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

Indolylmaleimides is a specific class of protein kinase C inhibitors that derived from staurosporine, which cause a extensive research in the resent years. The structure modification, synthesis and biological activity of indolylmaleimide derivatives have been reviewed in this paper. The synthetic routes are also introduced, both merits and limitations of the synthetic methods have been discussed.In the recent years, our research group is interested in the synthesis and development of indolylmaleimide derivatives as protein kinase C inhibitors. According to mechanism and structure relationship about indolylmaleimides with protein kinase C inhibitors, a series of novel 3-amino-4-indolylmaleimides have been designed and synthesized. The thesis includes the following part:(1) 3,4-Dibromomaleimide 50 could be easily synthesized from succinimide by bromination with bromine, and the 3,4-dibromo-N-methylmaleimide 66 was synthesized from compound 50 by methylation with methyl idodide. The intermediate 3-bromo-4-(1H-indol-3-yl)-maleimide 51 was prepared by reaction of indole with compound 50 in the presence of magnesium and ethyl bromide, and 3-bromo-4-(1H-indol-3-yl)-N-methylmaleimide 107 was got by reaction of indole with compound 66 in the presence of magnesium and ethyl bromide. Then the intermediate 3-bromo-4-(N-methyl-indol-3-yl)-N-methylmaleimide was obtained from compound 107 by methylation with methyl idodide. With compound 51 in hand, it was treated with different amines in DMSO and TEA, to give 3-piperazinyl-4-indolylmaleimides,3-aminethylamino-4-indolyl maleimide and ethyl 2-(4-(1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-lH-pyrrol-3-ylamino) acetate. (2) The N-monoacylpiperazine was prepared by treated piperazine and acyl chloride in acetic acid at room temperature. The reaction prccedure was optimized.(3) 2-(4-(1H-indcl-3-yl)-2,5-dioxo-2,5-dihydro-lH-pyrrol-3-ylamino) acetic acid was synthesized by two routes, the first route is though the oxidation of the 2-(4-(1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-lH-pyrrol-3-ylamino)acetaldehyde, the second route is the hydrolysis of the ethyl 2-(4-(1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-lH-pyrrol-3-ylamino) acetate in LiOH solution. 3-Hydroxy-4-(1H-indol-3-yl)furan-2,5-dione, a by-product was obtained, and the reaction mechanism was discussed. Both merits and limitations of the two synthetic routes have been discussed.(4) The nucleophilic substitution reaction between 3-bromo-4-indolylmaleimide and substituted amines was discussed. We optimized this reaction by use DMSO as the solvent, cesium carbonate and triethylamine as base.(5) Sixteen target compounds were synthesized with substituted amines and 3-bromo-4-(1H-indolyl-3-yl)-maleimide. All of them have not been reported. Their structures were confirmed by IR, 1HNMR, MS,HRMS.(6) The cytotoxicities of these compounds were evaluated against various cancer cell lines by standard MTT assay. The pharmacological results showed that some of the compounds have some antitumor activity at 10μM concentration, the compound X04 showed 47% inhibitory activity against Hela cell. Further biological activity evaluation of indolylmaleimide derivatives is under way.