Synthesis Of Novel Indole Alcohol Derivatives As Tyrosine Kinase Inhibitors

As the food safety and environment pollution are deteriorating,the incidence of malignant tumors is increasing year by year,which becomes a major killer of human health.As the largest kinase system in human body,tyrosine kinase plays a significant role in the regulation of cell growth,proliferation and apoptosis.Vascular endothelial growth factor(VEGF)is closely related to angiogenesis.It has been shown that blocking the interaction of VEGF and vascular endothelial growth factor receptor-2(VEGFR-2)tyrosine kinase can inhibit the proliferation of tumor cells.In this paper,we mainly discussed the synthesis and activity of the indole alcohol compounds that were designed by the method of computer aided drug design(CADD).The main contents of this thesis are as follows:1.With substituted indole as raw material,substituted indole-3-formaldehydes were synthesized by Vilsmeier-Haack reaction,which were further reacted with bromo reagents to obtain N-substitued indole-3-formaldehydes in the system of dimethyl sulfoxide and sodium hydroxide.Finally,indole-3-methnol derivatives were synthesized by reduction of indole-3-formaldehyde derivatives with odium boron hydride.2.With substituted o-phenylenediamine as raw material,2-chloromethyl benzimidazole derivatives were synthesized throughcyclization reaction with chloroacetic acidunder acidic condition.Besides,the reaction condition of synthesizing 2-bromomethyl benzimidazole compounds was also explored.3.With 5-substituted indole-3-formaldehydes as raw material,5-substituted indole-3-formaldehyde oximes were synthesized by reaction with hydroxylamine hydrochloride,and then in the presence of thePd/C catalyst,5-substituted-3-aminomethyl indoles were obtained by the reaction of 5-substituted indole-3-formaldehyde oximes and ammonium formate as the regent.4.After a number of experimental exploration,we eventually chose the reaction condition that with acetone as solvent,potassium carbonate as acid binding agent,indole-3-methanol derivatives reacted with 2-halogenmethyl benzimidazole derivatives to synthesize the indole-benzimidazoletarget compounds linked by ether bond.In addition,the inhibitory activity of some target compounds on VEGFR-2 tyrosine kinase and four kinds of tumor cells was tested respectively.