Synthesis of Active Analogs of Adjuvant Quillaja Saponins in Order to Determine the Structure-Activity Correlation. Studies towards the Synthesis QS-21 (PDF)

The class of plant-derived compounds known as saponins contain some moieties that have potential as vaccine adjuvants, most notably those originating from Quillaja saponaria Molina are potent immunostimulants. Particularly a purified fraction known as QS-21 has been shown to be a potent adjuvant for cytotoxic T-lymphocyte (CTL) induction. Triterpenoid and steroidal glycosides bearing the trisaccharide moiety of Quillaja saponins have been revealed important in immune responses, viral and bacterial infections, inflammation and many other inter and intracellular transductions. Some non-Quillaja saponins containing distinct aglycone moieties showed to be potent immunomodulators when administered together with alum for increasing immune responses in mammals and to be suitable for veterinary and human vaccines. In order to find new biologically active compounds for application in subunit vaccines and to investigate the structure-activity correlation, glycyrrhetic acid and friedelanol triterpenes were chosen as the aglycone moieties. Besides immunoadjuvanticity, other biological activities of interest could possibly be found in compounds bearing the aglycones glycyrrhetic acid and friedelanol, since some of their derivatives are known to have cytoprotective effects on carbon tetrachloride-induced hepatic injury or to be inhibitors of human lymphocyte proliferation and growth of human cancer cell lines in vitro. The biological properties previously mentioned as well as the adjuvant properties found for triterpenoid trisaccharide saponins, make the trisaccharide glycyrrhetic acid and friedelanol saponins interesting target molecules from a biological point of view, and therefore their syntheses are here described. Furthermore, a gypsogenin perbenzylated trisaccharide building block should be synthesized in order to provide a milestone for the total synthesis of QS-21 and analogs.