其他题名The chemical components of three Hedychium plants and the monoterpene alkaloid-like compounds with their bioactivities
摘要本论文由两部分组成。内容包括:三种姜科姜花属植物滇姜花、圆瓣姜花和毛姜花的化学成分研究,二菇成分的结构修饰或改造。以桅子昔为原料,制备了一系列的拟单菇生物碱。对部分姜花属植物化学成分与拟单菇生物碱进行了一系列的生物活性筛选。对姜花属植物化学成分研究进行了综述;对三种环烯醚菇普类成分的含氮衍生物的制备进行了综述。第一部分三种姜花属植物化学成分与活性研究为了寻找姜花属中具有抗肿瘤活性或抗炎活性的二菇成分,我们对三种姜科姜花属植物滇姜花、毛姜花和圆瓣姜花化学成分进行了研究。利用植物化学成分研究中的多种提取分离方法和材料,包括硅胶柱层析(Lc)、硅胶-AgN03柱层析、氧化铝柱层析、SePhadex LH-20凝胶柱层析、ODs反相柱层析、溶剂萃取分段及重结晶等手段,以及化学结构的波谱解析技术(uV、琅、Ms、-维和二维NMR),辅以结构转换、薄层层析(TLC)对照,从上述三种植物中共分离鉴定了50个化合物。其中,从滇姜花根茎中分离得到23个化合物,从圆瓣姜花根茎中分离得到13个化合物,从毛姜花根茎中分离得到16个化合物,包括了二菇、倍半菇、单菇、三菇、幽体、糖及普类成分,其中包括20个新化合物。采用了光敏氧化、Diels-Alder反应、还原反应,对部分二稽成分进行结构修饰及转化,制备了18个二菇衍生物。对其中10个二菇成分进行了初步的抗肿瘤活性研究。7-坤droxy-hedychenone、滇姜花素A、滇姜花素B对人白血病细胞株K562具较为明显的细胞毒活性,滇姜花素A、滇姜花素B和圆瓣姜花素B对人肺腺癌细胞株A549具有较为明显的细胞毒活性,所有被测试的成分对人胃腺癌细胞株BGc-823无活性或者具有很弱的细胞毒活性。此外,化合物16-坤droxy-labda-8(17),11,13-en-15,16-olide与15-droxy-11,15-oxylabda-8(17),12-dien- 16-al对1-1细胞、IMWT细胞、IMBB细胞均显示了显著的细胞毒活性。最后,我们对姜花属植物化学成分研究进行了综述。第二部分拟单菇生物碱的合成与活性研究环烯醚菇普类成分是一类重要的夫然产物,其中的seeolog耐n又是单菇画噪生物碱的重要中间体。借鉴了secolog耐n与色胺反应、从而在单菇分子中引入氮原子的仿生合成途径,我们以不含氮的前体桅子昔为原料,与胺类等成分进行了合成,得到了拟单菇生物碱。首先,我们从药用植物桅子中分离得到桅子昔,并经酶水解得到桅子普元。然后以桅子普元为原料,与胺类等成分在不同的条件下进行胺化或还原胺化反应。其中主要包括了如下手段:桅子昔元与胺类或醇胺类等直接进行胺化反应;桅子昔元与胺类在NaB玩作为还原剂时的还原胺化反应,桅子普元与胺类或氨基酸甲酷盐酸盐在NaBH3CN作为还原剂时的还原胺化反应,氢化桅子昔元与胺类进行反应。共计合成了92个拟单菇生物碱;此外还分离或制备了32个中间体。对部分拟单菇生物碱进行了生物活性筛选,其中包括:抗血小板凝集活性筛选(包括样品对AA、RAF和ADP三种诱导剂引起兔血小板聚集的影响);抑菌或抗真菌活性筛选(包括金黄色葡萄球菌、结核分枝杆菌和橙色青霉菌);抗乙酞胆碱酷酶活性筛选;对糖尿病药物靶标PTPIB酶的抑制活性筛选。最后,对三种环烯醚菇昔类成分的含氮衍生物的制备进行了综述。
其他摘要This dissertation is composed of two parts. Part A described the isolation and identification of chemical components from Hedvchium unnaense. H. villosum, and H. forrestii, together with the antitumor activity of some diterpenes, and the modification or transformation of some diterpenes. In the last chapter, the chemical components from Hedychium genus were summarized. From the plants mentioned above, 50compounds were isolated and identified on the basis of spectral evidences. Among them, 20 compounds were proved to be new ones, Part B elaborated the Studies on the preparation and bioactivities of 92 monoterpene alkaloid-like compounds obtained from the reactions of geninpin and amines or other nitrogen-containing compounds under different conditions. In the last chapter transformations of secologanin, gentiopicroside, geniposide, or their analgs into nitrogen-containing derivatives were summarized. Part A Studies on the chemical components of three species of Hedychium genus and bioactivity Hedychium is a genus of Zingiberaceae, which is widely distributed in east Asia and south-east Asia. The ethanol extracts of H. yunnanense, H. villosum, and H. forrestii were separated by chromatographic methods, including silica gel column, silica-AgNCb column, alumina column, Sephadex LH-20, and ODS chromgatography. Totally 50 compounds including 20 new ones were obtained, whose structures were mainly determined on the basis of spectral methods. H. yunnanense is mainly distributed