Photoinduced Selective Oxidation Of N-Functionalized Ammoniums And Construction Of Aza-heterocycles With Anticancer Activities

Among small molecular pharmaceuticals approved on the market,more than half of these compounds comprise at least one nitrogenous heterocycles.These N-heterocycles are immensely important due to the widespread application in various fields and diverse biological activities.Focusing on the efficient construction of nitrogen-containing skeletons,the first part of this thesis is that a series of N-functional heterocycles,such as pyrroles,pyridines,isoquinolinones and quinolones,were constructed by the visible light-enabled selective oxidation of pyridinium salts with oxygen as the terminal oxidant;the other is to study two types of transition metal-catalyzed reactions,namely,Pd-catalyzed insertion of isonitriles and Cu-atalyzed coupling of indoles.Imidazothiazoles and bis-indolones were successfully synthesized as two bioactive class of nitrogen heterocyclic analogs,respectively.After screening for anti-tumor agents in vitro,it was found that some compounds had obvious inhibitory effects on some cancer cells,which has reference value and important significance for the lead compound library of new anti-cancer drugs.The researches mainly consist of the following four chapters:Chapter 1:Due to the low energy and poor chemical selectivity of pyridine?-system,the direct functionalization of pyridines have been limited.Therefore,pyridinium halides can be prepared by derivatization of nitrogen atoms of pyridine ring,which makes these organic salts show a variety of reaction activities.In this chapter,under the conditions of visible light and air,there were two different types of conversion of pyridiniums:?1?Under the catalysis of Rhodamine B?RhB?,pyridiniums carried out[2+2]oxidative cycloaddition with oxygen in the air,followed by ring-opening and re-cyclization process.The pyridiniums of six membered ring were successfully converted into pyrroles of five membered ring at room temperature.The ring shrinking products were obtained via the C-C bond breaking and re-cyclization of pyridine ring.The mechanism was proved by density functional theory?DFT?calculations;?2?Another transformation was the in-situ formation of benzyl radicals from N-benzyl pyridiniums catalyzed by cobalt tetramethoxyphenylporphyrin?CoTMPP?,which were migrated to the 4-position of pyridine ring by Ladenburg rearrangement and further oxidized to form 4-carbonyl pyridines.Photocatalysts,substrates and light sources were the key factors to the success of the cyclization and rearrangement of N-functionalized pyridiniums.The two novel atomic economic strategies and sustainable development of catalytic methods had made the good supplement to the development of the transformation and application of N-heterocyclic aromatics.Chapter 2:Under mild visible-light-mediated conditions,the iso-and quinoliniums could efficiently and conveniently realize the sp² carbonylation of carbon atoms in different regions:?1?Under the action of 1,4-diazabicyclo[2.2.2]octane?DABCO?and the visible-light induction,the regions adjacent to the nitrogen atom of the onium salt substrates were oxidized by oxygen in the air to form iso-and quinolones analogues through the onium salts as photosensitizers without additional photocatalyst.Unlike the traditional oxidations,this method not only avoided the use of excessive oxidants,such as K₃Fe?CN?₆,but also had a wide range of substrate application and high atom economy.This is a kind of oxidation method in the mild reaction conditions and environmental protection;?2?The oxidation reaction site of quinoliniums were switched from the C2 position to the C4 position to form 4-quinolones only by adding the catalyst ruthenium complex,without changing other reaction conditions.The outstanding advantages of the two transformations were that sp²C carbonylation in different regions of the substrates initiated by free radicals.The oxidation processes were directly introduced oxygen in the air into the nitrogen heterocyclic skeletons.Chapter 3:Imidazo[1,2-c]thiazoles were synthesized through Pd-catalyzed cascade bicyclization from isonitriles with thioamides.The new heterobicyclic scaffolds were constructed by inserting three molecules of isonitriles into two molecules of thioamides and then cycling them in a one-pot procedure.In this reaction,the transition metal Pd?OAC?₂ was used to construction of C-C bonds or C-hetero bonds.The novel class of bicyclic analogs were obtained with moderate to good yields from the use of cheap and readily available starting materials and the simple operation.The in vitro antitumor activities of all products were tested against T-24?human bladder cancer?,MGC-803?human gastric cancer?,HepG2?human hepatocellular cancer?,SK-OV-3?human ovarian cancer?cells,by MTT colorimetric assay to explore the potential pharmacological activity of these compounds.Compound 3c showed excellent inhibitory effect,and 3c outstandingly inhibited cell-proliferation-induced apoptosis were further evaluated by apoptosis rate,cycle arrest,intracellular ROS generation and the intracellular free Ca²⁺level in HepG2 cells.Chapter 4:A copper-catalyzed the dearomatization and intermolecular oxidative homocoupling of indoles had been developed for the direct construction of valuable C3-C3biindolyl scaffolds under the conditions of TBHP as a oxidant and morpholine as a base.Using this protocol,the 3,3'-bisindolin-2-ones containing quaternary carbon center were obtained in good yields and excellent chemo-and regioselectivity.The methodology showed good functional group tolerance,easily available inexpensive precursors,simple operation,and mild reaction conditions.The functional reaction of indoles also had the characteristics of selective carbonylation at C2 position.Screening of SCG-7901?human gastric cancer?,HepG2?human liver cancer?,Ishikawa?human endometrial cancer?,MDA-MB-468 and MDA-MB-435?human breast cancer?cell lines,compound 2r exhibited good inhibitory effect against HepG2 in vitro antitumor activities.Further studies,the proliferation effects of compound 2r on HepG2 were inhibited in a concentration-dependent manner by cell apoptosis,TUNEL staining and cell cycle analysis.