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Synthesis and Cytotoxicity of Indolylmaleimide Derivatives as Protein Kinase C Inhibitors

Author: YangYanWu
Tutor: ZhaoShengYin
School: Donghua University
Course: Organic Chemistry
Keywords: Protein kinase C inhibitor 3 - amino-4 - indole -N-methyl maleimide Reaction Mechanism The anti-tumor activity
CLC: R96
Type: Master's thesis
Year: 2010
Downloads: 66
Quote: 1
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Abstract

Series of indole-maleimide compounds obtained by Staurosporine structural transformation is a new class of protein kinase C inhibitor. This paper summarizes and an overview of the research progress achieved in recent years, structural modification, synthesis and biological activity of indole maleimide compounds. The introduced maleimide compound indole synthesis method, and discusses the advantages and disadvantages of various synthetic methods. On the basis of preliminary studies by our group, we compound design, synthesis and anti-tumor activity of model indole maleimide compounds and the role of protein kinase C, the thesis work mainly includes the following aspects: 1) were synthesized 3 - bromo-succinimide as a starting material, of methyl bromide, methyl iodide, and an addition reaction with indole under the action of the magnesium and bromoethane step -4 - indole maleimide compound and 3 - bromo-4 - indole-N-methyl maleimide compound, and studied with a variety of amino alcohol, an amine and cuprous cyanide reaction Preparation of 3 - amino - 4 - indol-maleimide and 3 - cyano-4 - indol-maleimide compound. 2) more systematic study of 3 - bromo -4 - indol-maleimide and 3 - bromo-4 - indole-N-methyl maleic imide with an amine compound of a nucleophilic substitution reaction to obtain 3 - amino alcohol substituted indole maleimide and 3 - the aminoalcohol-N-alkyl substituted indole maleimide compound, found Regioselective ring opening reaction and the reaction mechanism discussed. The bis-indole maleimide ring-opening reaction with hydrazine hydrate to give 1 - amino-bis-indole maleimide compound, and without obtain diindolo pyridazine compound. Monocrystalline culture 3) in a mixed solvent of ethyl acetate and acetone (1:1), to obtain a 3 - dimethylamino -4 - maleimide indole and 3 - (2 - hydroxyethyl amine yl) -4 - indole-of N-(2 - hydroxyethyl) maleimide single crystal, the former is monoclinic, the latter is triclinic, is formed via intermolecular hydrogen bonding interactions The three-dimensional structure of the single crystal structure analysis. 4) through experiments, we synthesized the 3 - amino alcohol, 3 - amine, 3 - cyano-substituted maleimides of the indole and 3 - amino alcohol-N-alkyl substituted indole maleimide total of 12 the imine bisindole maleimides target compounds, and its structure was confirmed by mass spectrometry, NMR, and infrared spectroscopy, including 11 new compounds have not been reported. 5) The MTT assay was used to study the anti-tumor activity of the compound synthesized herein. The killing effect in vitro on human cervical cancer Hela cell lines, pharmacological studies show that the seven target compounds were measured: the target compounds in 10μM concentration of human cervical cancer Hela cell lines have different degrees of inhibition. Target compounds of other tumor cell lines, such as leukemia K562 such inhibitory activity and further anti-tumor activity, and mechanism of action study is ongoing.

Synthesis and Cytotoxicity of Indolylmaleimide Derivatives as Protein Kinase C Inhibitors

Abstract

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