吲哚-3-羧酸类化合物的设计、合成及体外降糖活性研究
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摘要
以苯醌及3-氨基巴豆酸乙酯为原料,经环合、苄基化得到关键中间体5-苄氧基-2-甲基-1H-吲哚-3-甲酸乙酯。关键中间体经水解及酰胺化得到3个目标化合物。关键中间体经磺酰化及水解可再次得到4个目标化合物,共合成7个目标化合物。其化学结构均经高分辨质谱、核磁共振氢谱及碳谱确证。人肝癌Hep G2细胞上的促糖消耗活性显示,所合成化合物均具有一定的促糖消耗活性。其中,5-苄氧基-2-甲基-1-(4-氯苯甲酰基)-吲哚-3-甲酸的降糖活性与先导化合物GY3相当。
Starting from benzoquinone and( E)-ethyl 3-aminobut-2-enoate,the key intermediate ethyl 5-( benzyloxy)-2-methyl-1 H-indole-3-carboxylate was synthesized via cyclization and benzylation,which was subjected to hydrolyzation and final amidation with various aryl acids to give three target compounds.The four desired compounds were also obtained from the key intermediate via sulfonylation and hydrolyzation. All the synthesized target compounds were confirmed by high resolution mass spectrometer( HR-MS) and nuclear magnetic resonance( NMR) H and C spectrum.The glucose-consumption activity assay in Hep G2 cell lines showed that all the synthetic compounds exhibited certain hypoglycemic activity,and 5-benzyloxy-2-methyl-1-( 4-chlorobenzoyl)-indole-3-formic acid demonstrated comparable activity with the lead GY3.
Starting from benzoquinone and( E)-ethyl 3-aminobut-2-enoate,the key intermediate ethyl 5-( benzyloxy)-2-methyl-1 H-indole-3-carboxylate was synthesized via cyclization and benzylation,which was subjected to hydrolyzation and final amidation with various aryl acids to give three target compounds.The four desired compounds were also obtained from the key intermediate via sulfonylation and hydrolyzation. All the synthesized target compounds were confirmed by high resolution mass spectrometer( HR-MS) and nuclear magnetic resonance( NMR) H and C spectrum.The glucose-consumption activity assay in Hep G2 cell lines showed that all the synthetic compounds exhibited certain hypoglycemic activity,and 5-benzyloxy-2-methyl-1-( 4-chlorobenzoyl)-indole-3-formic acid demonstrated comparable activity with the lead GY3.
引文
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[2]张屹,孟霞,秦大伟,等.吲哚类抗肿瘤药物的研究进展[J].化工中间体,2011,7(1):15-18.
[3]VERMA M,TRIPATHI M,SAXENA A K,et al. Antiinflammatory activity of novel indole derivatives[J]. Eur. J.Med.Chem.,1994,29(12):941-946.
[4]陈刚,郝小江.吲哚-2,3-二酮衍生物抗病毒活性研究进展[J].化学研究,2015,26(3):315-322.
[5]马晓,王建塔,曹俊,等.吲哚-3-羧酸衍生物的合成及降糖活性研究[J].化学试剂,2016,38(8):721-725.
[6]ZHANG J Q,WANG J T,WU H S,et al.Design,synthesis and insulin-sensitizing activity of indomethacin and diclofenac derivatives[J].Bioorg. Med. Chem. Lett.,2009,19(12):3 324-3 327.
[7]SI M M,YAN Y Y,TANG L,et al.A novel indole derivative compound GY3 improves glucose and lipid metabolism via activation of AMP-activated protein kinase pathway[J].Eur.J.Pharmacol.,2013,698(1/3):480-488.
[8]RUDERMAN N B,CARLING D,PRENTKI M,et al.AMPK,insulin resistance,and the metabolic syndrome[J].J.Clin.Invest.,2013,123(7):2 764-2 772.
[9]MADESEN A,BOZICKOVIC O,BJUNE J I,et al. Metformin inhibits hepatocellular glucose,lipid and cholesterol biosynthetic pathways by transcriptionally suppressing steroid receptor coactivator 2(SRC-2)[J]. Sci. Rep.,2015,5:16 430.
[10]LIN Z J,ZHANG B,LIU X Q.Advance of researches on AMPK-ACC signaling pathway in metabolic diseases[J].Chin.J.Diabetes,2013,21(5):474-477.
[11]RICHARD L B,JOHN E D,YUAN H Q,et al.Preparation of indole-3-carboxylic acid mides,esters,thioamides,and thiol esters sphingosine-1-phosphate(S1P)receptor agonists or antagonists:US 20 070 191 313[P].2007-08-16.
[12]LOVATI M R,MANZON C,CASTIGLIONI S,et al.Lupin seedγ-conglutin lowers blood glucose in hyperglycaemic rats and increases glucose consumption of Hep G2 cells[J].Br.J.Nutr.,2012,107(1):67-73.