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Dive into the research topics where Sharon Rossiter is active.

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Featured researches published by Sharon Rossiter.


Nature Medicine | 2007

Disruption of methylarginine metabolism impairs vascular homeostasis.

James Leiper; Manasi Nandi; Belen Torondel; Judith Murray-Rust; Mohammed Malaki; Bernard O'Hara; Sharon Rossiter; Shelagh Anthony; Melanie Madhani; David L. Selwood; Caroline L. Smith; Beata Wojciak-Stothard; Alain Rudiger; Ray Stidwill; Neil Q. McDonald; Patrick Vallance

Asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA) are endogenously produced amino acids that inhibit all three isoforms of nitric oxide synthase (NOS). ADMA accumulates in various disease states, including renal failure, diabetes and pulmonary hypertension, and its concentration in plasma is strongly predictive of premature cardiovascular disease and death. Both L-NMMA and ADMA are eliminated largely through active metabolism by dimethylarginine dimethylaminohydrolase (DDAH) and thus DDAH dysfunction may be a crucial unifying feature of increased cardiovascular risk. However, despite considerable interest in this pathway and in the role of ADMA as a cardiovascular risk factor, there is little evidence to support a causal role of ADMA in pathophysiology. Here we reveal the structure of human DDAH-1 and probe the function of DDAH-1 both by deleting the DDAH1 gene in mice and by using DDAH-specific inhibitors which, as we demonstrate by crystallography, bind to the active site of human DDAH-1. We show that loss of DDAH-1 activity leads to accumulation of ADMA and reduction in NO signaling. This in turn causes vascular pathophysiology, including endothelial dysfunction, increased systemic vascular resistance and elevated systemic and pulmonary blood pressure. Our results also suggest that DDAH inhibition could be harnessed therapeutically to reduce the vascular collapse associated with sepsis.


Tetrahedron Letters | 2002

A convenient synthesis of 3-methyleneoxindoles: cytotoxic metabolites of indole-3-acetic acids

Sharon Rossiter

Abstract 3-Methyleneoxindole is a cytotoxic metabolite of indole-3-acetic acid with potential for use in cancer therapy. This species and ring-substituted analogues are conveniently synthesised from the corresponding isatins via a Peterson olefination.


Bioorganic & Medicinal Chemistry Letters | 2002

Halogenated indole-3-acetic acids as oxidatively activated prodrugs with potential for targeted cancer therapy

Sharon Rossiter; Lisa K. Folkes; Peter Wardman

Substituted indole-3-acetic acid (IAA) derivatives, plant auxins with potential for use as prodrugs in enzyme-prodrug directed cancer therapies, were oxidised with horseradish peroxidase (HRP) and toxicity against V79 Chinese hamster lung fibroblasts was determined. Rate constants for oxidation by HRP compound I were also measured. Halogenated IAAs were found to be the most cytotoxic, with typical surviving fractions of <10(-3) after incubation for 2h with 100 microM prodrug and HRP.


Organic and Biomolecular Chemistry | 2003

Demethylation of 2,4-dimethoxyquinolines: the synthesis of atanine

Keith Jones; Xavier Roset; Sharon Rossiter; Philip J. Whitfield

The synthesis of the quinoline alkaloid atanine 6, by selective demethylation of the 2,4-dimethoxyquinoline 11 is presented. An alternative demethylation utilising a thiolate anion leads to the regioisomeric 4-hydroxyquinoline 13.


Chemical Communications | 2005

Inhibition of dimethylarginine dimethylaminohydrolase (DDAH) and arginine deiminase (ADI) by pentafluorophenyl (PFP) sulfonates

Patrick Vallance; Hannah D. Bush; B. James Mok; Ramon Hurtado-Guerrero; Herpreet Gill; Sharon Rossiter; Jonathan D. Wilden; Stephen Caddick

A range of pentafluorophenyl (PFP) sulfonate esters derived from the reaction of PFP vinyl sulfonate and various nitrones are shown to have significant inhibitory activity against the bacterial enzymes DDAH and ADI.


Chemical Research in Toxicology | 2002

Reactivity toward thiols and cytotoxicity of 3-methylene-2-oxindoles, cytotoxins from indole-3-acetic acids, on activation by peroxidases.

