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含鼠李糖的熊果酸和桦木酸皂苷的合成、细胞毒性及抗炎活性

Synthesis, cytotoxicity and anti-inflammatory activity of rhamnose-containing ursolic and betulinic acid saponins.

作者信息

Sylla Balla, Lavoie Serge, Legault Jean, Gauthier Charles, Pichette André

机构信息

Centre de Recherche sur La Boréalie (CREB), Chaire de Recherche sur Les Agents Anticancéreux D'origine Naturelle, Laboratoire LASEVE, Département des Sciences Fondamentales, Université du Québec à Chicoutimi 555, Boul. de L'Université Chicoutimi Québec Canada G7H 2B1

Institut des Sciences de la Forêt Tempérée, Université du Québec en Outaouais 58, Rue Principale, Ripon Québec Canada J0V 1V0.

出版信息

RSC Adv. 2019 Dec 2;9(68):39743-39757. doi: 10.1039/c9ra09389c.

DOI:10.1039/c9ra09389c
PMID:35541393
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9076072/
Abstract

Betulinic acid and ursolic acid are ubiquitous, naturally-occurring triterpenoids exhibiting various pharmacological activities including cytotoxic and anti-inflammatory activities. However, these triterpenoids display unfavorable pharmacokinetic properties as well as low aqueous solubility. It has been shown that the presence of α-l-rhamnose moieties positively modulates the anticancer activity of secondary metabolites. Herein we report the synthesis and evaluation of cytotoxic and anti-inflammatory activities of a series of rhamnose-containing ursolic and betulinic acid saponins. Relying on Schmidt's normal and inverse procedures, monorhamnosides, (1→4)-linked dirhamnosides as well as branched trirhamnosides and tetrarhamnosides were synthesized in high yields with full control of stereoselectivity. A betulinic acid saponin bearing a 3--α-l-rhamnopyranosyl-(1→4)-α-l-rhamnopyranosyl residue was found to be a potent cytotoxic agent against human colorectal adenocarcinoma cells without damaging the healthy cells (selectivity ratio > 20) whereas rhamnose-containing ursolic acid saponins potently inhibited NO overproduction induced by LPS-stimulated macrophages. Our results reveal that rhamnose-containing ursolic and betulinic acid saponins represent promising therapeutic agents.

摘要

桦木酸和熊果酸是普遍存在的天然三萜类化合物，具有多种药理活性，包括细胞毒性和抗炎活性。然而，这些三萜类化合物显示出不良的药代动力学性质以及低水溶性。研究表明，α-L-鼠李糖部分的存在对次生代谢产物的抗癌活性有正向调节作用。在此，我们报告了一系列含鼠李糖的熊果酸和桦木酸皂苷的合成及其细胞毒性和抗炎活性的评估。依靠施密特的常规和逆合成方法，以高产率合成了单鼠李糖苷、（1→4）连接的双鼠李糖苷以及支链三鼠李糖苷和四鼠李糖苷，并完全控制了立体选择性。发现一种带有3--α-L-鼠李吡喃糖基-（1→4）-α-L-鼠李吡喃糖基残基的桦木酸皂苷是一种对人结肠直肠腺癌细胞有效的细胞毒性剂，且不会损害健康细胞（选择性比率>20），而含鼠李糖的熊果酸皂苷能有效抑制脂多糖刺激的巨噬细胞诱导的一氧化氮过量产生。我们 的结果表明，含鼠李糖的熊果酸和桦木酸皂苷是有前景的治疗剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9320/9076072/5ec76d1d56fd/c9ra09389c-s6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9320/9076072/b5f590e61688/c9ra09389c-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9320/9076072/a5990870850f/c9ra09389c-s1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9320/9076072/16c815cc28fb/c9ra09389c-s2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9320/9076072/58c18863f19e/c9ra09389c-s3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9320/9076072/77b978ca8c1e/c9ra09389c-s4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9320/9076072/45b1d455a1b3/c9ra09389c-s5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9320/9076072/5ec76d1d56fd/c9ra09389c-s6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9320/9076072/b5f590e61688/c9ra09389c-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9320/9076072/a5990870850f/c9ra09389c-s1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9320/9076072/16c815cc28fb/c9ra09389c-s2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9320/9076072/58c18863f19e/c9ra09389c-s3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9320/9076072/77b978ca8c1e/c9ra09389c-s4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9320/9076072/45b1d455a1b3/c9ra09389c-s5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9320/9076072/5ec76d1d56fd/c9ra09389c-s6.jpg

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