Structure activity relationship studies of inhibitors of industrially and medicinally important enzymes.
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
This thesis presents the results of structure-activity relationship (SAR) studies on inhibitors of two important enzymes: alpha-amylase and steroid 5α-reductase. Ascorbic acid, a reported inhibitor of alpha-amylase, has been investigated to determine which of its structural features are necessary for its inhibitory action. These studies have involved the synthesis of thirteen derivatives of L-ascorbic acid and three derivatives of D-isoascorbic acid, incorporating systematic modifications of the functional groups present in both molecules. We have found that the ene-diol moiety in ascorbic acid is crucial for its inhibitory action. Modification of this functionality significantly reduces inhibitory activity. Ascorbic acid, and some of its derivatives, are shown to be potent inhibitors of barley-malt, porcine-pancreas, human-saliva, bacterial- and fungal alpha-amylases. Kinetic studies to determine the mode of inhibition of ascorbic acid demonstrate that it has characteristics of a competitive inhibitor of alpha amylase. SAR studies on inhibitors of steroid 5α-reductase were focused on three main areas; modification of known inhibitors to improve potency and isozyme selectivity, synthesis and investigation of a potential new class of inhibitor and investigation into the utility of a novel pharmacophore. A 4-methyl-octahydrobenzoquinolinone derivative, incorporating a photoisomerisable phenylazo group at the C9 position was synthesised, as was a dihydrophenanthrene-2-carboxylic acid derivative containing a styryl substituent at C7. A series of piperidone derivatives was synthesised to investigate their potential as steroid 5α-reductase inhibitors. Four lactam-based inhibitors of steroid 5α-reductase were modified to incorporate a thiolactam, a previously uninvestigated pharmacophore.