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Synthesis of functionalised sulfonamides

Mok, B.L.; (2008) Synthesis of functionalised sulfonamides. Doctoral thesis, UCL (University College London).

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Abstract

Sulfonamides are important therapeutic agents and have a diverse array of biological functions in biology and medicine. Their means of synthesis has often involved the use of unstable sulfonyl chloride species; however, recent research has established pentafluorophenyl (PFP) sulfonate esters as a useful stable alternative to such species. This thesis describes the use of PFP vinyl sulfonate in a [3+2] cycloaddition with a variety of N-methyl-nitrones, providing access to the corresponding 4C-substituted isoxazolidine in a regio- and diastereoselective manner. Aminolysis of the resultant PFP sulfonate ester then provides functionalised sulfonamides of potential biological utility. In addition, the [3+2] cycloaddition reaction of several vinyl sulfonamides with N-methyl-nitrones is reported. Regiospecificity of the reaction is poor, nevertheless a diverse collection of heterocyclic sulfonamide structures have been isolated. Further attempts to further diversify the isoxazolidine products generated from [3+2] cycloaddition chemistry were carried out. The synthesis of isoxazoles from isoxazolidines was explored, and in the process a novel tertiary amine catalysed 'cycloaddition' has been discovered. The resulting isoxazolidine products were assessed as potential biological probes against various enzymes/diseases, and as a result a collection of products were submitted for biological evaluation against the enzymes dimethylarginine dimethylamino hydrolase (DDAH) and arginine deiminase (ADI). Several compounds displayed \muM inhibition against DDAH and ADI; and in addition, these currently represent the first known inhibitors of ADI. During the course of our investigation, it was also revealed that a small assortment of our heterocyclic sulfonamides possess good anti-HIV activity at concentrations of 75-100\muM. Attempts to isolate the cellular target, through modifications to our drug candidates for the purpose of affinity chromatography have also been explored.

Type:Thesis (Doctoral)
Title:Synthesis of functionalised sulfonamides
Language:English
Additional information:Pending digitisation. Abstract contains LATEX text. Please see thesis for rendered formulae and equations
UCL classification:UCL > School of BEAMS > Faculty of Maths and Physical Sciences > Chemistry

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