Synthesis And Antitumor Acticity Of 3-amide-4-indolylmaleimide Derivatives As Protein Kinase C Inhibitors

Indolylmaleimides have been widely investigated as a new series of protein kinase C(PKC)recently.Studies have shown that these compounds,such as Ruboxistaurin,Enzastaurin,and JTT-010 in clinic trail,have anticancer,antibacterial effect,and can inhibit retinopathy caused from diabetes mellitus.This paper reviews the recent development of indolylmaleimide derivatives as PKC inhibitor.Based on it, we designed,synthesized a new series of indolylmaleimide derivatives.This paper contains mainly the following items:1.3,4-Dibromo-N-maleimide,an important intermediate,was synthesized by bromination and methylation with succinimide as starting materials.Maleimide was prepared by three steps from succinic anhydride.3,4-Dibromomaleimide was also prepared by brominition from maleimide.The reaction conditions were optimized. The procedure from succininimide is suitable for large scale preparation.2.We investigated the adduct reaction between indolylmagnesiumbromide and 3,4 -dibromomaleimide,or 3,4-dibromo-N-methylmaleimide,and optimized this reaction by changing temperature and reaction time.Mono- and bis- substituted substrates were obtained respectively by control the temperature.3.Ethyl 4-nitrophenylacetate was prepared from ethyl phenylacetate by nitration with nitric acid and sulfuric acid.The 1-methylindole-3-glyoxylamide was synthesized from indole by methylation with dimethyl carbonate,acylation with oxalyl chloride, and amination with ammonia.4.A series of 3-amideindolylmaleide derivatives were synthesized using 3-bromo-(1H-indol-3-yl)-maleimide as source material through a reaction sequence of substitute with sodium azide,reduction,selective acylation on amino group.The selective acylation productions on N-position of maleimide and amino group were obtained by using chloroacetyl chloride under different condition.The chemical structures of target compounds were identified by IR,ESI-MS and ~1H-NMR.5.Six target compounds were tested for antitumor activity in vitro against human Hela cell by means of colorimetric MTT assay.The preliminary results suggested the target compounds showed some antitumor activity at 10μM concentration.The further anticancer activity is under the way.