构棘中黄酮类化合物的分离表征和二氢黄酮肟类、腙类衍生物的合成及活性研究
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摘要
天然黄酮类化合物因具有抗氧化、抗病毒、抗肿瘤等多种生理活性而广受关注。目前,关于黄酮类化合物的分离、表征、结构修饰、全合成及生理活性研究是化学和医药工作者研究的热点之一
文献报道柘属植物富含结构新颖的异戊烯基黄酮类化合物,且多显示抗炎、保肝、抗脂质过氧化及抗肿瘤活性。构棘((Cdrania cochinchinensis)为桑科柘属常绿灌木,其根部常用于消化道疾病的治疗。在民间,构棘根作药材“穿破石”使用,用于肺结核、淋病、腮腺炎、黄疸、胃和十二指溃疡、跌打损伤、胃癌等的治疗；构棘果具有理气、消食、利尿的功效,主治疝气、食积、小便不利等。目前,国内外只有少量文献进行了构棘根化学成分的研究,而构棘果化学成分及生物活性尚属空白。为充分利用广西丰富的构棘资源、进一步对比各部位的成分异同,本文对构棘根和构棘果化学成分进行了较系统的研究。此外,广西优势农产品柚子皮、柑橘皮中富含二氢黄酮类成分,具有降低胆固醇、抑菌、抗抗动脉粥样硬化、抗氧化、抗肿瘤等多种生物活性。为提高天然二氢黄酮的药理活性、开发具有高效低毒的抗肿瘤药物分子,本文还以橙皮素、柚皮苷两种天然二氢黄酮为原料进行了化学修饰,分别合成了二氢黄酮肟类、二氢黄酮腙类两类衍生物,并用MTT蛋白染色法对所合成的化合物进行了体外抑制胃癌细胞SGC-7901增殖活性筛选。
1、应用硅胶、凝胶、聚酰胺柱层析的方法从构棘根乙醇提取物中分离出17个单体化合物,其中有3个Xanthone、11个黄酮、2个三萜。通过1H-NMR、13C-NMR、HMBC、HSQC、HR-MS技术及文献对照分别表征为：Isocudraniaxanthone B (I-1)、1,6,7-trihydroxy-4-(1,1-dimethylallyl)-3-methoxy xanthone (I-2)、Gerontoxanthones H (I-3)、桂木生黄素(Ⅰ-4)、环桂木黄素(I-5)、Cudraflavone A(I-6)、柚皮素(Ⅰ-7)、香橙素(Ⅰ-8)、山萘酚(Ⅰ-9)、桑色素(Ⅰ-10)、槲皮素(Ⅰ-11)、山萘酚-7-O-葡萄糖苷(Ⅰ-12)、槲皮素-7-0-葡萄糖苷(Ⅰ-13)、4-(乙氧基甲基)苯酚(Ⅰ-14)、β-谷甾醇(Ⅰ-15)、(13α,14p,17a,20R)-7,24-二烯-3-羟基羊毛甾烷(Ⅰ-16)、(13a,14p,17α,20R)-7,24-二烯-3-乙酰酯羊毛甾烷(Ⅰ-17)。其中化合物Ⅰ-2为新化合物,Ⅰ-14首次从桑科发现。
2、通过硅胶柱层析、聚酰胺柱层析、单晶衍射等方法首次对构棘果化学成分进行了研究,从中分离出9个单体化合物,其中苯并吡喃异黄酮5个,分别表征为染料木素(I-19)、Alpinumisoflavone (I-20)4'-O-methylalpinmumisoflavone (I-21)、4'-O-methylderrone (I-22) isoderrone (I-23)。异黄酮Ⅰ-22、Ⅰ-23为首次从本属分离得到。同时还培养了Ⅰ-21、Ⅰ-23的单晶,晶体结构显示化合物Ⅰ-21、Ⅰ-23均属单斜晶系,空间群为P2(1)/c,晶体以分子间氢键、分子内氢键、π-π堆积作用和范德华力构成三维超分子建筑结构。此外,还对含量较高的异黄酮isoderrone5-位、7位羟基进行了甲基、乙基、异戊烯基的衍生化修饰,得到了5个新的苯并吡喃异黄酮衍生物(Ⅰ-23a～Ⅰ-23e)。