Lisa K. Folkes; Sharon Rossiter; Peter Wardman

Oxidation of indole-3-acetic acid and its derivatives by peroxidases such as that from horseradish produces many products, including 3-methylene-2-oxindoles. These have long been associated with biological activity, but their reactivity has not been characterized. We have previously demonstrated the potential value of substituted indole acetic acids and horseradish peroxidase as the basis for targeted cancer therapy, since the compounds are of low cytotoxicity until oxidized, when high cytotoxicity is observed; the combination of prodrug and enzyme depletes intracellular thiols. In this study, 3-methylene-2-oxindole and derivatives substituted in the 4-, 5-, or 6-position with methyl, F, or Cl have been synthesized and their reactivity toward representative thiol nucleophiles (glutathione, cysteine, and a cysteinyl peptide) measured using stopped-flow kinetic spectrophotometry. Rate constants were in the range approximately 2 x 10(3) to 2 x 10(4) M(-)(1) s(-)(1) at pH 7.4, 25 degrees C, implying a lifetime of a few tens of milliseconds for these methylene oxindoles in the cellular environment and diffusion distances of a few micrometers. As expected, halogen substitution decreased the rate of production of the methylene oxindoles on treatment of horseradish peroxidase. The cytotoxicities of the compounds were measured using Chinese hamster V79 fibroblast-like cells in vitro. The halogen-substituted derivatives were much more cytotoxic than the 5-methyl analogue or the parent (unsubstituted) compound, consistent with the trends in rate constant for reaction with the thiols. The results show that the cytotoxic response in the prodrug (indole acetic acid) and enzyme (horseradish peroxidase) system reflects the reactivity of methylene oxindoles toward nucleophiles much more than the rate of generation of the oxindoles, and helps explain the possible advantages of 5-fluoroindole-3-acetic acid compared to IAA as a lead compound for investigation in targeted cancer therapy.


Pharmaceutics | 2018

In Silico Structural Evaluation of Short Cationic Antimicrobial Peptides

Ilaria Passarini; Sharon Rossiter; John P. Malkinson; Mire Zloh

Cationic peptides with antimicrobial properties are ubiquitous in nature and have been studied for many years in an attempt to design novel antibiotics. However, very few molecules are used in the clinic so far, sometimes due to their complexity but, mostly, as a consequence of the unfavorable pharmacokinetic profile associated with peptides. The aim of this work is to investigate cationic peptides in order to identify common structural features which could be useful for the design of small peptides or peptido-mimetics with improved drug-like properties and activity against Gram negative bacteria. Two sets of cationic peptides (AMPs) with known antimicrobial activity have been investigated. The first reference set comprised molecules with experimentally-known conformations available in the protein databank (PDB), and the second one was composed of short peptides active against Gram negative bacteria but with no significant structural information available. The predicted structures of the peptides from the first set were in excellent agreement with those experimentally-observed, which allowed analysis of the structural features of the second group using computationally-derived conformations. The peptide conformations, either experimentally available or predicted, were clustered in an “all vs. all” fashion and the most populated clusters were then analyzed. It was confirmed that these peptides tend to assume an amphipathic conformation regardless of the environment. It was also observed that positively-charged amino acid residues can often be found next to aromatic residues. Finally, a protocol was evaluated for the investigation of the behavior of short cationic peptides in the presence of a membrane-like environment such as dodecylphosphocholine (DPC) micelles. The results presented herein introduce a promising approach to inform the design of novel short peptides with a potential antimicrobial activity.


Reference Module in Chemistry, Molecular Sciences and Chemical Engineering#R##N#Comprehensive Heterocyclic Chemistry III | 2008

Three heterocyclic rings fused (5:6:5).

Sharon Rossiter; Stephen Hilton

The chapter gives an updated overview of the many chemically and structurally diverse 5-6-5 fused tricyclic heterocyclic systems that are reported in the literature. These include fully conjugated systems, some of which have attracted interest for their electronic properties, e.g., dipyrazolopyridines, and non-conjugated systems such as the biologically interesting fused diketopiperazines. The systems outlined in the chapter are classified according to the central six-membered ring. Six-membered rings with one or more nitrogens are the most abundant and are further classified according to the number and positioning of the nitrogen(s) and ring saturation. Rings containing O, P, S or mixed heteroatoms are less abundant, but represent some very interesting and diverse chemistry. Theoretical and spectral methods and the physical properties of these ring systems are explored. Reactivity of ring carbons and heteroatoms and ring substituents are described. Synthesis of the numerous classes of compounds is reviewed for linear, angular, peri- and epi-fused ring systems. Routes from acyclic, monocyclic, and 5,6-bicyclic precursors, or by ring transformations, are also reviewed. Common methods are synthesis by cyclization onto a central six-membered ring or formation of the central six-membered ring by a wide variety of reaction types, making this an interesting and varied area of heterocyclic synthetic chemistry.


Journal of Medicinal Chemistry | 2005

Selective substrate-based inhibitors of mammalian dimethylarginine dimethylaminohydrolase

Sharon Rossiter; Caroline L. Smith; Mohammed Malaki; Manasi Nandi; Herpreet Gill; James Leiper; Patrick Vallance; David L. Selwood


Molecular Cancer Therapeutics | 2001

Horseradish peroxidase-mediated gene therapy : choice of prodrugs in oxic and anoxic tumor conditions

Olga Greco; Sharon Rossiter; Chryso Kanthou; Lisa K. Folkes; Peter Wardman; Gillian M. Tozer; Gabi U. Dachs

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James Leiper

Imperial College London

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Herpreet Gill

University College London

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Madhu Goyal

University of Hertfordshire

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