紫红参化学成分、指纹图谱及生物活性的研究
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摘要
紫红参（Purple red ginseng）是将人参反复蒸制烘干而得到的一种人参深加工产品。在将人参炮制加工成紫红参的过程中，会发生美拉德反应及降解反应等，部分化学成分会发生变化。到目前为止，对紫红参化学成分及生物活性研究较少。本论文首次对紫红参的化学成分、指纹图谱及生物活性进行了研究，为紫红参的质量监控以及进一步的临床应用与推广提供了坚实的理论基础。
首先对紫红参的化学成分进行了研究，利用现代的提取、分离和纯化手段首次从紫红参中分离出了27个化合物，通过理化性质、TLC对照、波谱（13C-NMR、1H-NMR、HMBC、HMQC等）解析以及X-射线晶体衍射等手段，鉴定了其中25个化合物的结构。
首次采用UPLC-ESI-MS/MS方法对紫红参和生晒参中皂苷类成分及其含量进行了对比研究。
首次建立了紫红参的指纹图谱，并对其进行了评价，为紫红参的质量控制提供了参考。
以20(S)-原人参三醇（PPT）为原料，采用酰氯法、DCC法合成了22个PPT脂肪酸酯衍生物，其中20个为新的脂肪酸酯衍生物。同时，采用MTT法系统地研究了PPT脂肪酸酯衍生物的体外抗肿瘤生物活性，初步对其构效关系进行了探讨。
首次采用UPLC-ESI-MS/MS分析方法，鉴定灌胃紫红参后大鼠血清中的移行成分，明确了紫红参入血的有效成分，阐明了紫红参的体内作用物质基础，为其在临床上的广泛应用提供了理论依据。
首次研究了紫红参提取物对老龄雄性大鼠性功能的影响，为紫红参作为壮阳药物的开发利用提供了理论依据。
Purple red ginseng was the ginseng deep processing products by steaming anddrying of ginseng repeatedly. In the preparation process, Maillard reaction anddegradation occcred, part of the chemical constituents have been changed. So far,there were few studies on the chemical constituents and bioactivities of this new deepprocessed products of ginseng. In this thesis, the chemical constituents, fingerprintand bioactivities of Purple red ginseng were studied for the first time, which wasexpected not to discover the different constituents but to offer scientific basis toaccelerate its further application and guarantee the quality control.
Firstly, the chemical constituents of purple red ginseng were investagated.27kinds of compounds were extracted, separated and purified by various methods. Then25of them were identified according their physicochemical properties, TLC,spectrum analysis(~(13)C-NMR、~1H-NMR、HMBC、HMQC) and X-ray diffraction bycrystals. The structures of them were identified as follows:20(S)-protopanaxadiol (1);20(R)-protopanaxadiol (2); Ginsenoside Rd (3);20(S)-ginsenoside Rg_3(4);20(R)-ginsenoside Rg_3(5); Ginsenoside Rk_1(6); Ginsenoside Rg_5(7);20(S)-protopanaxatriol (8);20(R)-protopanaxatriol (9); Ginsenoside Rg_6(10);20(S)-ginsenoside Rh_1(11);20(R)-ginsenoside Rh1(12);20(S)-ginsenoside Rg2(13);20(R)-ginsenoside Rg2(14);Ginsenoside Rf (15); Notopanaxoside R_2(16); Ginsenoside Ro (17); Zingibroside R_1(18);β-sitosterol (19); β-daucosterol (20);4-O-α-D-glucopyranosyl-D-Glucose (21)；palmitic acid (22); Hexadecane (23); n-Dodecane (24);2-oxopropyl-α-D-glucopyranoside (25).
On the basis of extraction and separation of chemical constituents of purple redginseng, saponins and their contents of purple red ginseng and white ginseng were compared by UPLC-ESI-MS/MS method. The results showed that in the preparationprocess, Maillard reaction and degradation occcred, and the types and quantities ofginseng saponins changed, resulting in20(S)-ginsenoside Rg3,20(R)-ginsenoside Rg3,20(R)-ginsenoside Rh_1,20(R)-ginsenoside Rg_2, ginsenoside Rk_1, ginsenoside Rg5,ginsenoside Rd, ginsenoside Ro, zingibroside R_1,20(S)-protopanaxatriol,20(R)-protopanaxatriol,20(S)-protopanaxadiol,20(R)-protopanaxadiol and so on.
In this paper, the fingerprints of purplish red ginseng was established andevaluated for the first time.12common peaks were found in the HPLC-PDAfingerprint. In the precision, reproducibility and stability test, RSD of each commonpeak relative retention time was less than1%, and RSD of relative peak area less than3%. Samples of10batches were of high similarity and the similiarity degree were0.885～1.000. The fingerprint of purplish red ginseng showed good reproducibility,and the method is stable and reliable, which can be used for the quality control ofpurplish red ginseng.
