Total Synthesis and Biological Evaluation of 19-Hydroxysarmentogenin-3-O-α-l-rhamnoside, Trewianin, and Their Aglycons
Total Synthesis and Biological Evaluation of 19-Hydroxysarmentogenin-3-O-α-l-rhamnoside, Trewianin, and Their Aglycons
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19-Hydroxysarmentogenin-3-O-α-l-rhamnoside、Trewianin及其配基的全合成及生物学评价
DOI：
10.1021/acs.joc.8b02219
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Inoue Masayuki
中科院分区：
文献类型：
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作者：
Urabe Daisuke;Nakagawa Yuki;Mukai Ken;Fukushima Kei-ichiro;Aoki Naoto;Itoh Hiroaki;Nagatomo Masanori;Inoue Masayuki
强心内酯是一类重要的天然甾体化合物，具有广泛的生物活性。虽然19-羟基沙拐枣皂苷元-3-O-α-l-鼠李糖苷（1a）和trewianin（1b）的结构被确定为具有Cardenoprotein结构，但它们的生物活性尚未被评价。化合物1a和1b的6/6/6/5元ABCD环均由一个β-取向的C17-丁烯基、三个C11，14，19-羟基和一个C3-O-1-鼠李糖苷修饰。另一方面，1a和1bare在C5-位的差向异构体。1a和1b的结构是由四个简单的片段通过应用收敛和统一的策略组装而成的。AB-环10a/带和D-环8/9与乙缩醛部分初步连接，随后通过立体选择性的6-外消旋反应将两个片段连接起来。接下来，羟醛缩合反应使得能够同时引入5aa和54的C环的三个新的立体中心。将C17-丁烯酰化物连接到糖苷配基2a和2b上，然后将l-鼠李糖连接到2a和2b上，分别得到目标物1a和1b。最后，评估1a、1b、2a和2b对MCF-7人乳腺癌细胞的生长抑制活性。与2a和2b相比，1a和1bin的活性显著更高，证明了单糖子结构的生物学重要性。
Cardenolides comprise an important family of natural steroids with a wide spectrum of biological activities. Although 19-hydroxysarmentogenin-3-O-α-l-rhamnoside (1a) and trewianin (1b) were structurally determined to have cardenolide structures, their biological activities have not been evaluated. The 6/6/6/5-membered ABCD-ring systems of both1aand1bare decorated by a β-oriented C17-butenolide, three C11,14,19-hydroxy groups, and a C3–O-l-rhamnoside moiety. On the other hand,1aand1bare epimeric at the C5-position. The structures of1aand1bwere assembled from four simple fragments by applying a convergent and unified strategy. The AB-ring10a/band the D-ring8/9were tentatively tethered at the acetal moiety, and a subsequent stereoselective 6-exoradical reaction linked the two fragments. Next, an aldol reaction enabled simultaneous introduction of three new stereocenters of the C-rings of5aaand54. Attachment of the C17-butenolide led to aglycons2aand2b.l-Rhamnose was then installed into2aand2bto yield the targets1aand1b, respectively. Finally, the growth inhibitory activity of1a,1b,2a, and2bwas assessed against MCF-7 human breast carcinoma cells. The significantly higher activities of1aand1bin comparison to2aand2bdemonstrated the biological importance of the monosaccharide substructure.