Synthesis and bioactivity evolution of diversely functionalized pyrrolo-indole derivatives for novel bioactive lead compounds

我们发展了立体选择性的高效多米诺骨牌反应方法，合成了具有生物活性的吡咯吲哚类化合物，如苯丝氨酸衍生物(乙酰胆碱酯酶抑制剂)和氨基(抗高血压)，1.通过2-烯丙氧基吲哚-3-酮的串联烯化、异构化、Claisen重排和还原环化反应，合成了具有3a位和苯氨基甲酰基的苯丝氨酸衍生物。苯丝氨酸衍生物的不对称合成也得到了有效的实现。将其进一步应用于3a-羟基苯丝氨酸的合成，实现了3a-羟基吡咯-吲哚的全合成。评价了这些化合物作为胆碱酯酶(ChE)抑制剂在体外对人AChE和BChE的抑制作用，并与苯丝氨酸的活性进行了比较。其中一些受试化合物显示出选择性中等的抗乙酰胆碱酯酶活性，但缺乏抗BChE活性。以吡咯-吲哚亚胺与异腈的乌吉反应及相应的氨基酸环化-异构化为关键步骤，实现了作为氨基类似物的果子素A和虎杖苷的全合成。其他类型的苯丝氨酸衍生物的生物活性测试和胺胺及其类似物的合成目前正在进行中。

We have developed our methodology of stereoselective and efficient domino reactions into synthesis of biologically active pyrrolo-indole compounds such as phenserine derivatives (acetylcholine esterase inhibitor) and amauromine (antihypertensive),1. Phenserine derivatives with a variety of substituents at 3a-site and on phenylcarbamoyl moiety were prepared by the tandem olefination, isomerization and Claisen rearrangement of 2-allyloxyindolin-3-ones followed by reductive cyclization as the key-steps. The asymmetric syntheses of phenserine derivatives have been also accomplished efficiently. As its further application to construction of 3a-oxyganated phenserine, we have achieved the total synthesis 3a-hydroxypyrrolo-indole, alline.2. The evaluation of these compounds as choline esterase (ChE) inhibitor was assessed against human AChE and BChE in vitro, alongside and compared to the activity of phenserine. Some of these tested compounds have shown the selectively moderate anti-AChE activity, but lacked anti-BChE activity.3. We have achieved the total syntheses of fructigenine A and verrucofortine as the amauromine analogues using Ugi reaction of pyrrolo-indole imine with isonitrile and the corresponding amino acid followed by cyclization-epimerization as the key-process. The bioactive test of other type of phenserine derivatives and synthesis of amauromine and its analogues are now in progress.