3、以天然橙皮素(Ⅱ-1)和柚皮苷(Naringin)为原料,通过酸水解,选择性甲基、异戊烯基、苯乙酮基、吲哚甲醛基的取代分别合成了橙皮素衍生物(Ⅱ-2、Ⅱ-3)和柚皮苷衍生物(Ⅲ-1-Ⅲ-9),然后分别与盐酸羟胺、盐酸甲氧胺、盐酸苄氧胺反应,高产率的合成得到了3个E-橙皮素肟(Ⅱ-1a～Ⅱ-3a)、6个E橙皮素肟醚(Ⅱ-1b～Ⅱ-3c)、9个E-柚皮素肟(Ⅲ-1a～Ⅲ-9a)和13个E-柚皮素肟醚(Ⅲ-1b～Ⅲ-9b, Ⅲ-1c～Ⅲ-6c)。并通过红外、核磁、高分辨质谱等分析手段对所合成的化合物进行了结构表征。
4、从丰富易得的柚皮苷(Naringin)出发,通过酸水解得到了柚皮素(Ⅲ-1)。分别以橙皮素(Ⅱ-1)和柚皮素(Ⅲ-1)为母体,通过4-位羰基与水合肼作用合成了中间体橙皮素腙(Ⅱ-4)和柚皮素腙(Ⅲ-10),进而与各种不同类型的醛缩合,设计合成了28个新型N-苄叉二氢黄酮腙(Ⅱ-4a～Ⅱ-4n、Ⅲ-10a～Ⅲ-10n)。该合成方法原料易得、操作简捷、产物活性显著,可为进一步开发利用天然二氢黄酮资源、设计抗肿瘤药物提供新的思路。
5、利用MTT法对分离得到的Xanthone、异黄酮、isoderrone衍生物进行了体外抗肿瘤活性研究。初步的结果显示Xanthone(Ⅰ-1,Ⅰ-3)、异黄酮(Ⅰ-23)对胃癌细胞SGC-7901有较弱的抗细胞增殖活性；7-O-烷基化修饰不能增强底物isoderrone的细胞活性。同时,还对所合成得到的二氢黄酮肟类衍生物(Ⅱ-1a～Ⅱ-3c, Ⅲ-1a～Ⅲ-9b)也进行了对胃癌细胞SGC-7901活性的研究,结果显示二氢黄酮肟比前体对胃癌细胞SGC-7901的细胞活性有了显著地增强。二氢黄酮4位肟基的存在是关键因素,而当肟基转化成肟醚时其活性显著降低。此外,采用胃癌细胞SGC-7901对N-苄叉二氢黄酮腙类衍生物(Ⅱ-4a～Ⅱ-4n,Ⅲ-10a～Ⅲ-10n)体外抑制肿瘤细胞增长活性试验,发现N-苄叉橙皮素腙的活性比柚皮素腙活性高。其中化合物Ⅱ-4c,Ⅱ-4e,Ⅱ-4h, Ⅱ-4n与顺铂具有相近的抗肿瘤活性,对应的IC50值分别为10.6μM、6.9μM、9.8μM、9.6μM。
综上所述,构棘根化学成分以Xanthone、黄酮、黄酮醇为主,而构棘果则以异黄酮为主。经化学合成的部分二氢黄酮肟(29个新化合物)和部分N-苄叉二氢黄酮腙(28个新化合物)对胃癌细胞SGC-7901显示出显著的抑制作用。初步的抗肿瘤活性测试及构效关系研究可为进一步的设计合成新抗肿瘤药物提供参考。
Natural flavonoids were popular for the biological activities of antioxidant, antivirus, antitumor and so on. At present, study of isolation, elucidation, structure modification and physiological activities of flavonoids is one of focus topics in chemical and medical fields.
