Studies of enzyme inhibition by compounds containing small rings.

Our interest in the enzyme chemistry of compounds containing small rings developed from a speculative study of the inhibition of alcohol dehydrogenase by allylic alcohols (MacInnes et al., 1981) in which we found that 3-thioethylprop-2-en1-01 (I) was a potent inhibitor of this enzyme. Our original strategy was that oxidation of (I) would lead to an a,/?-unsaturated aldehyde to which a nucleophile at the active site would add leading to the inhibited enzyme. However, we found that, although inhibition accompanied oxidation of (I), the enzyme recovered activity on standing or on gel filtration apparently through hydrolysis. It turned out that the persistence of inhibition was due to ethanethiol, a hydrolysis product, bound at the active site. We argued that, in view of the similarities between alkene and cyclopropane chemistry, oxidation of cyclopropylmethanols (e.g. 11) to the aldehydes would activate the cyclopropane ring to nucleophilic attack and ring opening. The reverse of this reaction would be improbable and inhibition should be permanent. This strategy proved successful (MacInnes et al., 1983a) as will be discussed below.