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Evaluation of novel arginine based inhibitors of DDAH and investigations into radical hydroacylation of vinyl sulfonates

Khanom, N.; (2010) Evaluation of novel arginine based inhibitors of DDAH and investigations into radical hydroacylation of vinyl sulfonates. Doctoral thesis, UCL (University College London). Green open access

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Abstract

The thesis is in two main sections. In the first section, studies on methylarginine processing enzymes are presented. Dimethyalrginine dimethylaminohydrolase (DDAH) is a class of enzymes involved in the metabolism of methylarginines ADMA and L-NMMA, which indirectly regulate physiological nitric oxide levels. It is desirable to inhibit excess NO in pathological situations, and the arginine mimetic L-257 is a DDAH inhibitor which reduces levels of NO. Synthesis of ester analogues of L-257 proved to be troublesome with a low yielding key guanidine forming reaction. However, amide analogues were readily synthesised, and testing for DDAH inhibition showed the dimethylamide analogue possessed similar activity to L-257. Further design and synthesis of a 7-membered cyclic analogue, based on the crystal structure of huDDAH1 with L-257, provided a novel analogue with no significant inhibition for rat kidney DDAH. Purified and isolated huDDAH2 protein showed activity after incubation with substrate L-NMMA. In the second part studies on aldehyde auto-oxidation are presented. Aldehydes autoxidise to their acids, via an acyl radical, which can undergo addition reactions with electron-deficient acceptors in a radical hydroacylation reaction. An α- iodo and α-chloro hexanal failed to autoxidise, however 7-hydroxycitronellal readily autoxidised and added to pentafluorophenyl(PFP)-vinyl sulfonate. Further studies on hydroacylation of butanal with PFP-vinyl sulfonate led to functionalised β-ketosulfonates which undergo elimination to form an enone and can then undergo further conjugate addition in situ by nucleophiles. Conjugate addition was carried out using carbon, nitrogen, oxygen and phosphorus nucleophiles, providing a method of obtaining products which are challenging to make via hydroacylation of electron-rich alkenes. Decarbonylation of pivaldehyde to the t-butyl radical, via auto-oxidation, was optimised and the alkyl radical captured by a number of electron-deficient acceptors, providing a complementary method to current methods of t-butyl addition using metal reagents.

Type:Thesis (Doctoral)
Title:Evaluation of novel arginine based inhibitors of DDAH and investigations into radical hydroacylation of vinyl sulfonates
Open access status:An open access version is available from UCL Discovery
Language:English

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