Synthesis And Biological Evaluation Of GDC0068 Derivatives As Akt Inhibitors

In recent years,maligancy,characterized with high incidence,high fatality rate and low cure rate,is becoming a huge threat to people's health and life span.With the rising incidence of disease,the age of patients is younger.The limitations of conventional radiotherapy and surgery is more and more obvious while molecular targeted therapy has become a new choice for patients.Molecular targeting the crucial kinases which associated with cell differentiation and proliferation is a new strategy.It is convenient to discover new anti-cancer drugs targeting specific kinase.It is found that the excessive activation of PI3K/Akt pathway is widespread in a variety of malignant tumors,which plays significant role in the survival and proliferation of cancer cells.Akt,a crucial kinase in PI3K/Akt signaling,has been hotspot of social attention.ATP-competitive inhibitor,include GDC0068 and AZD5363,is a hot topic of research.Both of the two compounds could selectively inhibit Akt and cell proliferation of refractory solid tumors.The former had passed phase 1 human clinical trials.In this paper,we analyzed the interactive mode of GDC0068 and AZD5363 with Akt,then designed and synthesized a series of GDC0068 derivatives as Akt inhibitors.The inhibitory activity of Akt1 kinase of derivatives was evaluated.Intermediate C was synthesized from raw material 4-chloro-7H-pyrrolo[2,3-d]pyrimidine through halogenating reaction,nucleophilic substitution and deprotection reaction.Then 4-substituted benzene methyl acetate was provided through esterification of 4-substituted phenylacetic acid,which then reacted through nucleophilic substitution,elimination reaction to generated intermediate F.Intermediate G was produced by F by addition reaction,deprotection and hydrolysis reaction.Preparation of target compounds was using C and G through condensation reaction and deprotection.All of the structures of target compounds were confirmed by 1H-nuclear magnetic resonance(1H-NMR),13C-nuclear magnetic resonance(13C-NMR).Results indicated that all of the compunds showed excellent inhibitory activity of Akt1 kinase.Compared with GSK690693,J-3,J-4,J-5,J-9,J-11,J-14 and J-15 show excellent inhibitory activity about 100%at luM level and the inhibitory activity of other compounds was above 92%.The inhibitory activity of J-2,J-5,J-8 and J-9 was 83.23%,83.87%,90.81%and 86.52%respectively at 10nM level,better than GSK690693.In the follow-up work,the inhibitory activity Aktl kinase will be investigated at lower concention and their anti-proliferative activity against cancer cells will be evaluated.