迈克尔加成反应预测冬凌草活性成分及其乙酰化产物抗肿瘤活性

doi:10.3969/j.issn.0253-2417.2016.01.004

摘要/Abstract

摘要： 为了快速、简便地评价冬凌草(Isodon rubescens(Hemsley) H. Hara)活性成分的抗肿瘤活性,以冬凌草活性成分冬凌草甲素和冬凌草乙素及其乙酰化产物与对硝基苯甲酰乙酸乙酯(ENBA)进行迈克尔加成反应,以反应动力学得出迈克尔加成反应的反应活性,首次以反应活性预测了对冬凌草甲素(1)、冬凌草乙素(2)、1,14-二乙酰基冬凌草甲素(1a)和1,6-二乙酰基冬凌草乙素(2a) 4个对映-贝壳杉烯的抗肿瘤活性。结果表明: 4种活性成分的迈克尔加成反应均符合二级动力学方程,反应活性1 > 1a > 2 > 2a,根据阿伦尼乌斯公式,测得冬凌草甲素活化能(E_a)为(38.7±5.8) kJ/mol,冬凌草乙素E_a为(46.8±7.1) kJ/mol。采用¹H NMR和¹³C NMR等波谱技术鉴定冬凌草甲素与ENBA经迈克尔加成反应得到的新化合物为1α,6β,7β,14β-四羟基-7α,20-环氧-17-(2-(3-(4-硝基苯基))-3-氧-丙酸乙酯)-对映贝壳杉烷-15-酮,命名为nitrobenoridonin(1b)。4个对映-贝壳杉烯具有较强的体外抗肿瘤活性,经测定它们的抗肿瘤活性大小依次为1 > 1a > 2 > 2a,与其迈克尔加成反应活性排序一致,表明迈克尔加成反应活性与抗肿瘤活性之间存在较好的相关性,可以通过测定迈克尔加成反应活性预测对映-贝壳杉烯的抗肿瘤活性。

关键词: 迈克尔加成反应, 反应动力学, 抗肿瘤活性, 对映-贝壳杉烯, 冬凌草甲素, 冬凌草乙素

Abstract: The kinetics of the Michael addition reaction among four ent-kaurenes, i.e. oridonin (1) and ponicidin (2) from Isodon rubescens (Hemsley) H.Hara, 1, 14-diacetyl oridonin (1a), 1, 6-diacetyl ponicidin (2a) and ethyl 4-nitrobenzoylacetate (ENBA) was investigated for the first time in order to conveniently predict their antitumor activity.Stoichiometric analysis indicated that the reaction between these ent-kaurenes and ENBA followed second order kinetics.The descending order of reaction rates of the four ent-kaurenes was clearly showed as 1, 1a, 2 and 2a.According to the Arrhenius equation, the activation energy of the overall reaction between oridonin, ponicidin and ENBA was (38.7±5.8) and (46.8±7.1) kJ/mol, respectively.A new major adduct named as nitrobenoridonin (1b) of oridonin and ENBA was isolated and identified as 1α, 6β, 7β, 14β-tetrahydroxy-7α, 20-epoxy-17-(2-(3-(4-nitrophenyl))-3-oxo-ethylpropanoate)-kaurane-15-one based on the spectroscopic evidence such as NMR.Moreover, these compounds were evaluated for their cytotoxicities against four cancer cell lines and exhibited significant in vitro antitumor activities.The results indicated that the order of in vitro antitumor activities of the four ent-kaurenes generally consistented with the order of their Michael addition reaction activities.A hypothetical conclusion was proposed that the antitumor activities of ent-kaurenes were probably related to their Michael addition reaction activities.Based on these novel findings, a convenient method for evaluating the antitumor activities of ent-kaurenes should be established according to their Michael addition reaction activities.

Key words: Michael addition reaction, reaction kinetics, antitumor activity, ent-kaurene, oridonin, ponicidin

中图分类号:

TQ35
R285.5

刘建群, 高俊博. 迈克尔加成反应预测冬凌草活性成分及其乙酰化产物抗肿瘤活性[J]. 林产化学与工业, 2016, 36(1): 27-34.

LIU Jian-qun LIU Jian-qun, GAO Jun-bo. Antitumor Activity of Components from Isondon rubescens (Hemsley) H.Hara and Their Acetyl Derivatives Predicted by Michael Addition Reaction[J]. Chemistry and Industry of Forest Products, 2016, 36(1): 27-34.

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