Design, Synthesis And Biological Activity Of Molecular Diversity Natural Product-like Heterocyclic Compounds

Natural heterocyclic products such as polycyclic pyridines and polycyclic indoles exhibit a broad range of biological activities, such as antibacterial, antitumor, anti-HIV, and so on. Based on the lead compounds of natural drug molecules, we focused on the design and synthesis of potent activities containing natural-like heterocycles via diversity-oriented synthesis strategies. Moreover, the biological characters of these natural-like heterocycles were evaluated. In thus, it is of great significant in the development of natural-like heterocyclic drugs which possess proprietary intellectual property.In this thesis, twelve libraries of natural-like heterocycle compounds were rapidly constructed by heterocyclic ketene aminals (HKAs) and2-nitroglycals. Furthermore, the biological activities including antibacterial, antitumor, the properties of fluorescence and cell imaging of some target compounds have been evaluated.Part one:Synthesis and characterization of polycyclic pyridinesIndenoquinoline compounds:We developed a novel one-pot cascade reaction for the preparation of molecular diversity indenoquinolines. The further preliminary antitumor activities have shown that10c and10r have good cytotoxicity (Scheme1).Polycyclic xanthone and bicyclic pyridine compounds:In this study, the novel polycyclic xanthones and bicyclic pyridines were designed and synthesized. The fluorescence spectroscopy and cell imaging were studied. The results showed that parts of them have excellent pH-fluorescence properties as well as better biological compatibility and cell penetrating.Chromeno[3,4-c]pyridine compounds:the library has been built (Scheme3).Imidazopyridine compounds:the compound library has been constructed (Scheme4). Pyrimidine/benzodiazepin compounds:the pyrimidine analogues compound with chiral side-chain library has been built (Scheme5).Part two:Polycyclic indoles-synthesis of spirooxindole and halogenated indole compoundsSpirooxindole compounds:the compound library has been established with high stereo-and region-selectivity (Scheme6).Halogenated indole compounds:the compound library has been constructed (Scheme7).Part three:synthesis of a-substituent heterocyclic ketene aminalsThe synthetic method of2-diethyl phosphate mercaptals in the presence of complex catalytic systems of Mn(OAc)2/KMnO4instead of Mn(OAc)3was developed (Scheme8). Z configuration-substituent heterocycle ketene amines:the2-pyrazolone HKA compound library and the2-coumarin HKA compound library have been built (Scheme9).2-Nitroso heterocyclic ketene amines:the protocol of construction of2-nitroso HKA compound library catalyzed by a novel organic nitro sating reagent was developed (Scheme10).