This project addresses the synthesis, computer modeling, and enzymatic studies of potential small molecule inhibitors of carbohydrate-processing enzymes. A general, efficient asymmetric synthesis, starting from commercially-available sugars, will be developed for every stereoisomer of a family of polyhydroxylated pyrrolidines, pyrrolizidines and indolizidines, some of which are known to inhibit carbohydrate processing enzymes. Although these classes of hydroxylated alkaloids have been known for a long time, not every possible stereoisomer of the compounds within each class has been studied. Central to the syntheses of all three classes of compounds is a one-pot reductive ring opening/reductive amination reaction that starts with the reduction of a 6-halopyranoside to a substituted 5-hexenal. The aldehyde of 5-hexenal is then reductively aminated to form a substituted 6-amino-1-alkene in the same reaction mixture. In the case of the pyrrolidines, the 6-amino-1-alkene immediately undergoes an intramolecular nucleophilic substitution reaction to form substituted 2-vinyl-pyrrolidine. If the amine used in the reductive amination is properly substituted, both the indolizidines and pyrrolizidines systems can be synthesized by performing a ruthenium-catalyzed metatheses reaction before the internal nucleophilic substitution. The resulting polyhydroxylated alkaloids will be tested for their ability to inhibit carbohydrate-processing enzymes. The inhibition results will be coupled with computer modeling and docking studies to establish criteria for predicting which stereoisomers of these alkaloids should inhibit specific glycosidases
With this RUI award, the Organic and Macromolecular Chemistry Program is supporting the research of Professor Louis J. Liotta, of the Department of Chemistry at Stonehill College, and Professor Kenneth R. Overly, of the Department of Chemistry and Biochemistry at Providence College. Carbohydrates are the most widely distributed, naturally occurring organic compounds on earth. This project will provide both new synthetic methodology and new insight into the nature of carbohydrate-processing enzymes. The ability to obtain every stereoisomer of the alkaloids in this proposal in conjunction with modeling and docking studies will allow for a more thorough study of the structure/function relationship of carbohydrate-processing enzymes. This study of structure/function relationships will lead to a better molecular understanding of many important biological processes and could lead to the design of better inhibitors, ultimately leading to a greater chance that successful drugs will be developed. The project will be carried out by a diverse group of undergraduate students and will also include two economically disadvantaged high school student collaborators and one high school teacher each summer.
