Improved Targeting and Biopharmaceutical Properties of Prodrugs of Anti-infective Agents.

Abstract

The prodrug strategy has been frequently used as a chemical approach for the enhancement of certain disadvantages of parent drugs. In this dissertation, I synthesized prodrugs of two anti-infective agents, ganciclovir and ciprofloxacin, and demonstrated their potential advantages in targeting and biopharmaceutical profiles over the respective parent compounds. In the first project, it was demonstrated that four monoester prodrugs of ganciclovir, N-benzyloxycarbonyl-(L)-alanine-ganciclovir (CbzAlaGCV), N-benzyloxycarbonyl-(α,L)-aminobutyric acid-ganciclovir (CbzAbuGCV), N-acetyl-(L)-phenylalanine-(L)-alanine-ganciclovir (AcPheAlaGCV) and N-acetyl-(L)-phenylalanine-(α,L)-aminobutyric acid-ganciclovir (AcPheAbuGCV), could be hydrolyzed by the human cytomegalovirus (hCMV) protease, a serine protease that possesses intrinsic esterase activities. CbzAlaGCV and AcPheAlaGCV were found to be activated at a higher rate by the hCMV protease than CbzAbuGCV and AcPheAbuGCV. These ganciclovir prodrugs could potentially be targeted to selective activation by hCMV protease. Tissue stability and cellular uptake of these ganciclovir prodrugs were also characterized. The acetylated dipeptide prodrugs of ganciclovir were generally more stable than Cbz-amino acid prodrugs in cell homogenates, plasma and liver microsomes. Among the four prodrug candidates, AcPheAbuGCV was the most stable one in the uninfected tissue matrices and also possessed a superior cellular uptake profile. Since the targeted selective activation of a ganciclovir prodrug is governed by not only its rate of hydrolysis catalyzed by hCMV protease but also its stability in normal tissue matrices as well as the extent of its cellular uptake, AcPheAbuGCV was considered the best overall candidate among the four ganciclovir prodrugs for further development. In another application of the prodrug strategy, I synthesized ciprofloxacyl-glycine methyl ester (Cipro-Gly-OMe), an amide prodrug of ciprofloxacin, the latter classified as a Biopharmaceutical Classification System (BCS) class IV drug. Cipro-Gly-OMe displayed a potentially much higher solubility in the physiological pH range than ciprofloxacin does. Furthermore, Cipro-Gly-OMe may also have a higher intestinal permeability at neutral pH than that of the parent compound. Therefore, through the prodrug methodology, a BCS class IV drug was converted to a potential class I compound. Taken together, the versatility of the prodrug approach makes it an effective and promising strategy for improving the targeting and biopharmaceutical properties of existing anti-infective drugs.