Structural Modifications And Anti-Tumor Activity Of Indolazine C3

Reactions for functionalization of C-H bonds are more rational and efficient than conventional cross-coupling reactions and allow direct conversion of C-H bonds,which occupy a very important position in organic synthesis.However,due to the special stability of the C-H bond,some C-H bonds may cause difficulties in carrying out functionalization reactions.Therefore,transition metals must be added to the reaction to lower the energy barrier and allow the reaction to proceed smoothly under relatively mild conditions.However,the use of transition metals may again limit their use in pharmaceutical and natural product synthesis due to the high catalyst cost and metal residues.Therefore,the development of metal-free functionalization reactions using C-H bonds has become one of the research priorities in organic synthesis in recent years.Indolizines are a class of nitrogen-containing heterocyclic compounds with medicinal and biological activity and are widely used in pharmaceuticals,biomaterials,fluorescent materials and dyes.In recent decades,numerous functionalization reactions of indolizines with hydrocarbon bonds have been reported both at home and abroad,but there is still little research on functionalization reactions with hydrocarbon bonds that do not involve metals.In this work,we focus on the structural modification of the C3 position of indolizines by hydrocarbon functionalization reactions and the anti-tumor activity of the synthesized products.The specific work consists of two main parts.(1)Dithiocarbamylation of indolizines in C3 position.The effects of additives,temperature,and solvent on the reaction yields of 2-phenylindolizine and TMTD as template substrates were investigated to determine optimal reaction conditions.Under these conditions,27indolizine-3-dimethyldithiocarbamylation products and 13 indolizine-3-diethyldithiocarbamylation products can be obtained in high yield.The method is not only environmentally friendly,but also easy to handle and does not require multistep reactions.(2)Formylation reaction of indolizin at C3 position.The effects of catalyst,temperature and solvent on the reaction yield were investigated when 2-phenylindolizine and 3-phenyl-1,4,2-dioxazol-5-one were used as template substrates,and the most suitable reaction conditions were determined.43 indolizine-3-carboxamidation products were obtained in high yields.The products were further investigated for luminescence properties,molecular docking technique,and biological activity.In the study of luminescence properties,it was found that the compounds exhibited better UV absorption in Me CN(acetonitrile)solution and better fluorescence emission intensity in DCM(dichloromethane)solution.Among the 43 products bound to CYP3A4 protein,eight compounds with high affinity were found.The proliferation inhibition of these 8 compounds on Hep G2 cells was determined using the MTT method.The results showed that all eight compounds inhibited the growth of Hep G2 cells,and four compounds showed a higher proliferation inhibition rate than the control drug cisplatin,providing a basis for studying the pharmacokinetics and pharmacology of indolizine-3-carboxamide analogues after the compounds.