N-芳酰基取代的二氢吲哚-3-乙酸类衍生物的设计、合成与体外降糖活性研究
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篇名: N-芳酰基取代的二氢吲哚-3-乙酸类衍生物的设计、合成与体外降糖活性研究
TITLE:
摘要: 目的:设计、合成N-芳酰基取代的二氢吲哚-3-乙酸类衍生物,并评价其体外降糖活性。方法:以吲哚衍生物2-[5-(苄氧基)-1-(4-氯苯甲酰基)-2-甲基-1H-吲哚-3-基]乙酸(GY3)为先导化合物,以4-苯甲氧基苯肼盐酸盐及4-氧戊酸甲酯为原料,经Fischer吲哚环合、还原、酰胺化及水解等4步反应得到8种N-芳酰基(3-羟基苯甲酰基、3-氰基苯甲酰基、4-硝基苯甲酰基、4-甲磺酰基苯甲酰基、4-乙酰胺基苯甲酰基、3-乙酰氨基苯甲酰基、异烟酰基、吡啶-2-甲酰基)取代的二氢吲哚-3-乙酸类衍生物。采用人肝癌细胞HepG2测试目标化合物的体外促葡萄糖消耗活性。结果:共合成8个N-芳酰基取代的二氢吲哚-3-乙酸类目标化合物,其结构均经质谱、核磁共振氢谱及碳谱确证。在1.0 μmol/L条件下,所合成化合物在HepG2细胞上的促葡萄糖消耗百分率为5.4%~9.1%,其中,2-[(2R,3S)-5-苄氧基-2-甲基-1-(4-甲磺酰基苯甲酰基)-2,3-二氢-吲哚-3-基]乙酸的降糖活性最好,其促葡萄糖消耗百分率为(9.10±1.81)%,与阳性对照药物二甲双胍接近[(10.58±1.68)%],但仍弱于先导化合物GY3[(12.15±0.78)%]。结论:二氢吲哚类化合物的N-芳酰基芳环上引入不同吸电子取代基团,如氰基、硝基、甲磺酰基等,其降糖活性不同程度下降,且弱于卤素取代基的GY3。
ABSTRACT: OBJECTIVE: To design and synthesize N-aroyl substituted indoline-3-acetic acid derivatives and evaluate their in vitro hypoglycemic activity. METHODS: Using indoline derivative 2-[5-(benzyloxy)-1-(4-chlorobenzoyl)-2-methyl-1H-inclol-3-yl]acetic acid (GY3) as leading compound, 4-(benzyloxy)phenyl hydrazine hydrochloride and methyl 4-oxopentanoate as raw material, 8 kinds of N-aroyl (3-hydroxybenzoyl, 3-cyanobenzoyl, 4-nitrobenzoyl, 4-methylsulfonylbenzoyl, 4-acetamidobenzoyl, 3-acetylaminobenzoyl, isoniacyl and pyridine-2-formyl) substituted indoline-3-acetic acid derivatives were synthesized via 4 steps reactions: Fischer indole cyclization, reduction, amidation and hydrolyzation. The human hepatoma HepG2 cell lines were used to investigate the glucose consumption activity of the target compounds. RESULTS: Totally 8 various N-aroyl substituted indoline-3-acetic acids were synthesized and their structures were confirmed by mass spectrum(MS), nuclear magnetic resonance 1H-NMR and 13C spectrum. Under the condition of 1.0 μmol/L, the percentage of glucose- promoting consumption of the synthesized compounds on HepG2 cells was 5.4%-9.1%. 2-[(2R, 3S)-5-benzyloxy-2-methyl-1-(4-methylsulfonyl benzoyl)-2,3-dihydro-indole-3-yl] acetic acid showed the best hypoglycemic activity. The percentage of glucose- promoting consumption was (9.1±1.81)%, which was close to that of positive control metformin [(10.58±1.68)%], but less potent than that of leading compound GY3[(12.15±0.78)%]. CONCLUSIONS: Different electron-withdrawing substituents are introduced into N-aroyl aromatic rings of dihydroindole compounds, such as cyano, nitro, methyl sulfonyl; hypoglycemic activity decreases in varying degrees and is weaker than halogen substituents.
期刊: 2019年第30卷第3期
作者: 张吉泉,武婷婷,马才玉,马晓,王建塔,汤磊
AUTHORS: ZHANG Jiquan,WU Tingting,MA Caiyu,MA Xiao,WANG Jianta,TANG Lei
关键字: 二氢吲哚-3-乙酸类衍生物;降糖活性;合成;构效关系
KEYWORDS: Indoline-3-acetic acid derivative; Hypoglycemic activity; Synthesis; Structure-activity relationship
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