Synthetic Studies of Complex Immunostimulants from Quillaja saponaria:  Synthesis of the Potent Clinical Immunoadjuvant QS-21A_api

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.

Chemical Synthesis of Saponins

“…49 The parent D-fucose (30) was first transformed into the 2,4-diol 31 by anomeric allylation and regioselective benzylation via the stannylene acetal intermediate. The equatorial 2-OH group of 31 was masked as its TBS ether, while the 4-OH group was acetylated, thus yielding a fully orthogonally protected intermediate 32.…”

“…59 In 2006, Gin and coworkers reported that global deprotection of the QS-21A api skeleton 64 under various conditions of acidic hydrolysis-hydrogenolysis yielded only trace amount of QS-21A api (66) because the acid-mediated cleavage of the isopropylidene group installed in the apiose moiety could not be effected without compromising the glycosidic linkages (Scheme 13). 49 However, when the isopropylidene group was substituted by a benzylidene group (compound 65), the synthesis of QS-21A api could be successfully completed.…”

“…137 A typical class of oleanane saponins is represented by the glucuronide oleananetype triterpenecarboxylic acid 3,28-O-bidesmosides (GOTCABs), and considerable efforts have been devoted to their synthesis. 49,[138][139][140] The saponin 261, isolated from Aralia dasyphylla, a Chinese medicinal plant for treating hepatitis and diabetes, is claimed to be highly cytotoxic against the KB and HeLa-S 3 human cancer cell lines, with IC 50 values of 1.2 and 0.02 μg/mL, respectively. 141 As a typical member of the family, this saponin (261) was efficiently synthesized in 2004 (Scheme 39).…”

Oxidation of Alcohols, Carbohydrates and Diols

“…The reagent TPAP/NMO/PMS/ CH 3 CN effected a diol to lactone step in the synthesis of the antitumour agent entclavilactone B [358] and the antileukemic agents (−)-eriolangin and (−)-eriolanin [359]. During synthesis of the protein phosphatase inhibitor okadaic acid three oxidations with TPAP/NMO/PMS/CH 2 Cl 2 were used, two of primary alcohol to aldehydes and one of a diol to a lactone [109], and in the synthesis of the immunoadjuvant QS-21A api a diol-to-lactone step is involved [360], as in the case of the lypophilic macrolide rapamycin (cf. 1.11) [181].…”

Drug discovery and development with plant-derived compounds

“…The major aglycone is quillaic acid. A particular feature of Quillaja saponins are the aldehyde group attached to C-4, and a structurally elaborate branched acyl moiety with a terminal L-arabinose [146].…”