Design, Synthesis And Activity Evaluation Of Ftis

Signaling transduction pathway was closely related to the formation and growth of tumor. The rapid development of cell biology and cancer genetics offer new targets to therapy of tumor.Currently, targeting on the signaling transduction pathway is a hot research point for the design and development of anticancer drug.Ras proteins function as molecular switches in the transduction of extracellular signals which controls cell differentiation and proliferation. Ras proteins cycle between an active, GTP-bound form and an inactive, GDP-bound form and are oncogenic when constitutively activated, Mutated form of Ras proteins is found in approximately 30% of all human cancers, including 90% of pancreatic, 50% of colon, and 50% of thyroid tumors. The biological function of Ras proteins was depended on the post-translational modification.Farnesyltransferase is the key in translational modifications of the Ras proteins. FTIs can prevent the membrane localization and function of Ras proteins by blocking the post-translational attachment of prenyl-moiety to its C-terminal cysteine. After encouraging pre-clinical results, FTIs are currently in clinical development.such as SCH66336 and R115777.The aim of this topic is to design and synthesize FTIs, which have higher activity and lower toxicity.The contents and results of the research in this paper included as follows:1. Constructing the pharmacophore model of FTI and designing the target compounds.The pharmacophore model of FTIs was established by the Catalyst software. Combining with the structures of active compounds, selected 4-(Aminomethyl) benzoic acid as mother structures and designed 8 of target compounds. Moreover,we analysised the drug-likeness. 2. Synthesizing and identifying the target compounds.Combining microwave irradiation and routine method, we used 4-(Aminomethyl) benzoic acid as mother structures,by the esterize reaction,the acylation reaction,the alkylation reaction and so on to synthesize the target compounds.The microwave irradiation technology could short reaction time and elevate the yield.The compounds were all characterized by IR,P1PH-NMR and P13 PC-NMR.3. Pharmacological activity test in vitro.Human HepG2 cell and A549 cell was selected as experiment cells and 5-Fu as positive control, the antitumor activities of the compounds were tested by MTT method. The results of antitumor activities show that the majority of the target compounds have good inhibitory activity, some of the compounds have higher activity than the positive control. Moreover, the results authenticate the significance of the group which combined with the Zn²⁺.4. Checking the pharmacophore model.By comparing the results of pharmacological activity with the predictive values of FTI pharmacophore model, the reliability and forecast ability of the pharmacophore model were verified.5. The characteristics points:â‘´Pharmacophore model of FTIs was constructed and its predicting ability was verified well.⑵According to the pharmacophore model of FTIs ,8 new compounds were designed and synthesized which 4-(Aminomethyl) benzoic acid as mother structures.⑶The results of antitumor activities of the target compounds show that most of the compounds have antitumor activitiy. According to the pharmacophore model, authenticated the significance of the pharmacophore feature of PI which combined with the Zn²⁺.