in Yunnan Provice of south-west China. From the rhizomes of H. yunnanense, 23 compounds were isolated and identified to be yunnancoronarin C (1), D (2), E (3), c/j-hedychenone (4), hedyforrestin A (5), 7-epi-y-eudesmol (6), 5P-hydroperoxy- p-eudesmol (7), hedytriol A (8), 4-O-methyl-cryptomeridiol (9), hedychiol A (10), y-cadinene (11), 6-cadinene (12), a-muurolene (13), epicubenol (14), hedychtriol B (15), C (16), nerolidol (17), oplopanone (18), succinic acid (19), isoheptanol -2-0- (l-*6) - P- D- apiofuranosyl - p- D- glucopyranoside (20), fructose (21), sucrose (22), and daucosterol (23). Compound 1, 2, 3, 4, 8, 10, 15, 16, and 20 were new ones. Their structures were illustrated in Fig. A. H. villosum is mainly distributed in south China, Nepal, Burma, and Vietnam. From the rhizomes of H. villosum, 16 compounds were isolated and identified to be coronarin E (1), 16-methoxy-15,16-epoxylabda-8(17),ll, 13-triene (2), 16-ethoxy-15,16-epoxylabda-8(17),ll,13-triene (3), labda-8(17), 11,13 -trien-16,15-olide (4), labda-8(17),13-dien-15,16-olide (5), 15-hydroxy-ll,15- epoxylabda-8(17),12-dien-16-al (6), labda-8(17),12,14-trien-16,15-olide (7), 15,16-epoxylabda-8(17),ll-dien-16-ethoxy-13,14-diol (8), 16-hydroxy-labda- 8(17),ll,13~trien-15,16-olide (9), 14,15,16-trinorlabda-8(17),ll- (E)dien-13-carboxylic acid (10), 13,14,15,16-tetranorlabda-8(17)-en-12-carboxylic acid (11), (E)-15,16-dinorlabda-8(17), ll-dien-13-one (12), spathulenol (13), friedelin (14), ethyl ferulate (15), and p-sitosterol (16). Compound 2, 3, 6, 7, 8, 9, and 10 were new ones. Their structures were illustrated in Fig. B. H. forrestii is widely distributed in south-west China. From the rhizomes of H. forrestii, 13 compounds were isolated and identified to be labda-8(17), 11, 13-trien-7p-hydroxyl-15(16)-olide (1), labda-8(17),ll,13-trien-7p,16-dihydroxyl -16(15)-olide (2), labda-8(17),ll,13-trien-6p\15- dihydroxyl-15(16)-olide (3), labda-8(l 7), 11,13-trien-6(3-hydroxyl-l 5~ethoxy-15(16)-olide (4), yunnancoronarin A (5), yunnancoronarin B (6), yunnancoronarin C (7), yunnancoronarin D (8), and monoterpenes 9,10,11,12 and 13. Some compounds from Hedychium genus were subjected to the bioassay of antitumor activity. 7-hydroxy-hedychenone, yunnancoronarin A and B showed moderate cytotoxic activity against K562 cells, the others showed weak or no activity. labda-8(17), 11,13-trien-7p-hydroxyl-15(16)-olide, yunnancoronarin A and B showed moderate cytotoxic activity against A549 cells, the others showed weak or no activity. All tested compounds showed weak or no activity against BGC-823 cells. Furthermore, 16-hydroxy-labda-8(17),ll,13~trien-15,16-olide and 15-hydroxy-ll,15-epoxylabda-8(17),12-dien-16-al showed significant cytotoxic activity against 1-1 cells, IMWT cells, and IMBB cells. In attempt to provide diterpene derivatives for bioassay, modification and transformation of some diterpenes were performed.. Photosensitized oxidation of furanoid diterpenes were carried out and various products were