Study On The Synthesis And Anti-tumor Activity Of Active Indole Alkaloids Calothrixin B And Trigonostemonine F And Its Analogues

Objective:Taking the indole alkaloid Calothrixin B as the object of study,we explored a method to obtain Calothrixin B from a polycyclic skeleton substrate in a single step of oxidation by combining literature and the previous work of our group.On the other hand,the total synthesis of Trigonostemonine F was achieved from literature research using the double Bischler-Napieralski reaction,and a series of structural modifications were designed around Trigonostemonine F.The synthesis and antitumor activity studies of new compounds were carried out in the expectation of obtaining better antitumor active compounds.Methods:A pentacyclic skeleton of unsaturated heterocycles was obtained in 66%yield by Diels-Alder cyclization reaction,which was then reduced to obtain a polycyclic substrate containing functional groups such as amine groups and alcohols,with which the oxidation conditions were screened to obtain Calothrixin B.On the other hand,the bisindole amide structure was prepared by the acyl-halogen method,and then the corresponding amine was reduced to obtain the formylated compound,which was synthesized as Trigonostemonine F using the double Bischler-Napieralski reaction,and the derivatives were prepared based on this method,and the modified compound was tested for antitumor activity in HEL cell lines using the MTT method.Results:In this study,an oxidation condition was found and used to achieve the goal of obtaining Calothrixin B from a polycyclic backbone substrate by one-step oxidation in 20%yield.On the other hand,the total synthesis of Trigonostemonine F was successfully achieved by the simultaneous construction of two six-membered ring structures from the formylated amine using the double Bischler-Napieralski reaction,and similar compounds were successfully synthesized using this method,and the corresponding compounds were obtained by structural modification.The results of MTT method showed that among them,compounds A6,C2,C3,C10 and D9 had better inhibitory activity on the proliferation of HEL cells,and the IC₅₀values at 48 h were 4.13±1.70μg/m L,6.29±0.44μg/m L,6.66±0.82μg/m L,6.34±0.14μg/m L,5.17±0.38μg/m L.Conclusions:In this paper,we discovered an oxidation method and utilized it to explore a synthetic route for the conversion of Calothrixin B from a polycyclic backbone substrate to Calothrixin B in 20%yield by one-step oxidation.On the other hand,a total synthesis method of Trigonostemonine F was developed,the applicability of the method was demonstrated by the derivative synthesis of six compounds,and 42analogues of Trigonostemonine F were obtained by modification,which provided some scientific and theoretical basis for the synthesis and activity studies of this class of indole alkaloids.