Design And Synthesis Of Pim-1 Kinase Inhibitor And Study On Structure-Activity Relationship

The expression product of pim-1, kinase pim-1, is highly conserved proto-oncogene. Besides kinase pim-1, there are other two members in the pim family, kinase pim-2 and kinase pim-3. Kinase pim-1 belongs to calcium/calmodulin regulated kinases which can regulate normal cell apoptosis and differentiation. It plays great important role in the formation and development of tumors. So we want to inhibit the activity of kinase pim-1, by this way we could control or slow down the formation and development of tumors.This work was mainly divided into three stages:the first stage is the design and screening of kinase pim-1 inhibitors. We select randomly 1280 compounds from the Library of Pharmacologically Active Compounds (LOPAC) for virtual screening. And then we select two compounds from the top 1% before the docking experiments. The two compounds with higher scores are thioridazine and chlorprothixene. From the test results of biological activity determination we can get that phenoxazine analogues---10-DEBC showed good biologically inhibitory activity. Based on this, we decide to modify structure of 10-DEBC from the aspects of the length of the aliphatic chain, the electrical property of the salt bridge group, the space steric hindrance of the structure, and the hydrogen bonds formed in the complex. The second stage is the chemical synthesis of target compounds. We synthesized 15 new compounds in total, including some important synthetic intermediates. The problems we solved are as follows:1. We explored the synthetic route and different synthetic conditions of compound 5C6', obtaining a better experimental results; 2.We explored the docking methods of 2-chlorphenoxazine compounds with compound 5C6'; 3. We tried a new synthetic conditions for the preparation of compound phenoxazine and obtained a good result. The third stage is the activity test of the drugs that we synthesized before and study on the relationship of structure-activity. It was discovered that inhibitory activity (IC5o) of compound C3 for kinase pim-1 was 112.3nM, compared to that of the 10-DEBC compounds (3860nM). The study of the structure-activity relationship was then performed. It turned out that the aliphatic chain of the compound should be five-carbon chain to make sure the formation of a salt bridge with Asp 128 of kinase pim-1; otherwise, the salt bridge group could be affected by space steric hindrance and electrical property, which was important for the inhibitory activity. Besides, the chlorine atoms in the phenoxazine compounds also affected the bioactivity.