Synthesis And Anticancer Activity Evaluation Of Bisindole Compounds And Lycopodium Alkaloids Lycopodine

Cancer is one of the major diseases that seriously threaten human life and health.Therefore,isolation and synthesis of anti-tumor compounds has become a hot research field of organic synthesis.Synthesis of natural product derivatives is a common way to obtain active compounds.Isolation and purification of natural products with anti-tumor activity are another method.However,most of the active compounds in nature are extremely scarce so synthesis is used to make products in large quantity.Focusing on the potential anti-tumor activity of the natural products containing bisindole skeleton as well as the Lycopodium alkaloids,efficient synthesis of them were developed in this thesis,involving the strategies of palladium-catalyzed tandem Heck cyclization reaction,palladium-catalyzed tandem C,N-coupling cyclization reaction,Diels-Alder/aza-Prins tandem cyclization reaction and rhodium-catalyzed[3+2]/aza-Prins（Mannich）cyclization reaction.Anti-tumor activity test of some compounds were carried out.The specific results are as follows:（1）A method was developed for the palladium-catalyzed tandem Heck cyclization reaction to produce 3,3’-diindolylmethanes.This reaction demonstrates good functional group tolerance and broad substrate scope.A total of 37 3,3’-diindolylmethanes were synthesized.In addition,derivatization experiments were also performed.The more valuable N,O-acetal or N,N-acetal compounds were obtained by cyclization reactions.Finally,a possible reaction mechanism was proposed.（2）A method was developed for the palladium-catalyzed synthesis of 2,3’-bisindoles via tandem C,N-coupling cyclization reaction.The reactions proceed with a wide range of substrates with good functional group tolerance.A total of 37 2,3’-bisindoles were synthesized.The scaling-up experiment can also be obtained in high yield,making the method potentially promising for application.Finally,a detailed explanation of the reaction mechanism was given.（3）We proposed an efficient one-step Diels-Alder/aza-Prins tandem cyclization strategy to construct BCD tricycles in the Lycopodine skeleton.It was expected to construct BCD tricyclic structure,key building blocks,towards the synthesis of a series of Lycopodine-type lycopodium alkaloids.In this strategy,the D-ring was not successfully constructed due to the occurrence of aromatization.Then we proposed a rhodium-catalyzed[3+2]/aza-Prins（Mannich）cyclization reaction strategy.The ABC ring system was successfully constructed,the construction of the D ring is in progress.（4）We performed a primary screening of some synthetic compounds for their anti-tumour activity in vitro.It was found that compound 3-3av has good inhibitory activity against a wide range of tumour cells,with the best inhibitory activity against human acute promyelocytic leukaemia cells（HL60）(IC₅₀=1.47μM).A general screening trial for anti-tumour activity is currently underway.