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76 results on '"Caddick, Stephen"'

3. Cysteine Promoted C-Terminal Hydrazinolysis of Native Peptides and Proteins.

Author

Adams, Anna L., Cowper, Ben, Morgan, Rachel E., Premdjee, Bhavesh, Caddick, Stephen, and Macmillan, Derek

Subjects
ERYTHROPOIETIN, HYDRAZIDES, PEPTIDES, ESTERIFICATION, CHEMICAL reactions
Abstract

Tagging the terminus: N→S acyl transfer in native peptides and proteins can be reliably intercepted with hydrazine. The method allows selective labeling and ligation, without recourse to the use of protein‐splicing elements. NCL=native chemical ligation. [ABSTRACT FROM AUTHOR]

Published
2013
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4. The design, synthesis and pharmacological characterization of novel β₂-adrenoceptor antagonists.

Author

Hothersall, J Daniel, Black, James, Caddick, Stephen, Vinter, Jeremy G, Tinker, Andrew, and Baker, James R

Subjects
DRUG design, ADRENERGIC receptors, HORMONE antagonists, PHARMACOLOGY, RECEPTOR-ligand complexes, DRUG activation, PHARMACEUTICAL chemistry
Abstract

Background and Purpose: Selective and potent antagonists for the β(2) -adrenoceptor are potentially interesting as experimental and clinical tools, and we sought to identify novel ligands with this pharmacology.Experimental Approach: A range of pharmacological assays was used to assess potency, affinity, selectivity (β(2) -adrenoceptor vs. β(1) -adrenoceptor) and efficacy.Key Results: Ten novel compounds were identified but none had as high affinity as the prototypical β(2) -adrenoceptor blocker ICI-118,551, although one of the novel compounds was more selective for β(2) -adrenoceptors. Most of the ligands were inverse agonists for β(2) -adrenoceptor-cAMP signalling, although one (5217377) was a partial agonist and another a neutral antagonist (7929193). None of the ligands were efficacious with regard to β(2) -adrenoceptor-β-arrestin signalling. The (2S,3S) enantiomers were identified as the most active, although unusually the racemates were the most selective for the β(2) -adrenoceptors. This was taken as evidence for some unusual enantiospecific behaviour.Conclusions and Implications: In terms of improving on the pharmacology of the ligand ICI-118,551, one of the compounds was more selective (racemic JB-175), while one was a neutral antagonist (7929193), although none had as high an affinity. The results substantiate the notion that β-blockers do more than simply inhibit receptor activation, and differences between the ligands could provide useful tools to investigate receptor biology. [ABSTRACT FROM AUTHOR]

Published
2011
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5. Inhibition of HIV-1 Replication by Isoxazolidine and Isoxazole Sulfonamides.

Author

Loh, Belinda, Vozzolo, Luciano, Mok, B. James, Lee, Chien Chi, Fitzmaurice, Richard J., Caddick, Stephen, and Fassati, Ariberto

Subjects
ANTIVIRAL agents, HIV infections, GENE expression, VIRAL replication, DRUG resistance
Abstract

Targeting host factors is a complementary strategy for the development of new antiviral drugs. We screened a library of isoxazolidine and isoxazole sulfonamides and found four compounds that inhibited HIV-1 infection in human CD4+ lymphocytic T cells with no toxicity at IC90 concentrations. Structure-activity relationship showed that benzyl sulfonamides and a halo-substituted aromatic ring on the heterocycle scaffold were critical for antiretroviral activity. The size and position of the incorporated halogen had a marked effect on the antiretroviral activity. The sulfonamide derivatives had no significant effect on HIV-1 entry, reverse transcription and integration but impaired a step necessary for activation of viral gene expression. This step was Tat-independent, strongly suggesting that the target is a cell factor. A virus partially resistant to the least potent compounds could be selected but could not be propagated in the long term, consistent with the possibility that HIV-1 may be less likely to develop resistance against drugs targeting some host factors. Here, we provide evidence that novel synthetic methods can be applied to develop small molecules with antiretroviral activity that target host factors important for HIV-1 replication. [ABSTRACT FROM AUTHOR]

Published
2010
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6. Density functional and spectroscopic studies of nitrogen inversion in substituted dizocilpines.

Author

Aliev, Abil E., Sinclair, Alex j., Shen Zhou, Wilden, John D., Caddick, Stephen, Kullmann, Dimitri M., and Rusakov, Dmitri A.

Subjects
NITROGEN, HYDROXYLAMINE, CHEMICAL elements, DENSITY, ENANTIOSELECTIVE catalysis
Abstract

While developing a synthesis towards tagged dizocilpine (MK-801) analogues, we observed highly restricted inversion of a nitrogen centre in a number hydroxylamines obtained as key intermediates. These compounds are shown to possess some of the structural elements which are expected to significantly hinder the nitrogen inversion, potentially leading to hydroxylamines with a chiral nitrogen centre. Free energy barriers (ΔG≠) of the nitrogen inversion were estimated to be ca. 22 kcal mol-1 at temperatures near 420 K using variable temperature NMR measurements in DMSO-d6. Further density functional studies of a number model systems were undertaken in order to better rationalize the measured inversion barriers and follow the role of various structural factors in raising the barrier height of the nitrogen inversion process. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Published
2009
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9. 13th IIS (UK group) symposium.

Author

Caddick, Stephen, Stone-Elander, Sharon, Patching, Simon G., Herbert, Richard B., Henderson, Peter J. F., Brough, Adrian R., Middleton, David A., Coumbarides, Gregory S., Eames, Jason, Ghilagaber, Stephanos, Suggate, Michael J., Weerasooriya, Neluka, Spivey, Alan C., Diaper, Chris, Srikaran, Ratnasothy, Jones, Teyrnon, Noban, Catherine, Ellames, George J., Kohler, Andrew, and Wadsworth, Harry

Published
2004
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