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

我们已经发展了立体选择性和有效的多米诺反应的方法学，用于合成具有生物活性的吡咯并吲哚化合物，如苯丝氨酸衍生物（乙酰胆碱酯酶抑制剂）和amauromine（抗高血压药），1。以2-烯丙氧基吲哚啉-3-酮为原料，经烯化、异构化、Claisen重排和还原环化等关键步骤，合成了3a位和苯氨基甲酰基上具有多种取代基的苯丝氨酸衍生物。此外，还成功地完成了苯丝氨酸衍生物的不对称合成。作为其在3 α-氧代苯丝氨酸合成中的进一步应用，我们完成了3 α-羟基吡咯并吲哚alline的全合成.这些化合物作为胆碱酯酶（ChE）抑制剂的评价进行了评估，对人类乙酰胆碱酯酶和BChE在体外，旁边和比较的芬丝氨酸的活性。部分化合物具有选择性的抗AChE活性，但缺乏抗BChE活性.以吡咯并吲哚亚胺与异腈及相应的氨基酸发生Ugi反应，然后环化-差向异构化为关键步骤，实现了黑蒙素类似物果替精碱A和verrucofortine的全合成。其他类型的酚丝氨酸衍生物的生物活性测试和黑乌罗明及其类似物的合成正在进行中。

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.