Total Synthesis of Cleistrioside/Cleistetroside Analogues, Aminoglycoside Antibiotics and Their Structure Activity Relationship Study

The carbohydrate portion of natural products plays an important role in their biological activity. The Doherty group has been developing de novo methodologies to build the desired carbohydrate functionality and stereochemistry within each sugar from simple achiral starting materials. The methodologies depend on a highly diastereoselective palladium-catalyzed glycosylation reaction to control the anomeric stereochemistry, and a highly enantioselective Noyori reduction to install the sugar absolute stereochemistry. Appropriate post-glycosylation transformations can create the remaining stereochemistry in the sugar moiety.;To uncover the key structure component important for the biological activity of the cleistrioside/cleistetroside/mezzettiaside natural products, synthesis and SAR study was carried out. The guiding hypothesis of this aim is to find and understand the critical structural element that is responsible and required for the induction of their biological responses in both antibacterial and anticancer activity. Target compounds were successfully synthesized, and then tested for antibacterial and anticancer activities. These studies revealed that although these acylated oligo-rhamnoside natural products contain structural similarities, they showed different antibacterial and anticancer activities, which implied the importance of acylation of carbohydrates and sugar chain length. Based on the finding of antibacterial activity from the reduced sugar chain (dirhamnoside) derivative, a potent lead compound for the further optimization as an antibacterial agent was discovered.;To continue the effort in SAR study and improvement of the biological activities of these oligosaccharide natural products currently found, a series of new derivatives have been synthesized and their biological activities were evaluated with a particular interest in studying the effect of C4-acetate group in their presence and stereochemistry. For instance, four 1,4-alpha- manno-disaccharides and their C4-acetated analogues were synthesized, as well as eight 1,4-alpha-manno-trisaccharides and their C4-acetated analogues by using our palladium-catalyzed glycosylation. While the bactericidal effects of aminoglycosides are well understood, their therapeutic potential in human cells is emerging. Based on the de novo approach to carbohydrates developed in our group, we are attempting the synthesis of novel aminoglycosides with replacement of one or both sugars in known aminoglycosides. Toward this end, the key intermediate has already been synthesized, and the late bidirectional coupling of the sugar motif is under investigation.