We have synthesized a wide variety of intramolecular system which simulate the enzyme-substrate complex by having the molecule frozen into a single conformation very favorable to bringing the interacting groups into the closest possible juxta-position (stereopopulation control). These compounds undergo intramolecular reactions at rates approaching those catalyzed enzymes (but independently of any functional group assistance). As part of our studies of practical applications of stereopopulation control, we have explored the use of various SPC- derivatives of biogenic amines and antibiotics as prodrugs. The intent is to facilitate transport from the gut to the circulatory system to the desired site of action by temporary masking of change and polarity within the drug, by improvement in lipophilicity and by protection against enzymatic destruction. Release of the drug is based on local pH variation in ligand sites or on local concentration of a potent reducing enzyme. Recent studies have concentrated on o-nitrophenylpropionic acid derivatives as carriers. To date, these carriers have been coupled with GABA, DOPA derivatives and indolealkylamines. The nitro group is reduced enzymatically, and the resulting amine attacks an amide bond intramolecularly to release the drug. Rapid attack by the amine is ensured by placing a gem-dimethyl group . Surprisingly, xanthine oxidase and various NADH-coupled enzymes reduce the hindered nitro compound more readily than the unhindered. This result reveals that the enzyme must operate on the face of the nitro group, and not just an edge. Response to other reducing agents is now being explored with a view to using such prodrugs to deliver mustards and other anticancer agents to hypoxic cells.
