新型杨梅素衍生物S2-1-5的合成及抗肿瘤活性研究

Synthesis and study on the antitumor activity of a novel myricetin derivative S2-1-5

目的:评价新设计合成的杨梅素衍生物S2-1-5对人肝癌SMMC-7721细胞的抗肿瘤活性,以期为杨梅素衍生物的结构优化和抗肝癌药的进一步研发提供依据。方法:以杨梅素为母体,通过化学反应合成S2-1-5,并用核磁共振(NMR)和高分辨质谱(HRMS)进行结构和定量分析,再验证其抗肿瘤活性:将不同浓度的S2-1-5和阳性对照药吉西他滨作用于SMMC-7721细胞,DMSO作为阴性对照组,通过MTT实验和形态学观察检测S2-1-5对SMMC-7721细胞的增殖抑制作用,划痕实验检测SMMC-7721细胞迁移能力,流式细胞术检测SMMC-7721细胞周期和细胞凋亡。结果:NMR和HRMS确定了2-氟苄基4-((3-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)丙基)(甲基)氨基)哌啶-1-二硫代羧酸(S2-1-5)的分子结构,其化学式为C_(37)H_(43)FN_(2)O_(8)S_(2)。S2-1-5的抗肿瘤活性实验表明:与对照组相比,不同浓度下,S2-1-5的抑制活性更高,差异均具有统计学意义(P<0.05);S2-1-5能抑制SMMC-7721细胞迁移(P<0.05);S2-1-5使SMMC-7721细胞的细胞周期阻滞在S期(P<0.05);S2-1-5能诱导SMMC-7721细胞凋亡(P<0.01)。结论:成功合成S2-1-5,其能通过抑制SMMC-7721细胞增殖和迁移,诱导细胞周期阻滞和凋亡发挥其体外抗肿瘤作用。

Objective:To evaluate the antitumor activity of the newly designed and synthesized myricetin derivative S2-1-5 against human hepatoma SMMC-7721 cells,so as to provide theoretical and experimental basis for the structural optimization of myricetin derivatives and the further development of anti-hepatoma drugs.Methods:Using myricetin as parent,S2-1-5 was synthesized by chemical reactions,its structure and quantitative analysis were carried out by nuclear magnetic resonance(NMR)and high resolution mass spectrometry(HRMS),and then its anti-tumor activity was verified:SMMC-7721 cells were treated with different concentrations of S2-1-5 and positive control drug gemcitabine,and DMSO was used as negative control.The proliferation inhibition of S2-1-5 on SMMC-7721 cells was detected by MTT assay and morphological observation,and the migration ability of SMMC-7721 cells was detected by scrape assay.The cell cycle and apoptosis of SMMC-7721 were detected by flow cytometry.Results:The molecular structure of 2-fluorobenzyl 4-((3-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxy phenyl)-4H-chromene-3-yl)oxy)propyl)(methyl)amino)piperidine-1-dithiocarboxylic acid(S2-1-5)was determined by NMR and HRMS.Its chemical formula was C_(37)H_(43)FN_(2)O_(8)S_(2).The antitumor activity experiment of S2-1-5 showed that:Compared with the control group,the inhibition activity of S2-1-5 was higher at different concentrations,and the differences were significant;S2-1-5 could inhibit the migration of SMMC-7721 cells(P<0.05).S2-1-5 inhibited the cell cycle of SMMC-7721 cells in S phase(P<0.05);S2-1-5 could induce apoptosis of SMMC-7721 cells(P<0.01).Conclusions:S2-1-5 can inhibit the proliferation and migration of SMMC-7721 cells and induce cell cycle arrest and apoptosis to exert its antitumor effect in vitro.