Graduate School of Pharmaceutical Sciences , The University of Tokyo , 7-3-1 Hongo , Bunkyo-ku , Tokyo 113-0033 , Japan.
J Org Chem. 2018 Nov 16;83(22):13888-13910. doi: 10.1021/acs.joc.8b02219. Epub 2018 Oct 25.
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 both 1a and 1b are decorated by a β-oriented C17-butenolide, three C11,14,19-hydroxy groups, and a C3-O-l-rhamnoside moiety. On the other hand, 1a and 1b are epimeric at the C5-position. The structures of 1a and 1b were assembled from four simple fragments by applying a convergent and unified strategy. The AB-ring 10a/b and the D-ring 8/9 were tentatively tethered at the acetal moiety, and a subsequent stereoselective 6- exo radical reaction linked the two fragments. Next, an aldol reaction enabled simultaneous introduction of three new stereocenters of the C-rings of 5aa and 54. Attachment of the C17-butenolide led to aglycons 2a and 2b. l-Rhamnose was then installed into 2a and 2b to yield the targets 1a and 1b, respectively. Finally, the growth inhibitory activity of 1a, 1b, 2a, and 2b was assessed against MCF-7 human breast carcinoma cells. The significantly higher activities of 1a and 1b in comparison to 2a and 2b demonstrated the biological importance of the monosaccharide substructure.
卡多尼内酯是一类具有广泛生物活性的重要天然甾体化合物。虽然 19-羟基沙尔酮-3-O-α-L-鼠李糖苷（1a）和特雷维因（1b）的结构被确定为具有卡多尼内酯结构，但它们的生物活性尚未得到评估。1a 和 1b 的 6/6/6/5 元 ABCD 环系统均由β取向的 C17-丁烯内酯、三个 C11、14、19-羟基和 C3-O-L-鼠李糖苷部分修饰。另一方面，1a 和 1b 在 C5 位为差向异构体。1a 和 1b 的结构是通过应用集中统一的策略由四个简单片段组装而成。AB 环 10a/b 和 D 环 8/9 暂时在缩醛部分连接，随后立体选择性的 6-外消旋反应连接两个片段。接下来，醛醇缩合反应使 5aa 和 54 的 C 环的三个新的立体中心同时引入。C17-丁烯内酯的连接导致糖苷配基 2a 和 2b。然后将 L-鼠李糖安装到 2a 和 2b 中，分别得到目标物 1a 和 1b。最后，评估了 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 1b 的显著更高活性表明单糖亚结构的生物学重要性。
