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Semisynthesis of GPI-0100 Analogues and Synthesis of Its Glucuronide-Congeners as Immunostimulators
|Publication Year :||2019|
|Abstract:||皂皮樹（Quillaja saponaria）是一種富含皂苷的常綠樹。其樹皮的提取物已被廣泛研究並證明具有良好的佐劑活性。將其粗樹皮提取物在溫和的鹼性條件下水解化學不穩定的醯基側鏈，並以醯胺鍵與脂族十二烷基鏈連接，可以得到半合成的GPI-0100。與QS-21相比，它是一種更安全的佐劑，然而，其富含異質成分和潛在的毒性阻礙了其在臨床中的廣泛應用。由於在合成這種皂苷時，將葡萄醣醛酸基與皂皮酸C-3的鍵結是困難及有挑戰性的。為了解決這個問題，我們提出了兩種策略。首先，我們利用6-N-葡萄醣醛基取代葡萄醣醛酸基來合成GPI-0100的葡糖苷酸類源物。在室溫TBDMSOTf酸催化下，6-N-葡萄醣醛基與皂皮酸C-3位置的醣基化可以達到71%的產率。然後將N-6'位置的疊氮還原，並以Cbz保護基做保護，除去C-28的烯丙基後得到化合物39。去保護後的羧基與三醣進行醣基化得到88% 產率（α/β 比例 = 1/10）的40。在40個別與不同芳香基烷基酸鍵結後，進行去保護得到產物42a和42b。另外，我們也開發了一種能夠從皂皮樹皮提取物中以38％分離產率分離出在C-3含有三醣的皂皮酸皂苷44。接著以半合成的方式在C-28的羧基接上三醣，以BF3•OEt2為活化劑得到87%含有六醣的皂苷化合物。在全部去保護後，與末端含有芳香環的烷基胺以醯胺鍵做鍵結，得到最終產物51a和51b。這兩系列的化合物將會進一步評估其免疫刺激能力。|
Quillaja saponaria is an evergreen tree and rich in quillaic acid containing saponins. Extracts from its bark have been extensively studied and demonstrated as promising adjuvant activity. The crude bark extract was processed under mild basic hydrolysis and then conjugated with an aliphatic dodeacyl chain via a hydrolytically stable amide bond to give GPI-0100. Comparing to QS-21, it is a safer adjuvant. However, its heterogeneous composition and inherent toxicity prevent its wider use in clinic. These saponins bearing a glucuronyl group at C-3 position of quillaic acid made it difficult in synthesis process. To solve this problem, two strategies were conducted. Firstly, we synthesized the glucuronide congeners of GPI-0100 via replacing glucurosyl group by 6-N-glycosyl group. Using TBDMSOTf as a promotor, the glycosylation of 6-N-glycosyl donor with quillaic acid 3 gave 36 in 71% yield. Followed by azide reduction and Cbz formation at N-6′ position, and then removal of the allyl group at C-28 afforded compound 39. 39 was glycosylated with trisaccharide donor to afford 40 in 88% yield (/β ratio = 1/10). Compound 40 was then subjected to hydrogenolysis under 55 psi H2 catalyzed by 10% Pd(OH)2/C, followed by amide formation with two arylalkanoic acids, acid/base hydrolysis to afford final products 42a and 42b. Secondly, we developed an isolation method from Q. saponaria tree bark extract to get 3-O-trisaccharide containing quillaic acid 44 in 38% isolated yield, 44 was also semi-synthesized with trisachharide at C-28 position by using BF3•OEt2 as a promotor to afford 46 (87% yield), followed by global deprotections and then conjugated with two arylalkyl amines to give finals 51a and 51b. Both series of compounds will be evaluated for immunostimuating ability in the future.
|Appears in Collections:||藥學系|
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