Due to the higher content of20(S)-protopanaxatriol in purplish red ginseng, select20(S)-protopanaxatriol as raw material.22fatty acid esters of PPT，including two knownoleoy esters and other20new fatty acid esters，were synthesized using acyl chloride or fattyacid and N, N’-dicyclohexylcarbodiimide (DCC). The structures were elucidated by thecombined analysis of NMR and ESI-MS. The antitumor activities were tested in vitro in threecell lines, HepG2, Hela and SGC-7901, using the MTT method for the first time. The structuralrelationships between fatty acid derivatives of PPT and their cytotoxic properties were alsodiscussed preliminarily in this paper. The purpose is to find and prepare antitumor compoundswith high efficiency and low toxicity, and to provide the theoretical basis for development andinnovation of ginsenoside as anticancer drugs.
In this thesis, the serum pharmacochemistry of the extract of Purplish redginseng was studied. Serum was collected after oral administration of the extract ofPurplish red ginseng to rats. The sample was detected by UPLC-ESI-MS/MS, and themain compounds of the serum containing Purplish red ginseng were determined. Rat’sserum contains14transitional blood components, among which six were originalconstituents of extract of Purplish red ginseng and the other might be metabolites ofthe original constituents. The bioactive components of the purplish red ginseng after oral administration of the extracts were clarified, and the mechanisms of action ofPurplish red ginseng were illustrated, which will provide the theoretical basis for itswide application in clinic.
Investigation on the effect of purplish red ginseng on the sexual aetivity of agedmale rats. The results showed that purplish red ginseng can improve sexual activity ofsenile rats evidently compared with controlled groups, improve their sexual desire andcourtship times; It can act on hypothalamic-testicular-gonadal axis and regulate sexhormone levels, so as to promote the generation of androgen and serum testosterone;purplish red ginseng can increase the sperm vigor; It also can increase the content of5-HT and DA of rats’hypothalamus. Aphrodisiac of purplish red ginseng wassignificant, and some test index even better than the positive drug. These will providetheoretical basis for the development and utilization purplish red ginseng asimpotence drug.
The chemical constituents, fingerprint and bioactivities about purplish red ginsengwere made a deep investigation in the thesis for the first time. The results wouldsupply good methods for quality control and offere strong, accurate and scientifictheoretical basis to the wide application of this kind of ginseng, which might produceeven higher theoretical and economic value.
首先对紫红参的化学成分进行了研究，利用现代的提取、分离和纯化手段首次从紫红参中分离出了27个化合物，通过理化性质、TLC对照、波谱（13C-NMR、1H-NMR、HMBC、HMQC等）解析以及X-射线晶体衍射等手段，鉴定了其中25个化合物的结构。
首次采用UPLC-ESI-MS/MS方法对紫红参和生晒参中皂苷类成分及其含量进行了对比研究。
首次建立了紫红参的指纹图谱，并对其进行了评价，为紫红参的质量控制提供了参考。
以20(S)-原人参三醇（PPT）为原料，采用酰氯法、DCC法合成了22个PPT脂肪酸酯衍生物，其中20个为新的脂肪酸酯衍生物。同时，采用MTT法系统地研究了PPT脂肪酸酯衍生物的体外抗肿瘤生物活性，初步对其构效关系进行了探讨。
首次采用UPLC-ESI-MS/MS分析方法，鉴定灌胃紫红参后大鼠血清中的移行成分，明确了紫红参入血的有效成分，阐明了紫红参的体内作用物质基础，为其在临床上的广泛应用提供了理论依据。
首次研究了紫红参提取物对老龄雄性大鼠性功能的影响，为紫红参作为壮阳药物的开发利用提供了理论依据。
Purple red ginseng was the ginseng deep processing products by steaming anddrying of ginseng repeatedly. In the preparation process, Maillard reaction anddegradation occcred, part of the chemical constituents have been changed. So far,there were few studies on the chemical constituents and bioactivities of this new deepprocessed products of ginseng. In this thesis, the chemical constituents, fingerprintand bioactivities of Purple red ginseng were studied for the first time, which wasexpected not to discover the different constituents but to offer scientific basis toaccelerate its further application and guarantee the quality control.
