Studies On The Synthesis Of Minfiensine And The SAR Of Hybrid Compounds Of Indole And Imidazoles

The indole ring system is an important structural component presented in many natural products and pharmaceutical agents. The indole alkaloids are a diverse class of natural products possessing a range of chemical structures and a wealth of biological activities. The indole alkaloid minfiensine, containing the 1,2,3,4-tetrahydro-9a,4a-iminoethanocarbazole core, was isolated from the African plant Strychnos minfiensis by Massiot and co-workers in 1989. Due to their unusual polycyclic architecture and diverse biological activity, the total syntheses of minfiensine and its related indole alkaloids have continued to attract synthetic interest Developing efficient methods or strategies towards asymmetric construction of the key tetracyclic unit is a formidable challenge. To date, many research groups have completed the total synthesis of Minfiensine. However, the strategies that rendered efficient asymmetric syntheses are still limited. It is very important to explore alternative efficient and stereoselective method for the synthesis of tetracyclic unit presented in Minfiensine. Meanwhile, indole and its derivatives continue to capture the attention of medicinal community. Design, synthesis and biological studies of synthetic compounds containing indole moiety are important topics in medicinal chemistry.This thesis contains two parts:in the first part, a palladium catalyzed tandem asymmetric cyclization to form the key tetracyclic unit of Minfiensine was developed. In the second part of this thesis, a number of hybrid compounds bearing tetrahydroindole-?-carboline, an indole derivative, and imidazolium salts were synthesized, and its antitumor activities were evaluated.This dissertation includes four chapters.The. first chapter summarizes the recent progress on different methods of indole cyclization in the total synthesis of natural alkaloids.The second chapter focuses on the research towards the synthesis of indole alkaloid Minfiensine. A method based on intramolecular palladium-catalyzed stereoselective tandem cyclization has been developed. Based on this cascade, the key tetracyclic unit of Minfiensine was constructed efficiently from multifunctional 2,3-disubstituted indole substrate. A number of substrates bearing a branched allyl carbonate moiety have been tested in this cascade reaction condition. It was found that all eight substrates could be converted into corresponding tetracyclic skeleton efficiently. Additionally, ee values of these cyclization products are good to excellent, with bromine (Br) substituent at the C5 position of indole ring being the best (ee value 99%). In general, the present asymmetric cascade cyclization strategy could be used in the synthesis of other indole alkaloids.In the third chapter, thirty six novel hybrid compounds between tetrahydro-?-carboline and imidazole have been prepared and evaluated in vitro against a panel of human tumor cell lines. Further antitumor activity screening shows that the majority of these compounds have good anti-tumor activities. Cytotoxic activity results indicate that the most potential compound does less harm to normal human bronchial epithelial cells than taxol or cisplatin, and it is able to induce cell cycle arrest in Gl to inhibit tumor cell growth according to cell cycle and apoptosis in experiment. The molecule docking shows that these compounds might be potential inhibitors of mTOR (mammalian target of rapamycin) signaling. These interesting findings would be helpful for further research.The fourth chapter is the summary of this thesis. Based on the product obtained from the asymmetric palladium-catalyzed intramolecular cyclization, the indole alkaloid Minfiensine has been synthesized in a formal sense. Meanwhile, biological studies on the tetrahydro-?-carboline imidazolium salts also provide some useful information for future development.