Novel structures of prenylated flavonoids isolated from Cudrania genus have been reported and displayed anti-inflammatory, hepatorrotective, anti-peroxidation and anti-tumor activities. Cudrania cochinchinensis is one of a shrub of Cudrania genus. Its roots have been applied for the treatment of digestive apparatus tumor, especially gastric carcinoma, and were also used as Chinese folk medicine "Chuan-po-shi" against tuberculosis, gonorrhea, rheumatism, mumps, jaundice, boils, scabies, bruising, and dysmenorrhea. Cudrania cochinchinensis fruits had physiological effects for the treatment of shernia, dypepsia and urination. However, there were only a few of literatures reported the chemical components from roots of Cudrania cochinchinensis, and the fruits phytochemical constituents and its biological effect of this plant has not yet been investigated. To take full use of rich resources of this plant and compare the chemical components differences, the chemical constituents from Cudrania cochinchinensis roots and fruits were investigated systematically in this paper. Moreover, aboundant flavanones contained in peels of pomelo and citrus with effects of lower cholesterol, antimicrobial resistance, resistance to atherosclerosis, antioxidation, antitumor and so on. In order to enhance the pharmacological activities of natural flavanones and exploit antitumor medicines with effective effects and low toxicity, flavanones derivatives of oximes and hydrozones were synthesized using hesperitin and naringin as starting materials. In addition, the cytotoxity against human cancer cell SGC-7901of all synthesized compounds were also assayed by MTT method.
1. Seventeen compounds including three xanthons, ten flavonoids, two triterpenes, one sterol and one phenolic were isolated from roots of Cudrania cochinchinensis by silica gel column and polyamide column chromatography. Sructures of the compounds were elucidated on the basis of spectral data (MS,1H-NMR,13C-NMR, HMBC and HSQC) and by the comparison of spectroscopic data with the reported values in the literatures. They are isocudraniaxanthone B (Ⅰ-1),1,6,7-trihydroxy-4-(1,1-dimethylallyl)-3-methoxyxanthone (Ⅰ-2), gerontoxanthones H (Ⅰ-3), artocarpesin (Ⅰ-4), cycloartocarpesin (Ⅰ-5), cudraflavone A(Ⅰ-6), naringenin (Ⅰ-7), aromadendrin (Ⅰ-8), kaempferol (Ⅰ-9), morin (Ⅰ-10), quercetin (Ⅰ-11), kaempferol-7-O-β-Dglucopyranoside (Ⅰ-12), quercetin-7-O-β-D-glucopyranoside (Ⅰ-13),4-ethoxymethylphenol (Ⅰ-14), B-sitosterol (Ⅰ-15),(13α,14β,17a,20R)-lanosta-7,24-diene-3β-ol (Ⅰ-16),13α,14β,17α,20R-lanosta-7,24-diene-3β-O-aceta (Ⅰ-17). Among them, Ⅰ-2was a new prenylated xanthone,Ⅰ-14was first founded in Morus family.
2. The ethanol extract of Cudrania cochinchinensis fruits was separated by silica column chromatography, the structures were elucidated based on spectroscopic and X-ray diffraction. Five known benzopyranisoflavones were isolated and elucidated as genistein (Ⅰ-19), alpinumisoflavone (Ⅰ-20),4'-O-methylalpinmumisoflavone (Ⅰ-21),4'-O-methylderrone (Ⅰ-22), isoderrone (Ⅰ-23). Compounds Ⅰ-22, Ⅰ-23were isolated from this genus for the first time and obtained two crystals of Ⅰ-21and Ⅰ-23. Crystal structures showed compound Ⅰ-21and Ⅰ-23belong to monoclinic system, space group for P2(1)/c,3D-supramolecular structures were accumulated by hydrogen bond, π-π and van der waals force. Futhermore, using isoderrone as material, five new benzopyranylisoflavones (Ⅰ-23a～Ⅰ-23e) were synthesised by the mothods of modification Ⅰ-23at5-OH and7-OH with methyl, ethyl and isopentene.
3. Derivatives of hesperitin (Ⅱ-2, Ⅱ-3) and naringenin (Ⅲ-2～Ⅲ-9) were synthesized by the steps of hydrolysis, selective methylation, selective O-prenylation or substituted by other groups using natural hesperitin and naringin as starting materials. Three new E-hesperitin oximes (Ⅱ-1a～Ⅱ-3a), six E-hesperitin oxime ethers (Ⅱ-1b～Ⅱ-3c) and nine novel E-naringenin oximes (Ⅲ-1a～Ⅲ-9a), thirteen E-naringenin oxime ethers (Ⅲ-1b～Ⅲ-9c) were synthesiszed by reacting flavanone derivatives(Ⅱ-1～Ⅱ-3, Ⅲ-1～Ⅱ-9) with hydroxylamine hydrochloride, methoxylamine hydrochloride and benzyloxygen amine hydrochloride respectively. The structures of these prducts were characterizated by IR,1H NMR,13C NMR and HR-ESI-MS.
