Synthesis and structure-activity relationship study of cytotoxic germanicane- and lupane-type 3β-O-monodesmosidic saponins starting from betulin
Synthesis and structure-activity relationship study of cytotoxic germanicane- and lupane-type 3β-O-monodesmosidic saponins starting from betulin
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DOI：
10.1016/j.bmc.2007.06.033
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发表时间：
2007-09-15
影响因子：
3.5
通讯作者：
Pichette, Andre
中科院分区：
文献类型：
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作者：
Thibeault, Dominic;Gauthier, Charles;Pichette, Andre
德国烷型三萜别桦木醇（3）和28-氧代别桦木醇（4）可分别通过更有效的羽扇烷型三萜桦木醇（1）和桦木酸（2）的Wagner-Meerwein重排获得。桦木酸（2）及其衍生物的医疗用途是有限的，因为它们的水溶性和药物动力学性质差。为了克服这一主要问题，我们合成并研究了一系列基于6个不同天然糖残基的3 β-O-单链皂苷，它们分别来自白桦脂醇（14-16）、白桦脂酸（20-22）、别白桦脂醇（23-28）和28-氧代别白桦脂（29-34（D-葡萄糖、L-鼠李糖、D-阿拉伯糖、D-半乳糖、D-甘露糖和D-木糖）。该结构-活性关系研究证实，桦木酸皂苷通常是比桦木醇衍生物更好的体外抗癌剂，但桦木醇3 β-O-α-D-吡喃甘露糖苷（15）除外，其对肺癌（A-549）和结肠直肠腺癌（DLD-1）人细胞系具有强效细胞毒性活性，IC 50范围为7.3 - 10.1 μ mol/L。此外，虽然成功地合成了新的锗烷型皂苷，但这些糖苷的生物活性并不像我们预期的那么高，因为只有别桦木醇的3 β-O-β-D-吡喃葡萄糖苷和3 β-O-β-D-吡喃半乳糖苷（23，24）显示出中等的抗癌活性（IC 50 30-40 μ mol/L）。(c)2007爱思唯尔有限公司保留所有权利。
Germanicane-type triterpenes allobetulin (3) and 28-oxoallobetulin (4) can be obtained by the Wagner-Meerwein rearrangement of the more available lupane-type triterpenes betulin (1) and betulinic acid (2), respectively. The medical uses of betulinic acid (2) and its derivatives are limited because of their poor hydrosolubility and pharmacokinetics properties. In order to overcome this major problem, we synthesized and studied the in vitro anticancer activity of a series of 3 beta-O-monodesmosidic saponins derived from betulin (14-16), betulinic acid (20-22), allobetulin (23-28) and 28-oxoallobetulm (29-34) based on six different natural sugar residues (D-glucose, L-rhamnose, D-arabinose, D-galactose, D-mannose and D-xylose). This structure-activity relationship study confirmed that betulinic acid saponins are generally better in vitro anticancer agents than those derived from betulin with the exception of betulin 3 beta-O-alpha-D-mannopyranoside (15) which exerted a potent cytotoxic activity against lung carcinoma (A-549) and colorectal adenocarcinoma (DLD-1) human cell lines with IC50 ranging from 7.3 to 10.1 mu mol/L. Furthermore, although the synthesis of novel germanicane-type saponins was carried out with success, the bioactivity measured for these glycosides was not as high as we anticipated since only the 3 beta-O-beta-D-glucopyranoside and 3 beta-O-beta-D-galactopyranoside of allobetulin (23,24) showed moderate anticancer activity (IC50 30-40 mu mol/L). (c) 2007 Elsevier Ltd. All rights reserved.