Design, Synthesis And Activity Study Of Novel Potential Raf-1Inhibitors And The Structural Modifiction Of Olaparib

Seeking innovative and highly effective anti-cancer drugs is one of the important tasks oftoday’s cancer treatments. Based on targeted drug therapy, this thesis was focused on the design,synthesis and biological activity study of novel potential Raf-1inhibitors.Malignant tumors are also known as cancer, which is a disease characterized by cells rapidlyproliferation and migration, is serious threat to human health. The current treatment involves threeways: surgical removal of the tumor, radiotherapy and chemotherapy in clinical trials. In recentdecades, improvements in the understanding of the molecular basis of cancer have led to thedevelopment of targeted agents tailored to inhibit specific protein kinases involved in intracellularsignal transduction pathways that drive tumorigenesis and progression. In a variety of signalingpathways, the Ras/Raf/MEK/ERK signaling pathway plays significance role in tumorigenesis andprogression, especially related to Raf-1kinase. Therefore, anti-cancer drugs targeting at Raf-1have attracted special intetest in recent years. Sorafenib was choosed as lead compound in order toobtain novel Raf-1inhibitors with higher activity and lower side effect. We designed andsynthesized10target compounds based on the analysis of structure activity relationship ofsorafenib and the rule of bioisosterism. All the structures were confirmed by1H-NMR, HR-MS orMS. Preliminary inhibitory activities of these target compounds on Raf-1kinase were investigatedby the ADP Glo Kinase Assay. The results demonstrated that all the tested compounds except33fexhibited evident inhibitory potency against Raf-1kinase at a concentration of less than1μM. Inaddition.the antiproliferative activities (IC50values) of target compounds using the CellTiter-GloLuminescent Cell Viability Assay against HepG2human liver cancer cell line and A549humanlung cancer cell line together with that of Sorafenib as a reference compound. Most compoundsshowed weak antiproliferative activities against A549, whereas showed better antiproliferativeactivities against HepG2than Sorafenib. Especially, compound30f showed the best activity andselectivity against HepG2at about the6time level of sorafenib. So it is worthy of further study.The discussion of structure-activity relationships has a certain significance to search the newanti-cancer drugs which are high efficiency, low toxicity and high selectively target in Raf-1kinase.In addition, the chemical modification to the active ingredients of known compounds was animportant measure of drug discovery. The thesis was focused on the exploratory structure modification of Olaparib which is an antitumor drug with an entirely unique preclinical profile. theinnovative research results achieved are as follows: In this paper the olaparib was used as astarting material and with the treatment of oxidant K2Cr2O7in acetic acid to form the ketonecompound olaparib-1, which has better bioactivity.Then the product was reduced by NaBH4to givea novel hydroxyl olaparib derivative, which has a weak cytotoxic activity, and is a keyintermediate. The structure of final product was identified by MS and1H-NMR. On this basisfurther research of substituents are made to obtain new chemical compounds which may havebetter bioactivity and great innovation significance.