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Full-Text Articles in Medicinal-Pharmaceutical Chemistry

Rational Drug Design Directed At Blocking The Initial Signaling Events In Lipopolysaccharide-Induced Sepsis., Christopher A. Tipton Jul 2017

Rational Drug Design Directed At Blocking The Initial Signaling Events In Lipopolysaccharide-Induced Sepsis., Christopher A. Tipton

Theses

Systemic Inflammatory Response Syndrome (SIRS) is classified as an immune system response to an infectious state. If left untreated, SIRS leads to sepsis, septic shock, end-organ dysfunction, and death. As a patient progresses through these stages, associations of acute respiratory distress, disseminated intravascular coagulation, and acute renal failure persist, resulting in millions of deaths annually. Lipopolysaccharide (LPS), a bacterial endotoxin, is released into the blood stream, triggering SIRS. LPS is found in the outer cell-wall of Gram-negative bacteria and is responsible for initiation of a devastating cytokine storm. One of the regions of LPS, lipid A, is a polyacylated glucosamine ...


Diverse Stimuli Engage Different Neutrophil Extracellular Trap Pathways, Elaine F. Kenny, Alf Herzig, Renate Krüger, Aaron Muth, Santanu Mondal, Paul R. Thompson, Volker Brinkmann, Horst Von Bernuth, Arturo Zychlinsky Jun 2017

Diverse Stimuli Engage Different Neutrophil Extracellular Trap Pathways, Elaine F. Kenny, Alf Herzig, Renate Krüger, Aaron Muth, Santanu Mondal, Paul R. Thompson, Volker Brinkmann, Horst Von Bernuth, Arturo Zychlinsky

Thompson Lab Publications

Neutrophils release neutrophil extracellular traps (NETs) which ensnare pathogens and have pathogenic functions in diverse diseases. We examined the NETosis pathways induced by five stimuli; PMA, the calcium ionophore A23187, nigericin, Candida albicans and Group B Streptococcus. We studied NET production in neutrophils from healthy donors with inhibitors of molecules crucial to PMA induced NETs including protein kinase C, calcium, reactive oxygen species, the enzymes myeloperoxidase (MPO) and neutrophil elastase. Additionally, neutrophils from chronic granulomatous disease patients, carrying mutations in the NADPH oxidase complex or a MPO-deficient patient were examined. We show that PMA, C. albicans and GBS use a ...


Design, Synthesis, And Biological Activity Of 1,2,3-Triazolobenzodiazepine Bet Bromodomain Inhibitors [Accepted Manuscript], Phillip P. Sharp, Jean-Marc Garnier, Tamas Hatfaludi, Zhen Xu, David Segal, Kate E. Jarman, Hélène Jousset, Alexandra Garnham, John T. Feutrill, Anthony Cuzzupe, Peter Hall, Scott Taylor, Carl Walkley, Dean Tyler, Mark A. Dawson, Peter Czabotar, Andrew F. Wilks, Stefan Glaser, David C. S. Huang, Christopher J. Burns Jan 2017

Design, Synthesis, And Biological Activity Of 1,2,3-Triazolobenzodiazepine Bet Bromodomain Inhibitors [Accepted Manuscript], Phillip P. Sharp, Jean-Marc Garnier, Tamas Hatfaludi, Zhen Xu, David Segal, Kate E. Jarman, Hélène Jousset, Alexandra Garnham, John T. Feutrill, Anthony Cuzzupe, Peter Hall, Scott Taylor, Carl Walkley, Dean Tyler, Mark A. Dawson, Peter Czabotar, Andrew F. Wilks, Stefan Glaser, David C. S. Huang, Christopher J. Burns

Faculty of Health Sciences Publications

A number of diazepines are known to inhibit bromo- and extra-terminal domain (BET) proteins. Their BET inhibitory activity derives from the fusion of an acetyl-lysine mimetic heterocycle onto the diazepine framework. Herein we describe a straightforward, modular synthesis of novel 1,2,3-triazolobenzodiazepines and show that the 1,2,3-triazole acts as an effective acetyl-lysine mimetic heterocycle. Structure-based optimization of this series of compounds led to the development of potent BET bromodomain inhibitors with excellent activity against leukemic cells, concomitant with a reduction in c-MYC expression. These novel benzodiazepines therefore represent a promising class of therapeutic BET inhibitors.