The goal of this project is to optimize the drug delivery system of Paclitaxel (Taxol), an anticancer therapeutic agent. Its low solubility inhibits Taxol's widespread usage. To overcome this drawback, novel compounds of nitro esters and their derivatives will be synthesized and characterized as pro-prodrugs for Taxol. The pro-prodrug being developed for this system is based on ortho-nitrophenylpropionic acid derivatives. The activation of the pro-prod rug into the drug involves two distinct stages. The first is an enzymatic reduction of the ortho-nitro group to an amino group, and the second is a chemical process of side-chain cyclization to form a lactam with simultaneous release of the parent drug. The reduction step is expected to take place in the reductive environment of hypoxic cells, low oxygen regions found in solid tumors. Coupled to the synthetic work are hypoxic cell studies which are expected to offer information about the cellular uptake of the pro-prod rug as well as the cleavage of the pro-prod rug and Taxol.
