Synthesis Of Several Compounds Based On PARP-1 Inhibitors And Synthesis And Activity Test Of 1,6-Disubstituted-2-Pyridone Compounds

The main process of drug discovery is to find lead compounds and to optimize them by using reasonable structure modification methods. During this process, a compound library can be founded and the structure activity relationship be obtained and analyzed. With years of efforts, a candidate may be got. To get a candidate, a lot of work focusing on lead optimization is essential.In part I of this dissertation, four kinds of derivatives with three cores of the promising PARP-1 inhibitors were designed and synthesized based on the basic medicinal strategies such as biosostere theory and alterations of compounds with ring. Then a small compound library was constructed so as to find PARP-1 inhibitors. Unfortunately, of all these compounds in the library, only one compound 1-45a has potent activity with IC50=2.87 nM, which is at the same level of the well-known PARP-1 inhibitors AZD-2281.In part II of this dissertation, N-arylation methodology of pyridin-2(1H)-one has been optimized and O-arylation methodology of C-6 substituted pyridin-2(1H)-one been disclosed for the first time by using Chan-Lam coupling reaction. Based on this, by utilizing the privileged scaffold pyridin-2(1H)-one as the model of the cis-olefin bridge of CA-4, a series of 1,6-substituted diarylation pyridin-2(1H)-one derivatives was obtained with potent antitumor activity in vitro and in vivo. Furthermore, a series of 6-amino pyridin-2(1H)-one derivatives were designed and synthesized and their anti-proliferation activity were tested using HCT116 in vitro.