Synthesis of Saponin Immunoadjuvants

360 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2009.The clinical success of conjugate anticancer and antiviral vaccines critically depends on the identification of, and access to, novel adjuvants with high potency and attenuated toxicity. The QS-21 fraction of Quillaja saponaria extracts comprises an isomeric mixture of complex triterpene saponins and is currently the most promising immunopotentiator in several antitumor and infectious disease vaccine therapies. However, the clinical use of QS-21 has been hindered by the difficulty in obtaining sufficient quantities of homogenous saponin from the natural source as well as by the low-grade toxicity and hydrolytic instability of this adjuvant. In this work, a robust chemical route to the two principal isomeric constituents of QS-21 has been established, and synthetically pure adjuvant has been prepared to fuel several pilot trials. In addition, an improved semisynthetic route to pure QS-saponin adjuvants has been developed, facilitating the discovery of novel immunostimulants with increased potency, stability and attenuated toxicity. This method was applied to the synthesis of the natural product adjuvant QS-7-Api and to non-natural aza-saponins. In this initial foray into designed molecular adjuvants, hydrolytically stable saponins have been discovered that equal or excel QS-21 as immunoadjuvants.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD