Synthesis And Cytotoxicity Of Indolylmaleimide Derivatives As Protein Kinase C Inhibitors

Indolylmaleimides,derived from staurosporine,is a specific class of protein kinase C inhibitors.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.Recently,our research group is interested in the synthesis and development of indolylmaleimide derivatives as anticancer agents.In our continued research program directed toward the synthesis of novel indolylmaleimide derivatives in this area.A series of novel 3-amino-4-indolylmaleimides have been designed and synthesized.This thesis includes the following part:1) 2-Bromo-3-(1H-indol-3-y1)-N-methylmaleimide as the key intermediate could be easily synthesized from succinimide by bromination with bromine,methylation with methyl idodide and the adduction of indole with 2,3-dibromo-N-methyl-maleimide in the presence of magnesium and ethyl bromide in 35%overyield for three steps.2-Bromo-3-(1H-indol-3-y1)maleimide was obtained from the 2,3-bromomaleimide by the adduction of indole with 2,3-dibromo-N-methylmaleimide in the presence of magnesium and ethyl bromide in 49%all yield for two steps.With the 2,3-dibromo-N-methylmaleimide and 2-Bromo-3-(1H-indol-3-y1)maleimide in hand, it was treated with different amines in DMF to give 3-amino-4-indolylmaleimides and 3-amino-4-indolyl-N-methylmaleimides as red crystal.3-Cyano-4-indolylmaleimides were obtained by treating 3-bromo-4-indolylmaleimides with copper cyanide.2) 2,3-Dibromo-4-indolyl-N-methylmaleimide,2,3-dibromo-4-indolylmaleimide bisindolylmaleimide,prepared by the reaction of indole with 3,4-dibromo-N-methyl-maleimide in the presence of magnesium and ethyl bromide,were used as the substrate. They were subjeced to the regioselective amination with substituted amines to provide 3-aminoindolylmaleimides,3-amino-N-alkylated indolylmaleimides and N-alkylated bisindolylmaleimides in good yields.Based on the experimental results,a plausible mechanism can be proposed.The resulting indolylmaleimides represent a new class of potentially bioactive compounds.3) Two single crystals for 3-(dimethylamino)-4-indolylmaleimides and 3-(2-hydroxyethylamino)-N-(2-hydroxyethyl)-4-indolylmaleimide were obtained by dissolving the compounds in ethyl acetate and ethanol(1:1),and evaporating the solvent slowly at room temperature.X-Ray single crystals were solved by direct methods with SHELX-97.They are monoclinic and triclinic,respectively.4) Totally,twelve compounds were synthezied in this paper.Eleven of them were not reported in the literature.Their structures have been confirmed by IR,~1H-NMR and MS.5) The cytotoxicities of these compounds were evaluated against various cancer cell lines by standard MTT assay in vitro.The pharmacological results showed that some of the compounds displayed moderate or high cytotoxic activity against the tested cell lines.Structure-activity relationships are discussed based on the experimental data obtained.A hydroxyalkylamino group at 3-position in the side chain of indolylmaleimide is associated with an increase in cytotoxicity.