十二味中药炮制的色谱研究与DNA甲基转移酶抑制剂合成研究
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摘要
本论文分两部分，第一部分是以中药炮制前后化学成分的变化为对象，揭示中药炮制物质基础的研究；第二部分是关于新型DNA甲基转移酶抑制剂的合成研究。
中药炮制是依据药物性能和用药需要采取的制药技术。中药在炮制过程中受加热、水浸及辅料处理的影响，其化学成分可能会发生变化，相应地可能引起中药性能的改变，即化学成分的变化应该是药性改变的物质基础。本部分实验选取决明子等十二味中药作为研究对象，应用高效液相色谱法，研究它们炮制前后化学成分的变化。结果表明，中药炮制后有的成分含量增加了，有的减少了，有的成分消失了，也有新成分产生。这一研究将有助于寻求炮制增效减毒改变药性的内因，揭示炮制作用的物质基础，为炮制药理研究和临床用药安全提供科学依据。
DNA甲基化对肿瘤相关基因的表达起重要的调控作用，肿瘤细胞内甲基化模式的混乱是其发生的重要原因。研究表明DNA甲基转移酶抑制剂可以显著的抑制肿瘤生长，有很好的治疗效果。现常见的甲基转移酶抑制剂氮胞苷类，因其毒副作用大，临床应用有限。新型DNA甲基转移酶抑制剂，为小分子化合物，其作用机理独特，性能良好，有很好药用开发前景。本部分实验一步合成新型DNA甲基转移酶抑制剂及其新系列衍生物，共十个化合物，意图通过活性检测，筛选出具有良好性能的化合物，应用于抗癌药物的研制和开发。
This dissertation has two parts. The first part is the study of chemical changes of Traditional Chinese Medicine (TCM) during the preparing process, in order to reveal the substantial base and mechanism of increasing effectiveness and detoxication. The second part is the synthesis of the novel small-molecule inhibitors of DNA methylatransferase.
The preparing process of TCM is one of preparing techniques according to pharmic characters and clinical requirements. The chemical constituents of TCM are remarkably changed during the preparing process, due to the effect of heating, steeping and so on. The changes of the constituents consequentially result in the changes of the characters of TCM. It indicates that the changes of the constituents is the substantial base. Twelve kinds of TCM have been chosen as subjects, applying HPLC to analyse the whole chemical changes. For a certainty, there are chemical changes in the prepared drugs through comparing the chromatograms of raw and prepared drugs. The results let us have a good chance to reveal the substantial base of preparing process and show the scientific proof of the preparing process and improve the process to accelerate the development of the preparing process of TCM.
As the developing of epigenetics, it has been deeply realized that DNA methylation plays an important role in regulating genes expression. The possibility to reactive epigentically silenced genes has generated considerable interest in the development of DNA methyltransferase inhibitors. The most widely known methylation inhibitors are cytidine analogues. However, due to their substantial cytotoxicity, they are limited in their application. Therefore, it is urgent to identify chemical compounds with an ability to directly block human DNA methyltransferases. It has been reported that a small-molecule, novel, mechanism-independent compound has high activity in inhibiting the DNA methyltransferase. Based on the possibility for chemical modifications, a series of derivatives were synthesized by a very simple way with high yield, which all represent promising candidates for cancer drug development.
中药炮制是依据药物性能和用药需要采取的制药技术。中药在炮制过程中受加热、水浸及辅料处理的影响，其化学成分可能会发生变化，相应地可能引起中药性能的改变，即化学成分的变化应该是药性改变的物质基础。本部分实验选取决明子等十二味中药作为研究对象，应用高效液相色谱法，研究它们炮制前后化学成分的变化。结果表明，中药炮制后有的成分含量增加了，有的减少了，有的成分消失了，也有新成分产生。这一研究将有助于寻求炮制增效减毒改变药性的内因，揭示炮制作用的物质基础，为炮制药理研究和临床用药安全提供科学依据。
DNA甲基化对肿瘤相关基因的表达起重要的调控作用，肿瘤细胞内甲基化模式的混乱是其发生的重要原因。研究表明DNA甲基转移酶抑制剂可以显著的抑制肿瘤生长，有很好的治疗效果。现常见的甲基转移酶抑制剂氮胞苷类，因其毒副作用大，临床应用有限。新型DNA甲基转移酶抑制剂，为小分子化合物，其作用机理独特，性能良好，有很好药用开发前景。本部分实验一步合成新型DNA甲基转移酶抑制剂及其新系列衍生物，共十个化合物，意图通过活性检测，筛选出具有良好性能的化合物，应用于抗癌药物的研制和开发。
This dissertation has two parts. The first part is the study of chemical changes of Traditional Chinese Medicine (TCM) during the preparing process, in order to reveal the substantial base and mechanism of increasing effectiveness and detoxication. The second part is the synthesis of the novel small-molecule inhibitors of DNA methylatransferase.
The preparing process of TCM is one of preparing techniques according to pharmic characters and clinical requirements. The chemical constituents of TCM are remarkably changed during the preparing process, due to the effect of heating, steeping and so on. The changes of the constituents consequentially result in the changes of the characters of TCM. It indicates that the changes of the constituents is the substantial base. Twelve kinds of TCM have been chosen as subjects, applying HPLC to analyse the whole chemical changes. For a certainty, there are chemical changes in the prepared drugs through comparing the chromatograms of raw and prepared drugs. The results let us have a good chance to reveal the substantial base of preparing process and show the scientific proof of the preparing process and improve the process to accelerate the development of the preparing process of TCM.
As the developing of epigenetics, it has been deeply realized that DNA methylation plays an important role in regulating genes expression. The possibility to reactive epigentically silenced genes has generated considerable interest in the development of DNA methyltransferase inhibitors. The most widely known methylation inhibitors are cytidine analogues. However, due to their substantial cytotoxicity, they are limited in their application. Therefore, it is urgent to identify chemical compounds with an ability to directly block human DNA methyltransferases. It has been reported that a small-molecule, novel, mechanism-independent compound has high activity in inhibiting the DNA methyltransferase. Based on the possibility for chemical modifications, a series of derivatives were synthesized by a very simple way with high yield, which all represent promising candidates for cancer drug development.
引文
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[2]．郑美莺，对中药炮制原理的再认识，中国误诊学杂志，2006，6(13)：2634—2635．
[3]．刘斌．中药炮制过程中化学成分的变化及其机理．中草药，1997，28(9)：566．
[4]．邹文拴，等．附子生用与炮用的化学分析研究．中国中药杂志，1995，20(2)：86-88．
[5]．徐东铭，等．人参化学成分研究的新进展．中国中药杂志，1989，14(6)：3-6．
[6]．李向高．人参加工原理研究新进展．中药材，1990，13(2)：22-25．
[7]．刘星楷．黄芪蜜炙方法的历史沿革及效用的探讨．中国中药杂志，1993，18(2)：87-89．
[8]．刘成基，等．国外中药炮制研究．中药材，1990，13(5)：25-27．
[9]．陆敏仪，等．双波长法测定马钱子中马钱子碱和士的宁含量及马钱子炮制原理探讨．中国中药杂志，1990，15(12)：18-21．
[10]．Cai Bao-chang，et al．生薬学雜志，1990，44(1)：42．
[11]．蔡宝昌，等．士的宁加热反应的研究．中国药学杂志，1994，29(5)：302-304．
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