obtained; in order to synthesize norcantharidin analogues, we underwent Diels-Alder reaction of furanoid diterpenes with maleic acid anhydride and obtained mainly thermodynamic products; some reduction products were prepared from the reduction of the diterpenes containing a,|3-unsaturated keto group. As a result, 18 derivatives were prepared. Chemical components from Hedychium genus and their bioactivities were summarized in the last chapter. Part B Synthesis of monoterpene alkaloid-like compounds from geniposide and bioactivity Iridoids and their glycosides constitute an important class of natural products; more over, they are biosynthetic precursors to a broad range of indol alkaloids, with joint biosynthetic key intermediates like secologanin. Given the in some cases well-investigated incorporation of nitrogen atoms into iridoids or its glycosides to give iridoid alkaloids, the presumably biomimetic synthesis of monoterpene alkaloid-like compounds from its nitrogen-free starting material, genipin, may be rewarding. Genipin was obtained from the enzymatic hydrolysis of geniposide, which was isolated from Gardenia jasminoides. Genipin could be considered to be the analogue of glutaraldehyde, therefore it could easily react with amines, ethanolamine, or other nitrogen-containing compounds under various conditions to get monoterpene alkaloid-like compounds. The methods introduced to prepare the monoterpene alkaloid-like compounds were listed below: (1) Reaction of genipin and amines, ethanolamine and its analogues, and ethylenediamine. (2) Reductive animation of genipin and amines in ethanol-HaO solution, with as reductant. (3) Reductive animation of genipin and amines in methanol solution, with as reductant; Reductive animation of genipin and amino acid methyl ester in methanol solution, with NaBH^CN as reductant. (4) Reaction of dihydrogenipin and amines. Totally 92 monoterpene alkaloid-like compounds prepared from genipin and amines or other nitrogen-containing compounds were obtained; furthermore, more than 30 intermediates or starting materials, such as geniposide, genipin, amines, amino acid methyl esters, etc., were synthesized or isolated. Preliminary bioactivity tests of some products were performed. Some products showed weak inhibition effect against AA or PAF induced blood platelet aggregation. Some have the weak activity to inhibit bacteria strain Staphylococcus aureus and Mycobacterium tuberculosis. Some have weak inhibitory activity against acetylcholine esterase. Some exhibit weak inhibitory activity against diabetes PTP1B target enzyme. Some showed inhibition effect against fungus strain Penicillium avellaneum UC-4376. In the last chapter, transformations of secologanin, gentiopicroside, geniposide, or their analogs into nitrogen-containing derivatives were summarized.
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赵庆. 三种姜花属植物化学成分与拟单萜生物碱合成及活性研究[D]. 中国科学院昆明植物研究所. 中国科学院昆明植物研究所,2005.
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