Design, Synthesis And Screening Of The Small Molecular C-Fms Kinase Inhibitors

Malignant tumor, Also known as cancer, is a class of diseases in which a group of cells display uncontrolled growth, invasion and sometimes metastasis. It seriously threats to human health. According to statistics data of the World Health Organization in 2008 show that in 2007 the number of patients died of cancer is 7.9 million in the world. It is thirteen percent of the total number of human deaths. In 2015 nine million people will die of cancer, in 2030 the number of patients died of cancer will be 11.4 million. So we can find that how to prevent and cure cancer is a difficult and important task that we must face to. At present, chemotherapy is one of the important means of cancer treatment. Research and development of anticancer drugs in today's life sciences is of great significance.As the rapid development of the tumor pharmacology and molecular pharmacology, the nature of the tumor is being gradually clarified. Anticancer drug development has transferred from the traditional cytotoxic drugs to the molecular targeted drugs which target signal transduction path of the tumor cells. How to find the new anticancer agents has become a hot topic, which affect a specific molecular target and have high efficiency, low toxicity, high selectively.In particular, it is most likely to get a breakthrough in the field and has very broad development prospects that protein tyrosine kinases are used as targets for research and development of anticancer drugs in the 21st century. Protein tyrosine kinases are a group of enzymes that can transfer a phosphate group from ATP to a tyrosine residue in a protein, then activate various substrate enzyme, through a series of reactions regulate cell growth, proliferation and differentiation. Protein tyrosine kinases in the majority of tumor cells abnormal activate, so protein tyrosine kinases have important significance not only in the mechanism of tumor, but also in tumor treatment. In recent years, protein tyrosine kinases have been widely used as a target for anticancer drug development and have been paid great attention by major international research institutions and pharmaceutical groups. Protein tyrosine kinases inhibitors have become hot spots of the anticancer drugs research. Among them, the small molecule receptor tyrosine kinases inhibitors have made significant progress, an amount of researches are reported in every year.c-Fms, a member of the Platelet-derived Growth Factor (PDGF) receptor family of receptor tyrosine kinases, is the receptor for macrophage colony stimulating factor (M-CSF) that regulates proliferation, differentiation and survival of cells of the mononuclear phagocyte lineage. Abnormal activating of c-Fms is associated with a significant number of human pathologies, including a variety of cancers and rheumatoid arthritis. Accordingly, c-Fms represents an attractive therapeutic target.Up-regulation of the M-CSF/c-Fms receptor pathway plays a role in human malignancies growth, progression and metastasis, such as breast cancer, ovarian cancer and endometrial carcinoma. Additionally, in inflammatory diseases is seen in rheumatoid arthritis, arteriosclerosis, glomerulonephritis, and also in allograft rejection.So far, the existing small molecule c-Fms kinase inhibitors are all through acting on the ATP binding site of the kinase, competitively inhibit ATP binding with the kinase. So that the tyrosine kinase residues cannot autophosphorylate, thereby the activation of c-Fms is inhibited.In this paper, c-Fms kinase is used as a target of the research. GW2580 is used as a positive compound which is reported as a small molecule c-Fms kinase inhibitor by GlaxoSmithKline. We design target compounds on the basis of GW2580 and c-Fms kinase binding site analysis and the rule of bioisosterism. We have designed and synthesized two types of compounds, 5-substituted benzyl-2, 4-diamine pyrimidine and 5-substituted benzyl-2-mercapto-4-aminopyrimidine. We have synthesized twelve novel compounds, their structures have been confirmed by 1H-NMR, EI-MS and FAB-MS.We have done cytotoxicity experiments of target compounds in vitro to observe target compounds in inhibiting different tumor cell proliferation effect and find selectively inhibit tumor cell proliferation compounds. A normal cell and six tumor cell is used in the experiment, including Human Lung Fibroblast (HLF), A549, MDA-MB-231, HL60, K562, IM9 and M-CSF-dependent myeloid leukemia cells in mice (NFS-60). The experimental results show that compound 30b and compound 30c is similar with positive compounds in inhibiting c-Fms kinase activity. Compound 30c selectively inhibit tumor cell proliferation which is related with c-Fms kinase. It is less toxicity to normal cells than the positive compounds, so it is worthy of further study. The discussion of structure-activity relationships has a certain significance to search the new anti-cancer drugs which are high efficiency, low toxicity and high selectively target in c-Fms kinase.