Ruoho A E, Hokin L E, Hemingway R J, Kupchan S M
Science. 1968 Mar 22;159(3821):1354-5. doi: 10.1126/science.159.3821.1354.
Hellebrigenin, which diflers from strophanthidin only in its lactone ring, has 30 times the affinity of strophanthidin for the brain (Na + K)-activated adenosinetriphosphatase. Hellebrigenin 3-acetate and hellebrigenin 3,5-diacetate are about three times more potent toward this enzyme than hellebrigenin is. The 3-iodoacetate and 3-bromoacetate of hellebrigenin were synthesized and were highly potent irreversible inhibitors of the enzyme. The iodoacetate was 20 times more potent than the bromoacetate, as expected from the superior alkylating power of iodoacetate as compared to bromoacetate. The irreversible inhibition of the enzyme by hellebrigenin 3-bromoacetate and by strophanthidin 3-bromoacetate paralleled the affinities of the nonesterified steroids for reversible inhibition; this is further strong evidence for the site-directed alkylation of the (Na + K)-activated sinetriphosphatase by the haloacetate derivatives of the cardiotonic steroids.
嚏根草苷元与毒毛旋花子苷元的区别仅在于其内酯环，它对脑（钠+钾）激活的三磷酸腺苷酶的亲和力是毒毛旋花子苷元的30倍。嚏根草苷元3-乙酸酯和嚏根草苷元3,5-二乙酸酯对该酶的效力比嚏根草苷元高约三倍。合成了嚏根草苷元的3-碘乙酸酯和3-溴乙酸酯，它们是该酶的高效不可逆抑制剂。正如预期的那样，碘乙酸酯的烷基化能力优于溴乙酸酯，碘乙酸酯的效力是溴乙酸酯的20倍。嚏根草苷元3-溴乙酸酯和毒毛旋花子苷元3-溴乙酸酯对该酶的不可逆抑制作用与未酯化甾体的可逆抑制亲和力相当；这进一步有力证明了强心甾体的卤代乙酸酯衍生物对（钠+钾）激活的三磷酸腺苷酶进行了定点烷基化。
