Design, Synthesis And Evalution Of Acridine Derivatives As Src Kinase Inhibitors

Src is one of non-receptor type tyrosine kinases, which is wildly expressed in tumor cells, and it plays an important role in cell grow, proliferation and other life events, such as gene transcription, cell differentiation, migration, angiogenesis, and cell survival. Development of Src inhibitors has become a hot spot in antitumor drug design. At present, a series of Src inhibitors have entered into clinical research phases.Acridine derivatives are widely used in antitumor research. Generally, the targets of acridine derivatives are DNA and ralated enzymes, such as topoisomerase. In 2011, through high throughput virtual screening, our lab found that acridine derivatives could inhibit Src kinase, which provided a new way for antitumor mechanism rerearch of acridine derivatives. The Src inhibition of acridine derivatives was mainly due to the interaction between the hinge region of Src and acridine ring or the substituents on the acridine ring. Unfortunately, the activity was weak. In this article, we want to improve the Src inhibition activity and antitumor activity of acridine derivatives via computer-based design method. This thesis contained three parts.Part 1: Based on structures of reported Src inhibitors, 17 acridine derivatives were designed by computer and synthesized. The Src inhibition and antitumor activity, as well as the mechanism were studied. Some of the compounds displayed good Src inhibition activity, such as 8l with an inhibition of 59.67 % at 10 μM. The typical compound 8l displayed good antiproliferative activity against both K562 and HepG-2 cells with IC50 values below 10 μM. Moreover, compounds 8l could induce K562 cells appotosis.Part 2: Molecular-docking results indicated that the introduction of nitrogens to acridine ring could improve their kinase inhibition activity, however only little references reported their synthesis methods. We developed a simple, efficient method to synthesize azoacridine derivatives. This reaction started with a substitution reaction between the corresponding benzoic acids and chloro-pyrimidines, followed by POCl3-mediated cyclization reaction. The desired 24 pure azoacridones with different substitutents were afforded in high yields. The substitutent effects on the reaction were also discussed.Part 3: Based on the above results, new azoacridine derivatives were designed and 3 new compounds were synthesized. MTT results indicated that azoacridine derivatives may have better application prospect than acridines.