黄芩素的结构修饰以及抗肿瘤活性研究
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摘要
为了改善黄芩素的抗肿瘤活性。本实验以黄芩素为原料,对其进行结构修饰。首先通过mannich反应,在8位引入胺亚甲基,然后通过酰基化反应在7位(6位)酚羟基上引入不同的疏水性基团。并利用CCK-8法对目标化合物进行抗MCF-7肿瘤细胞的活性评价。结果合成得到了6个目标化合物,通过1H NMR、13C NMR、MS和化学手段相结合的方法确定了其结构,其中化合物2～6为新化合物。实验利用黄酮类邻二酚羟基的特性,通过与氯化锶的络合反应,巧妙而简单的确证了所得目标化合物的酯键是在化合物的7位羟基上。抗MCF-7肿瘤活性实验表明,在黄芩素8位上引入含氮原子的胺亚甲基后活性比先导化合物黄芩素强,在其7位上再引入酯键后3个化合物活性比先导化合物强。
In order to improve the anti-tumor activity of baicalein,it was structurally modified.First,an amine methylene group is introduced to the 8-position by a mannich reaction,and then a different hydrophobic group is introduced to the 7-position(6-position) phenolic hydroxyl group by an acylation reaction.The target compound was evaluated for activity against MCF-7 tumor cells by the CCK-8 method.As a result,six target compounds were synthesized,and compound 2-6 are new compounds.Their structures were determined by a combination of1 H NMR,13 C NMR,MS and chemical methods.The chemical methods utilized the characteristics of the o-diphenol hydroxyl group of flavonoid,which could react with ruthenium chloride to confirm that the ester bond of the compounds was at the 7-position hydroxyl group.Activity experiments showed that the activity of the compound with an amine-methylene group that containing a nitrogen atom at the 8-position is stronger than the lead compound.And after the ester bond is introduced at the 7-position,the activity of most compounds becomes better.
In order to improve the anti-tumor activity of baicalein,it was structurally modified.First,an amine methylene group is introduced to the 8-position by a mannich reaction,and then a different hydrophobic group is introduced to the 7-position(6-position) phenolic hydroxyl group by an acylation reaction.The target compound was evaluated for activity against MCF-7 tumor cells by the CCK-8 method.As a result,six target compounds were synthesized,and compound 2-6 are new compounds.Their structures were determined by a combination of1 H NMR,13 C NMR,MS and chemical methods.The chemical methods utilized the characteristics of the o-diphenol hydroxyl group of flavonoid,which could react with ruthenium chloride to confirm that the ester bond of the compounds was at the 7-position hydroxyl group.Activity experiments showed that the activity of the compound with an amine-methylene group that containing a nitrogen atom at the 8-position is stronger than the lead compound.And after the ester bond is introduced at the 7-position,the activity of most compounds becomes better.
引文
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13 Wen R.Drug synthesis reaction[M].Beijing:Chemical Industry Press,2009.
14 Wu LJ,Lou HX,Zhou J.Medicinal chemistry of natural products[M].Beijing:People’s Medical Publishing House,2011.
2 Inoue T,Jackson EK.Strong antiproliferative effects of baicalein in cultured rat hepatic stellate cells[J].Eur J Pharmacol,1999,378:129-135.
3 Li KJ.Preparation and SAR evaluation of scutellaria flavonoids mannich base derivatives as CDK1/Cyclin B inhibitors[D].Dalian:Dalian University of Technology(大连理工大学),2010.
4 Prevo R,Pirovano G,Puliyadi R,et al.CDK1 inhibition sensitizes normal cells to DNA damage in a cell cycle dependent manner[J].Cell Cycle,2018,17:1513-1523.
5 Guo MH.Total synthesis of baicalein and structure design of acylation mannich base derivatives[D].Dalian:Dalian University of Technology(大连理工大学),2016.
6 Ye F,Che YF,McMillen E,et al.The effect of scutellaria baicalensis on the signaling network in hepatocellular carcinoma cells[J].Nutr Cancer,2009,61:530-537.
7 Parajuli P,Joshee N,Rimando AM,et al.In vitro antitumor mechanisms of various Scutellaria extracts and constituent flavonoids[J].Planta Med,2009,75(1):41-48.
8 Chao J,Su WH.Baicalein induces cancer cell death and proliferation retardation by the inhibition of CDC2 kinase and survivin associated with opposite role of p38 mitogen-activated protein kinase and AKT[J].Mol Cancer Ther,2007,6:3039-3048.
9 Ying HZ.Design,synthesis and antitumor activity study of nitrogen-containing curcumin and flavonoid derivatives[D].Hangzhou:Zhejiang University(浙江大学),2008.
10 Huang W.Design,synthesis and antitumor activity of novel flavonoid derivatives[D].Wuhan:Central China Normal U-niversity(华中师范大学),2008.
11 Zhang L,Lin G,Chang Q,et al.Role of intestinal first-pass metabolism of baicalein in its absorption process[J].Pharm Res-Dordr,2005,22:1050-1058.
12 Sun X,Hu CQ,Huang XD,et al.Mannich reaction of baicalin[J].Chin J Org Chem(有机化学),2003,23(1):81-85.
13 Wen R.Drug synthesis reaction[M].Beijing:Chemical Industry Press,2009.
14 Wu LJ,Lou HX,Zhou J.Medicinal chemistry of natural products[M].Beijing:People’s Medical Publishing House,2011.