Smith P, Brown L, Boutagy J, Thomas R
J Med Chem. 1982 Oct;25(10):1222-6. doi: 10.1021/jm00352a025.
An improved method for the synthesis of cardiac glycosides was used to prepare 3 beta-glucosides of digitoxigenin derivatives in which the 17 beta side chain was CH=CHX (X = COOH, CONH2, COCH3, CN, or COOR). We compared the inotropic activity of the compounds with that of digitoxigenin glucoside using guinea pig left atria. All compounds were active except for the acid (7) and the amide (8). The inactivity of the amide, in spite of its favorable shape and high capacity for forming intermolecular hydrogen bonds, is incompatible with some previous structure-activity relationship theories. Of the active genins, glucosidation enhanced activity by a factor of about 2. All glucosides, including those with high potency, showed rapid onset and offset of action. The stepwise fall in potency that occurred when the ester group (CH=CHCOOR) was increased in bulk supported previous suggestions that the portion of the digitalis receptor that interacts with the C17 side chain lies within a cleft.
采用一种改进的强心苷合成方法制备了洋地黄毒苷元衍生物的3β-葡萄糖苷，其中17β侧链为CH=CHX（X = COOH、CONH2、COCH3、CN或COOR）。我们使用豚鼠左心房比较了这些化合物与洋地黄毒苷葡萄糖苷的变力活性。除了酸（7）和酰胺（8）外，所有化合物均具有活性。尽管酰胺具有良好的形状和形成分子间氢键的高能力，但其无活性与一些先前的构效关系理论不相符。在有活性的苷元中，糖基化使活性提高了约2倍。所有糖苷，包括那些高效的糖苷，作用起效和消失都很快。当酯基（CH=CHCOOR）体积增大时效力逐步下降，这支持了先前的观点，即与C17侧链相互作用的洋地黄受体部分位于一个裂隙内。
