Synthetic Studies of Complex Immunostimulants from <em>Quillaja saponaria</em>: Synthesis of the Potent Clinical Immunoadjuvant QS-21A<sub>api</sub>

Yong Kim

Pengfei Wang

Mauricio Navarro-Villalobos

Bridget Rohde

JohnMark Derryberry

David Gin

Contribution from the Department of Chemistry, University of Illinois, Urbana, Illinois 61801, and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021

^{Address correspondence to: Memorial Sloan-Kettering Cancer Center, E-mail:}gro.ccksm@dnig

Abstract

QS-21 is one of the most promising new adjuvants for immune response potentiation and dose-sparing in vaccine therapy given its exceedingly high level of potency and its favorable toxicity profile. Melanoma, breast cancer, small cell lung cancer, prostate cancer, HIV-1, and malaria are among the numerous maladies targeted in more than 80 recent and ongoing vaccine therapy clinical trials involving QS-21 as a critical adjuvant component for immune response augmentation. QS-21 is a natural product immunostimulatory adjuvant, eliciting both T-cell- and antibody-mediated immune responses with microgram doses. Herein is reported the synthesis of QS-21A_api in a highly modular strategy, applying novel glycosylation methodologies to a convergent construction of the potent saponin immunostimulant. The chemical synthesis of QS-21 offers unique opportunities to probe its mode of biological action through the preparation of otherwise unattainable nonnatural saponin analogues.

Abstract

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