, RNA, Messenger metabolism, Tumor Cells, Cultured, Arachidonate 5-Lipoxygenase genetics, Carrier Proteins, Gene Expression, Leukotriene B4 biosynthesis, Membrane Proteins genetics, SRS-A biosynthesis
- Abstract
Previous studies involving transfection of cDNAs for 5-lipoxygenase-activating protein (FLAP) and 5-lipoxygenase into osteosarcoma cells have shown that both these proteins are essential for leukotriene synthesis (Dixon, R. A. F., Diehl, R. E., Opas, E., Rands, E., Vickers, P. J., Evans, J. F., Gillard, J. W., and Miller, D. K. (1990) Nature 343, 282-284). In the present study we show that FLAP is present in a variety of cells known to produce leukotrienes, but is absent from a number of cells which do not synthesize leukotrienes. Furthermore, differentiation of the human promyelocytic HL-60 cell line towards granulocytic cells following exposure to dimethylsulfoxide is associated with the concurrent induction of both FLAP and 5-lipoxygenase and an increased capacity to synthesize leukotrienes. Cellular leukotriene synthesis in this system is functionally dependent on FLAP as shown by its inhibition by the leukotriene biosynthesis inhibitor MK-886, a compound which specifically binds to FLAP. more...
- Published
- 1990
22. MK886, a potent and specific leukotriene biosynthesis inhibitor blocks and reverses the membrane association of 5-lipoxygenase in ionophore-challenged leukocytes.
- Author
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Rouzer CA, Ford-Hutchinson AW, Morton HE, and Gillard JW
- Subjects
- Arachidonic Acid, Arachidonic Acids pharmacology, Calcimycin pharmacology, Calcium pharmacology, Cell Compartmentation drug effects, Cell Membrane enzymology, Dose-Response Relationship, Drug, Humans, In Vitro Techniques, Leukocytes enzymology, Structure-Activity Relationship, Arachidonate 5-Lipoxygenase metabolism, Arachidonate Lipoxygenases metabolism, Indoles pharmacology, Leukotrienes biosynthesis
- Abstract
Recently, we have shown that ionophore activation of human leukocytes results in leukotriene synthesis and a translocation of 5-lipoxygenase from the cytosol to cellular membrane. This membrane translocation was postulated to be an important early activation step for the enzyme. 3-[1-(p-Chlorobenzyl)-5-(isopropyl)-3-tert-butylthioindol-2-yl]-2, 2- dimethylpropanoic acid (MK886) is a potent and specific inhibitor of leukotriene biosynthesis in vivo and in intact cells, but has no direct effect on 5-lipoxygenase activity in cell-free systems. In this report, we show that MK886 can both prevent and reverse the membrane translocation of 5-lipoxygenase, in conjunction with the inhibition of leukotriene synthesis. Similar compounds of the indole class could also inhibit the membrane translocation of 5-lipoxygenase in a rank order of potency that correlated with their potencies for leukotriene synthesis inhibition. In contrast L-656,224, a direct 5-lipoxygenase inhibitor, had no effect on the translocation of the enzyme. Attempts to demonstrate the effects of MK886 on the association of 5-lipoxygenase with membrane in cell-free preparations failed due to a nonspecific Ca2+-dependent sedimentation of the enzyme. The mechanism of action of MK-886 is therefore to block translocation, prevent subsequent activation of 5-lipoxygenase, and hence block cellular leukotriene biosynthesis. more...
- Published
- 1990
23. Identification and isolation of a membrane protein necessary for leukotriene production.
- Author
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Miller DK, Gillard JW, Vickers PJ, Sadowski S, Léveillé C, Mancini JA, Charleson P, Dixon RA, Ford-Hutchinson AW, and Fortin R
- Subjects
- Amino Acid Sequence, Animals, Azides metabolism, Electrophoresis, Polyacrylamide Gel, Humans, Indoles metabolism, Inflammation, Kinetics, Leukotriene Antagonists, Membrane Proteins isolation & purification, Molecular Sequence Data, Molecular Weight, Rats, Affinity Labels metabolism, Indoles pharmacology, Leukotrienes biosynthesis, Membrane Proteins blood, Neutrophils metabolism
- Abstract
Several inflammatory diseases, including asthma, arthritis and psoriasis are associated with the production of leukotrienes by neutrophils, mast cells and macrophages. The initial enzymatic step in the formation of leukotrienes is the oxidation of arachidonic acid by 5-lipoxygenase (5-LO) to leukotriene A4. Osteosarcoma cells transfected with 5-LO express active enzyme in broken cell preparations, but no leukotriene metabolites are produced by these cells when stimulated with the calcium ionophore A23187, indicating that an additional component is necessary for cellular 5-LO activity. A new class of indole leukotriene inhibitor has been described that inhibits the formation of cellular leukotrienes but has no direct inhibitory effect on soluble 5-LO activity. We have now used these potent agents to identify and isolate a novel membrane protein of relative molecular mass 18,000 which is necessary for cellular leukotriene synthesis. more...
- Published
- 1990
- Full Text
- View/download PDF
24. Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis.
- Author
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Dixon RA, Diehl RE, Opas E, Rands E, Vickers PJ, Evans JF, Gillard JW, and Miller DK
- Subjects
- 5-Lipoxygenase-Activating Proteins, Amino Acid Sequence, Animals, Base Sequence, Cell Line, Gene Expression, Humans, Membrane Proteins genetics, Molecular Sequence Data, Osteosarcoma, Rats, Sequence Homology, Nucleic Acid, Transfection, Arachidonate 5-Lipoxygenase metabolism, Arachidonate Lipoxygenases metabolism, Carrier Proteins, Leukotrienes biosynthesis, Membrane Proteins metabolism
- Abstract
Leukotrienes, the biologically active metabolites of arachidonic acid, have been implicated in a variety of inflammatory responses, including asthma, arthritis and psoriasis. Recently a compound, MK-886, has been described that blocks the synthesis of leukotrienes in intact activated leukocytes, but has little or no effect on enzymes involved in leukotriene synthesis, including 5-lipoxygenase, in cell-free systems. A membrane protein with a high affinity for MK-886 and possibly representing the cellular target for MK-886 has been isolated from rat and human leukocytes. Here, we report the isolation of a complementary DNA clone encoding the MK-886-binding protein. We also demonstrate that the expression of both the MK-886-binding protein and 5-lipoxygenase is necessary for leukotriene synthesis in intact cells. Because the MK-886-binding protein seems to play a part in activating this enzyme in cells, it is termed the five-lipoxygenase activating protein (FLAP). more...
- Published
- 1990
- Full Text
- View/download PDF
25. Adriamycin analogues. Novel anomeric ribofuranoside analogues of daunorubicin.
- Author
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Israel M, Airey JE, Murray RJ, and Gillard JW
- Subjects
- Animals, Antineoplastic Agents metabolism, Antineoplastic Agents pharmacology, DNA metabolism, Daunorubicin chemical synthesis, Doxorubicin pharmacology, Humans, Leukemia L1210 drug therapy, Mice, Structure-Activity Relationship, Antibiotics, Antineoplastic chemical synthesis, Daunorubicin analogs & derivatives
- Abstract
The synthesis, cell growth-inhibitory activity, in vivo antileukemic activity, and extent of DNA binding of the alpha- and beta-anomeric 7-O-(3-amino-3,5-dideoxy-D-ribofuranosyl)daunomycinones and their trifluoroacetamides are described. These compounds are unique in that they are the first reported furanoside analogues of the antitumor antibiotics daunorubicin and adriamycin. Continuing analysis of structure-activity relationships amongst natural and semisynthetic anthracyclines fails to reveal a predictable relationship between in vivo antitumor activity and the in vitro properties of DNA complexation and cell growth inhibition. more...
- Published
- 1982
- Full Text
- View/download PDF
26. Regiochemical control in the Diels-Alder reactions of substituted naphthoquinones. Model studies on a regiospecific approach to adriamycinone.
- Author
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Kelly TR, Gillard JW, Goerner RN Jr, and Lyding JM
- Subjects
- Chemical Phenomena, Chemistry, Doxorubicin chemical synthesis, Methods, Naphthoquinones chemical synthesis, Doxorubicin analogs & derivatives
- Published
- 1977
- Full Text
- View/download PDF
27. Tetrahydrocarbazol-1-acetic acids: new class of thromboxane receptor antagonists.
- Author
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Girard Y, Yoakim-Rancourt C, Hamel P, Gillard JW, Guindon Y, Letts G, Evans J, Léveillé C, Ethier D, and Lord A
- Subjects
- Acetates pharmacology, Animals, Blood Platelets drug effects, Blood Platelets metabolism, Humans, In Vitro Techniques, Muscle Contraction drug effects, Platelet Aggregation drug effects, Receptors, Prostaglandin metabolism, Receptors, Thromboxane, Stereoisomerism, Structure-Activity Relationship, Thromboxane A2 metabolism, Carbazoles pharmacology
