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628 results on '"Caddick, Stephen"'

51. Synthesis of novel and potent vorapaxar analogues

Author

Knight, Emily, primary, Robinson, Eifion, additional, Smoktunowicz, Natalia, additional, Chambers, Rachel C., additional, Aliev, Abil E., additional, Inglis, Graham G., additional, Chudasama, Vijay, additional, and Caddick, Stephen, additional

Published
2016
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54. 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
Male, Models, Molecular, Guinea Pigs, Stereoisomerism, Research Papers, Propanolamines, Trachea, Structure-Activity Relationship, Adrenergic beta-2 Receptor Antagonists, Drug Design, Cyclic AMP, Animals, Combinatorial Chemistry Techniques, Female, Receptors, Adrenergic, beta-2, Protein Binding, Signal Transduction
Abstract

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.A range of pharmacological assays was used to assess potency, affinity, selectivity (β(2) -adrenoceptor vs. β(1) -adrenoceptor) and efficacy.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.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.

Published
2011

62. Synthetic ligands for apo-neocarzinostatin

Author

Caddick, Stephen, Muskett, Frederick W., Stoneman, Rhys G., and Woolfson, Derek N.

Subjects
Ligands -- Research, Statins -- Chemical properties, Bioflavonoids -- Atomic properties, Flavones -- Atomic properties, Flavonoids -- Atomic properties, Chemistry
Abstract

A new class of ligand for apo-neocarzinostatin (apoNCS) based on the flavone moiety is described. This serves as a synthetically accessible and manipulable small molecule, which has potential as an anchor for the attachment of molecular cargo for binding to apoNCS.

Published
2006

78. Post-translational site-selective protein backbone a-deuteration

Author

Galan, Sébastien R. G., Wickens, James R., Dadova, Jitka, Ng, Wai-Lung, Zhang, Xinglong, Simion, Robert A., Quinlan, Robert, Pires, Elisabete, Paton, Robert S., Caddick, Stephen, Chudasama, Vijay, and Davis, Benjamin G.

Abstract

Isotopic replacement has long-proven applications in small molecules. However, applications in proteins are largely limited to biosynthetic strategies or exchangeable (for example, N–H/D) labile sites only. The development of postbiosynthetic, C–1H ? C–2H/D replacement in proteins could enable probing of mechanisms, among other uses. Here we describe a chemical method for selective protein a-carbon deuteration (proceeding from Cys to dehydroalanine (Dha) to deutero-Cys) allowing overall 1H?2H/D exchange at a nonexchangeable backbone site. It is used here to probe mechanisms of reactions used in protein bioconjugation. This analysis suggests, together with quantum mechanical calculations, stepwise deprotonations via on-protein carbanions and unexpected sulfonium ylides in the conversion of Cys to Dha, consistent with a ‘carba-Swern’ mechanism. The ready application on existing, intact protein constructs (without specialized culture or genetic methods) suggests this C–D labeling strategy as a possible tool in protein mechanism, structure, biotechnology and medicine.

Published
2018
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85. Homogeneous antibody fragment conjugation by disulfide bridging introduces ‘spinostics’

Author

Schumacher, Felix F., primary, Sanchania, Vishal A., additional, Tolner, Berend, additional, Wright, Zoë V. F., additional, Ryan, Chris P., additional, Smith, Mark E. B., additional, Ward, John M., additional, Caddick, Stephen, additional, Kay, Christopher W. M., additional, Aeppli, Gabriel, additional, Chester, Kerry A., additional, and Baker, James R., additional

Published
2013
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90. Protein-small molecule interactions in neocarzinostatin, the prototypical enediyne chromoprotein antibiotic

Author

Baker, James R., Woolfson, Derek N., Muskett, Frederick W., Stoneman, Rhys G., Urbaniak, Michael D., Caddick, Stephen, Baker, James R., Woolfson, Derek N., Muskett, Frederick W., Stoneman, Rhys G., Urbaniak, Michael D., and Caddick, Stephen

Abstract

The enediyne chromoproteins are a class of potent antitumour antibiotics comprising a 1:1 complex of a protein and a noncovalently bound chromophore. The protein is required to protect and transport the highly labile chromophore, which acts as the cytotoxic component by reacting with DNA leading to strand cleavage. A derivative of the best-studied member of this class, neocarzinostatin (NCS), is currently in use as a chemotherapeutic in Japan. The application of the chromoproteins as therapeutics along with their unique mode of action has prompted widespread interest in this area. Notable developments include the discovery of non-natural ligands for the apoproteins and the observation that multiple binding modes are available for these ligands in the binding site. Mutation studies on the apoproteins have revealed much about their stability and variability, and the application of an in vitro evolution method has conferred new binding specificity for unrelated ligands. These investigations hold great promise for the application of the apoproteins for drug-delivery, transport and stabilisation systems.

Published
2007

99. Design and synthesis of a nitrogen mustard derivative stabilized by apo-neocarzinostatin

Author

Urbaniak, Michael D., Bingham, John P., Hartley, John A., Woolfson, Derek N., Caddick, Stephen, Urbaniak, Michael D., Bingham, John P., Hartley, John A., Woolfson, Derek N., and Caddick, Stephen

Abstract

Neocarzinostatin (NCS) is an antitumor antibiotic comprising a 1:1 protein-chromophore complex and exhibits cytotoxic action through DNA cleavage via H-abstraction. Cytotoxic activity resides with the chromophore 1 alone, while the protein (apoNCS) protects and transports labile 1. The naphthoate portion (2) of NCS chromophore (1) is important for binding to apoNCS and DNA intercalation. In this paper we describe our attempts to use apoNCS to improve the hydrolytic stability of novel bifunctional DNA alkylating agents. The nitrogen mustards, melphalan and chlorambucil, were both conjugated to 2, and the biological activities of these conjugates were assessed. Chlorambucil did not benefit from conjugation. The melphalan conjugate (6) formed covalent DNA adducts at guanine bases and exhibited greater in vitro cytotoxic activity than unmodified melphalan. Fluorescence and NMR spectroscopy showed that 6 binds to apoNCS. Binding to apoNCS-protected 6 reduced the extent of hydrolysis of the conjugate. This novel approach demonstrates for the first time that an enediyne apo-protein can be used to improve the stability of substances that are of potential interest in cancer chemotherapy.

Published
2004

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