Firstly, the chemical constituents of purple red ginseng were investagated.27kinds of compounds were extracted, separated and purified by various methods. Then25of them were identified according their physicochemical properties, TLC,spectrum analysis(~(13)C-NMR、~1H-NMR、HMBC、HMQC) and X-ray diffraction bycrystals. The structures of them were identified as follows:20(S)-protopanaxadiol (1);20(R)-protopanaxadiol (2); Ginsenoside Rd (3);20(S)-ginsenoside Rg_3(4);20(R)-ginsenoside Rg_3(5); Ginsenoside Rk_1(6); Ginsenoside Rg_5(7);20(S)-protopanaxatriol (8);20(R)-protopanaxatriol (9); Ginsenoside Rg_6(10);20(S)-ginsenoside Rh_1(11);20(R)-ginsenoside Rh1(12);20(S)-ginsenoside Rg2(13);20(R)-ginsenoside Rg2(14);Ginsenoside Rf (15); Notopanaxoside R_2(16); Ginsenoside Ro (17); Zingibroside R_1(18);β-sitosterol (19); β-daucosterol (20);4-O-α-D-glucopyranosyl-D-Glucose (21)；palmitic acid (22); Hexadecane (23); n-Dodecane (24);2-oxopropyl-α-D-glucopyranoside (25).
On the basis of extraction and separation of chemical constituents of purple redginseng, saponins and their contents of purple red ginseng and white ginseng were compared by UPLC-ESI-MS/MS method. The results showed that in the preparationprocess, Maillard reaction and degradation occcred, and the types and quantities ofginseng saponins changed, resulting in20(S)-ginsenoside Rg3,20(R)-ginsenoside Rg3,20(R)-ginsenoside Rh_1,20(R)-ginsenoside Rg_2, ginsenoside Rk_1, ginsenoside Rg5,ginsenoside Rd, ginsenoside Ro, zingibroside R_1,20(S)-protopanaxatriol,20(R)-protopanaxatriol,20(S)-protopanaxadiol,20(R)-protopanaxadiol and so on.
In this paper, the fingerprints of purplish red ginseng was established andevaluated for the first time.12common peaks were found in the HPLC-PDAfingerprint. In the precision, reproducibility and stability test, RSD of each commonpeak relative retention time was less than1%, and RSD of relative peak area less than3%. Samples of10batches were of high similarity and the similiarity degree were0.885～1.000. The fingerprint of purplish red ginseng showed good reproducibility,and the method is stable and reliable, which can be used for the quality control ofpurplish red ginseng.
Due to the higher content of20(S)-protopanaxatriol in purplish red ginseng, select20(S)-protopanaxatriol as raw material.22fatty acid esters of PPT，including two knownoleoy esters and other20new fatty acid esters，were synthesized using acyl chloride or fattyacid and N, N’-dicyclohexylcarbodiimide (DCC). The structures were elucidated by thecombined analysis of NMR and ESI-MS. The antitumor activities were tested in vitro in threecell lines, HepG2, Hela and SGC-7901, using the MTT method for the first time. The structuralrelationships between fatty acid derivatives of PPT and their cytotoxic properties were alsodiscussed preliminarily in this paper. The purpose is to find and prepare antitumor compoundswith high efficiency and low toxicity, and to provide the theoretical basis for development andinnovation of ginsenoside as anticancer drugs.
In this thesis, the serum pharmacochemistry of the extract of Purplish redginseng was studied. Serum was collected after oral administration of the extract ofPurplish red ginseng to rats. The sample was detected by UPLC-ESI-MS/MS, and themain compounds of the serum containing Purplish red ginseng were determined. Rat’sserum contains14transitional blood components, among which six were originalconstituents of extract of Purplish red ginseng and the other might be metabolites ofthe original constituents. The bioactive components of the purplish red ginseng after oral administration of the extracts were clarified, and the mechanisms of action ofPurplish red ginseng were illustrated, which will provide the theoretical basis for itswide application in clinic.
Investigation on the effect of purplish red ginseng on the sexual aetivity of agedmale rats. The results showed that purplish red ginseng can improve sexual activity ofsenile rats evidently compared with controlled groups, improve their sexual desire andcourtship times; It can act on hypothalamic-testicular-gonadal axis and regulate sexhormone levels, so as to promote the generation of androgen and serum testosterone;purplish red ginseng can increase the sperm vigor; It also can increase the content of5-HT and DA of rats’hypothalamus. Aphrodisiac of purplish red ginseng wassignificant, and some test index even better than the positive drug. These will providetheoretical basis for the development and utilization purplish red ginseng asimpotence drug.
The chemical constituents, fingerprint and bioactivities about purplish red ginsengwere made a deep investigation in the thesis for the first time. The results wouldsupply good methods for quality control and offere strong, accurate and scientifictheoretical basis to the wide application of this kind of ginseng, which might produceeven higher theoretical and economic value.
引文
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