L-色氨酸衍生物的合成及促凝活性

Synthesis and Coagulating Activity of L-Tryptophan Derivatives

摘要:

以L-色氨酸为原料，分别与以邻苯二甲酸酐保护的4-氨甲基苯甲酸、4-氨甲基环己基甲酸及6-氨基己酸反应合成了3种酰胺衍生物，分别是(S)-3-(1’ H-吲哚-3’-基)-2-{4’’-[(1’’’，3’’’-二氧代异吲哚-2’’’-基)甲基]苯甲酰氨基}丙酸（I）、(S)-3-(1’ H-吲哚-3’-基)-2-{4’’-[(1’’’，3’’’-二氧代异吲哚-2’’’-基)甲基]环己基甲酰氨基}丙酸（II）及(S)-3-(1’ H-吲哚-3’-基)-2-[6’’-(1’’’，3’’’-二氧代异吲哚-2’’’-基)己酰氨基]丙酸（III）。通过IR、MS、1H NMR及13C NMR对其结构进行了表征。反向筛选出两种与促凝活性相关的蛋白，再将L-色氨酸与3个目标化合物与其分别进行正向对接，通过凝血四项与血浆复钙时间实验表明化合物I及化合物III的促凝活性随其浓度的增加而增强，化合物II具有浓度依赖性调节作用。

Abstract:

Three L-tryptophan derivatives (S)-2-{4’’-[(1’’’,3’’’-dioxoisoindolin-2-yl)methyl]benzamido}-3-(1’ H-indol-3’-yl)propanoic acid (I), (S)-2-{4’’-[(1’’’,3’’’-dioxoisoindolin-2-yl)methyl]cyclohexanecarboxamido}-3-(1’ H-indol-3’-yl)propanoic acid (II) and (S)-2-[6’’-(1’’’,3’’’-dioxoisoindolin-2-yl)hexanamido]-3-(1’ H-indol-3’-yl)propanoic acid (III) were synthesized through amidation reaction with three hemostatic amine acids protected by phthalic anhydride, including, 4-(aminomethyl)benzoic acid, 4-(aminomethyl)cyclohexane-1-carboxylic acid and 6-aminohexanoic acid. The structures were confirmed by IR, MS and 1H NMR and 13C NMR. Two coagulating target proteins were reversely screened, and positively docked with L-tryptophan and three compounds through MOE, respectively. Blood concretion four items and plasma re-calcification time indicated that compounds I and III showed better coagulating activity with increasing concentration, while compound II showed dose-dependent activity.