- Published
- 1989
28. Metabolic synthesis of arylacetic acid antiinflammatory drugs from arylhexenoic acids. 2. Indomethacin.
- Author
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Gillard JW and Bélanger P
- Subjects
- Animals, Anti-Inflammatory Agents pharmacology, Indomethacin pharmacology, Prodrugs pharmacology, Rats, Species Specificity, Anti-Inflammatory Agents chemical synthesis, Indomethacin metabolism, Pharmaceutical Preparations chemical synthesis, Prodrugs chemical synthesis
- Abstract
Arylacetic acid antiinflammatory drugs can be metabolically produced by beta-oxidation of a 6-arylhex-5-enoic acid side chain. Such a mechanism provides for an in vivo sustained release of the active principle indomethacin from 6-[N-(p-chlorobenzoyl)-2-methylindol-3-yl]hex-5-enoic acid (7). Similarly, biphenylacetic acid was produced from both 6-(4'-biphenylyl)hex-5-enoic acid and its lower even homologue, 4-(4'-biphenylyl)but-3-enoic acid. The indole derivative produced sustained analgesia in a yeast-induced hyperalgesia model over a 12-h period. Indomethacin plasma levels of 2 micrograms/mL were observed for up to 24 h. Such levels were less than those achieved for the analogous case in which biphenylacetic acid was produced from biphenylylhex-5-enoic acid, suggesting metabolic discrimination between hex-5-enoic substrates. When indomethacin was dosed in equipotent analgesic levels, the level of circulating drug was considerably higher than that seen for metabolically derived drug. Hence 6-hex-5-enoic acid derivatives of indomethacin are metabolized to indomethacin in vivo to give sustained analgesia at low apparent circulating plasma levels of free drug. The possibility of tissue compartmentalization enhancing biological efficacy is suggested by these observations. more...
- Published
- 1987
- Full Text
- View/download PDF
29. The use of synthetic thromboxane A2 (TXA2-S) and a new class of thromboxane antagonists, indole-2-propanoic acids to characterize the thromboxane receptor.
- Author
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Gillard JW, Morton HE, Fortin R, Yoakim C, Girard Y, Lord A, Ethier D, Leveille C, Letts G, and Evans J
- Subjects
- 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid, Animals, Binding, Competitive, Blood Platelets drug effects, Blood Platelets metabolism, Guinea Pigs, Humans, In Vitro Techniques, Muscle Contraction drug effects, Platelet Aggregation drug effects, Prostaglandin Endoperoxides, Synthetic pharmacology, Receptors, Thromboxane, Thromboxane A2 pharmacology, Thromboxanes antagonists & inhibitors, Indoles pharmacology, Propionates pharmacology, Receptors, Prostaglandin metabolism, Thromboxane A2 metabolism
- Published
- 1989
30. Biogenesis of proteaceous alkaloids.
- Author
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Bick IR, Gillard JW, Leow HM, Lounasmaa M, Pusset J, and Sévenet T
- Abstract
A scheme is presented which outlines the possible mode of biogenesis of alkaloids so far reported from the proteaceous plants Bellendena montana and Agastachys odorata (both from Tasmania), Darlingia darlingiana and D. ferruginea (from Queensland) and Knightia deplanchei and K. strobilina (from New Caledonia). more...
- Published
- 1981
- Full Text
- View/download PDF
31. Photoaffinity labelling of the human platelet thromboxane A2/prostaglandin H2 receptor.
- Author
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Mais DE, Yoakim C, Guindon Y, Gillard JW, Rokach J, and Halushka PV
- Subjects
- Azides blood, Electrophoresis, Gel, Two-Dimensional, Humans, In Vitro Techniques, Kinetics, Photochemistry, Radioligand Assay, Receptors, Thromboxane, Receptors, Thromboxane A2, Prostaglandin H2, Thromboxane A2 chemical synthesis, Affinity Labels chemical synthesis, Azides chemical synthesis, Blood Platelets metabolism, Prostaglandin Endoperoxides blood, Prostaglandins H blood, Receptors, Prostaglandin metabolism, Thromboxane A2 analogs & derivatives, Thromboxane A2 blood
- Abstract
The synthesis, binding and photoincorporation of a thromboxane A2/prostaglandin H2 (TXA2/PGH2) analog (9,11-dimethylmethano-11,12-methano-16-(3-[125I]iodo-4-azidophenyl )-13,14- dihydro-13-aza-15 alpha beta-omega-tetranor-TXA2) [( 125I]PTA-Azido) to washed human platelets was characterized. Kinetic analysis of the binding of [125I]PTA-Azido at 30 degrees C yielded a k1 of 1.83.10(7) M-1.min-1 and k -1 of 0.195 min-1, Kd = k -1/k1 = 11 nM. Incubation of washed human platelets with [125I]PTA-Azido followed by photolysis resulted in the radiolabelling of a number of platelet proteins as assessed by SDS-PAGE autoradiography. The radiolabelling of three of these protein bands could be either uniformly blocked or reduced with a series of structurally dissimilar TXA2/PGH2 receptor antagonists or agonists and corresponded to proteins with a molecular mass of 43, 39 and 27 kDa. In addition, the incorporation of [125I]PTA-Azido into the three proteins was stereoselectively blocked by a pair of optically active stereoisomers that are TXA2/PGH2 receptor antagonists. Two-dimensional gel electrophoresis indicated that the 43 kDa protein possessed a pI value of 5.6 and that the 27 kDa protein exists in at least three isoforms with pI values of 4.9, 5.1 and 5.3. The labelling pattern was not altered by a mixture of proteinase inhibitors. The data suggest that one or more of these specifically radiolabelled proteins may represent the human platelet TXA2/PGH2 receptor. more...
- Published
- 1989
- Full Text
- View/download PDF
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