Perera, Madri Yasoja; (1991) Nitrogen containing heterocycles as potential inhibitors of serine proteinase. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Some nitrogen heterocycles such as pteridines and quinazolines undergo "covalent hydration" - the reversible addition of water across a C=N bond. Alcohols and other nucleophiles can also add across this C=N bond. Serine proteinases catalyse the hydrolysis of peptide bonds and contain an unusually reactive serine OH residue at the enzyme active site. So far, the most potent serine proteinase inhibitors have been boronic acid derivatives of appropriate peptide substrates, which act as transition-state (t.s.) analogues. Here, the peptide provides enzymic active site recognition and the serine oxygen electron lone pair adds to the boron atom to form a stable tetrahedial intermediate. Aldehydes and electron deficient ketones also form such tetrahedral complexes. It seemed possible that heterocycles which undergo covalent hydration should also act as t.s. analogues to provide a novel approach to designing inhibitors of serine proteinase. Several 2-substituted pteridines and quinazolines have been synthesised and tested against various serine proteinases such as the CCK-inactivating peptidase, trypsin, chymotrypsin and elastase. A good synthetic route to 2-N-alkylamidopteridines has also been achieved. Furthermore, the 2-N-alkylamidopteridines have been investigated by UV and 1H NMR spectroscopy and shown to undergo covalent addition much more readily than either 2-aminopteridine or pteridine itself; the addition follows first order kinetics on approaching equilibrium. Even though the compounds do not possess specific groups for enzymic active site recognition, some are active in the milli-molar range. It appears that suitably substituted pteridines and quinazolines may prove to be good inhibitors of serine proteinases but that they require appropriate additional groups to assist binding to the active sites. At this stage, it is concluded that nitrogen containing heterocycles that undergo covalent hydration are potential inhibitors of serine proteinase, where covalent hydration may determine activity, but is not a sufficient condition.

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