Design and synthesis of molecular probes to modulate cell membrane permeation: I. Design, synthesis, and biological evaluation of novel chicoric acid analogues as inhibitors of HIV-1 integrase. II. Design, synthesis, and biological evaluation of novel e

The discovery of effective new drugs is dependent not only upon identifying small molecule candidates that tightly bind to a desired biological target, but also upon finding ones with favorable pharmacological properties. In fact, predicting and controlling characteristics such as toxicity, stability, and bioavailability often proves to be much more troublesome than simply identifying ligands---receptor antagonists or enzyme inhibitors for example---that act on specific targets on or within cells.; This dissertation summarizes our attempts to better understand one pharmacological property of drug candidates: membrane permeability. The goal of the first project is to increase the bioavailability of an HIV-Integrase inhibitor, chicoric acid, by improving the membrane permeability of the compound.; The second project addresses the antithesis of the first project, which is engineering a compound so that it becomes membrane impermeable. The goal of this project is to prevent a membrane permeable steroid from entering a cell, thereby selectively modulating the membrane-bound population of the ligand's endogenous receptor.