Synthesis And Antitumor Activity Of 3-Amnioindolylmaleimide Derivatives As Protein Kinase C Inhibitors

Indolylmaleimide derivatives have been paied a wide attention as a new series of protein kinase C(PKC)inhibitors recently.Studies have shown that these compounds,such as Ruboxistaurin,Enzastaurin,and JTT-010,have antitumor,antibacterial activity,and can inhibit retinopathy caused from diabetes mellitus.The paper concerned the design,synthesis and anititumor activity of 3-aminoindolylmaleimide derivatives,and mainly included the following items:1.Starting from urea and maleic anhydride,maleimide was synthesized through three steps, and then,maleimide and succincide were bromated by bromine to provide 3,4-dibromomaleimide respectively.All of the reaction conditions was optimized.2.N-methylmaleimide was prepared by using dimethyl sulfate as methylation reagent.The paper investigated the addition of N-methyl-3,4-dibromomaleimide and indolylmagnesium bromide,and then 2-bromo-3-(1H-indolyl-3-yl)-N-methylmaleimide and 3,4-bis(1H-indolyl-3-yl-) -N-methyl-maleimide were obtained.We optimized this reaction by changing the ratio of indole and N-methyl-3,4-dibromomaleimide.3.Starting from 2-Bromo-3-(1H-indolyl-3-yl)-N-methylmaleimide,eight target compounds were synthesized by reacting with substituted amines.Seven of them have not been reported.Their structures were confirmed by IR,~1HNMR,MS,and element analysis.4.Meanwhile,the green methylation procedure of imides was developed by using dimethyl carbonate as methylation reagent.A series of imides,for example,phthalimide,3,4-dibromo-maleimide and succincide were used for substrates.The effects of DABCO(1,4-diazabicyclo [2.2.2]octane)and DBU(1,8-diazabicyclo[5.4.0]undec-7-ene)as a catalyst in this kind of reactions were investigated.2-Bromo-3-(1-methylindolyl-3-yl)-1-methyl-1H-pyrrole-2,5-dione was prepared by using dimethyl carbonate,which further expanded the use of dimethyl carbonate,as a green agent in organic synthesis.5.The paper reported that TMEDA(N,N,N',N'-tetramethylethylenediamine)could catalyzed N-methylation of N-heterocycles,such as benzimidazole,carbazole,benzotrizole and indole.The plausible mechnism also suggested to explain this reaction.6.Antitumor activity of the target compounds was carried out against HeLa cell in vitro by using MTT assay.The preliminary results suggested the target compouns showed some antitumor activity at 10μM concentration.The compound T06 showed 36.8%inhibitory activity against HeLa cell.The further antitumor activity is under the way.