We have synthesized a wide variety of intramolecular systems which simulate the enzyme-substrate complex by having the molecular frozen into a single conformation very favorable to bringing the interacting groups into the closest possible juxtaposition (stereopopulation control). These compounds undergo intramolecular reactions at rates approaching those catalyzed by 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 drugs as pro-prodrugs. The intent is to facilitate transport from the gut to the circulatory system to the desired site of action by temporary masking of charge and polarity within the drug, by improvement in lipophilicity and by protection against enzymatic destruction. Recent studies have concentrated on o-nitrophenylpropionic acid derivatives as carriers. The nitro group is reduced enzymatically, and the resulting amine attacks an amide or ester bond intramolecularly to release the drug. Rapid attack by the amine is ensured by placing a gem-dimethyl group on the adjacent carbon atom. Efficient enzymatic reduction of the nitro group, however, requires a reducing, or hypoxic, environment. Thus, such a carrier is ideally suited to effect selective drug release at an hypoxic cancer cell, while remaining largely unaffected at the surface of a normal cell with high oxygen content. Incubation of our first carrier-taxol complex with a clone of breast cancer cells has shown levels of toxicity comparable to those of taxol itself. Studies with additional complexes are in progress, on a scale large enough to determine the fate of the carriers. Much larger amounts of carrier-drug complex are being prepared for whole animal studies, which are necessary in order to evaluate the degree of selective taxol release at the hypoxic cancer cell. Additional studies are in progress to link these carriers to other cancer chemotherapeutic agents, such as 5-fluorouracil.
