| (1) Coumarin-based prodrugs. Clinical development of orally active peptide and peptidomimetic drugs has been hindered by their unfavorable physicochernical properties, which limit their permeation of biological barriers such as the blood brain barrier and the intestinal barrier. Finding solutions to these problems is a very contemporary issue. The undesirable physicochernical properties (e.g., charge, lipophilicity, hydrogen bonding potential, size) of these drugs can be optimized by prodrug strategies to facilitate their transport through these barriers. However, applying the strategy in making prodrugs of peptides and peptidomimetics has been difficult because of their structural complexity and the lack of appropriate methodologies.;We have developed a novel, esterase-sensitive, coumarin-based prodrug system for the preparation of prodrugs of amines, peptides, and peptidomimetics, which are otherwise difficult to make. The design takes advantage of the facile lactonization of cis-coumarinic acid and its derivatives. Using this prodrug strategy, we have prepared esterase-sensitive prodrugs of model amines, opioid peptides and peptidomimetic glycoprotein IIb/IIIa antagonists with greatly improved membrane permeability by optimizing their undesirable physicochemical properties. The cyclic prodrug of tirofiban, an FDA approved antithrombotic glycoprotein IIb/IIIa antagonist, showed greatly improved oral bioactivities in dogs.;(2) Fluorescence sensors. The development of fluorescent sensors for organic molecules is of great practical importance in chemical, biological, and pharmaceutical sciences. Using L-tryptophan and D-fructose as models, we have developed new ways of making polymeric fluorescent sensors using molecular imprinting techniques. The fluorescent polymers showed high selectivity for the template molecules. Because the approach used does not rely on any specific structural features of the template molecules or the prior knowledge of their three-dimensional structure, the same principle could potentially be useful for the future construction of practical fluorescent sensors.;In a related study, we also developed the first fluorescent sensor for boronic/boric acids with high sensitivity. The design takes advantage of the strong binding of the diethanolamine moiety to boronic and boric acids. The incorporation of the diethanolamine moiety into an anthracene unit allows for the modulation of the fluorescence intensity of the andiracene moiety through the suppression of the photoinduced electron transfer (PET) of the nitrogen lone pair electrons upon binding to boronic and boric acids. The sensor shows significant fluorescence intensity changes in the presence of boronic and boric acids at concentrations as low as 10−6–10 −7 M. Sensitive sensors for boronic/boric acids could be used for the analysis and detection of such compounds in a variety of applications in chemistry and biology. |