4. Intermediate hesperitin hydrazone (Ⅱ-4) and naringenin hydrazone (Ⅲ-10) were generated by reactions of hydrolysis in acidic condition and then reacted with hydrazine hydrate using natural hesperitin (Ⅱ-1) and naringin as starting materials. Novel twenty eight N-benzylidene flavanone hydrazones and analogues (Ⅱ-4a～Ⅱ-4n, Ⅲ-10a～Ⅲ-10n) were synthesised by the reaction of Ⅱ-4and Ⅲ-10with various aldehydes respectively. The synthetic route have the advantages of easy availability of starting materials, simple operation and good activities. In addition, it also can provide a new way for further exploitation and utilization of natural flavanone resources and development of antineoplastic drugs.
5. In vitro anti-tumor activities of xanthone, benzopyran isoflavones and isodrrrone derivatives were assayed against BEL-7404(human liver carcinoma) and SGC-7901(human gastric carcinoma) cell lines by MTT method. The results indicated that compounds Ⅰ-1, Ⅰ-3and Ⅰ-23displayed moderate anti-proliferative activity against human cancer cell line SGC-7901, and7-O-alkylation of isoderrone derivatives showed weaker activity than the parent compound. Meanwhile, the anti-proliferative activities of flavanone oximes (Ⅱ-1a～Ⅱ-3c, Ⅲ-1a～Ⅲ-9b) were also investigated against SGC-7901. The results revealed that the cytotoxicity of flavanone oximes increased dramatically compared with its precursor. And the oxime group fused at C-4of flavanones was the key factor to anti-tumor activities. For example, compounds Ⅱ-1a, Ⅱ-2a, Ⅱ-3a, Ⅲ-7a, Ⅲ-9a showed obvious cytotoxicities. However, the inhibition activities were decreased significantly when converted oximes to oxime ethers. Moreover, the cytotoxity against human cancer cell SGC-7901of the synthesized N-Benzylidene flavanone hydrazones (Ⅱ-4a～Ⅱ-4n, Ⅲ-10a～Ⅲ-10n) were also evaluated. The results showed N-Benzylidene hesperitin hydrazones displayed better activities than N-Benzylidene naringenin hydrazones. Compounds Ⅱ-4c, Ⅱ-4e, Ⅱ-4h, Ⅱ-4n had similar cytotoxicity to cisplatin's against SGC-7901, and the corresponding IC50values were10.6μM,6.9μM,9.8μM and9.6μM respectively.
In conclusion, prenylated isoflavones were the main compoents in Cudrania cochinchinensis fruits from the present investigation. It is different with prenylated flavonoids isolated from roots of this plant. Furhtermore, some of falvanone oximes (twenty-nine new compounds) and N-Benzylidene flavanone hdrazone derivatives (twenty-eight new compounds) showed obvious activities against SGC-7901, the relationship between structure and biological activity could be helpful in designing more potent anti-cancer agents for therapeutic use.
文献报道柘属植物富含结构新颖的异戊烯基黄酮类化合物,且多显示抗炎、保肝、抗脂质过氧化及抗肿瘤活性。构棘((Cdrania cochinchinensis)为桑科柘属常绿灌木,其根部常用于消化道疾病的治疗。在民间,构棘根作药材“穿破石”使用,用于肺结核、淋病、腮腺炎、黄疸、胃和十二指溃疡、跌打损伤、胃癌等的治疗；构棘果具有理气、消食、利尿的功效,主治疝气、食积、小便不利等。目前,国内外只有少量文献进行了构棘根化学成分的研究,而构棘果化学成分及生物活性尚属空白。为充分利用广西丰富的构棘资源、进一步对比各部位的成分异同,本文对构棘根和构棘果化学成分进行了较系统的研究。此外,广西优势农产品柚子皮、柑橘皮中富含二氢黄酮类成分,具有降低胆固醇、抑菌、抗抗动脉粥样硬化、抗氧化、抗肿瘤等多种生物活性。为提高天然二氢黄酮的药理活性、开发具有高效低毒的抗肿瘤药物分子,本文还以橙皮素、柚皮苷两种天然二氢黄酮为原料进行了化学修饰,分别合成了二氢黄酮肟类、二氢黄酮腙类两类衍生物,并用MTT蛋白染色法对所合成的化合物进行了体外抑制胃癌细胞SGC-7901增殖活性筛选。
1、应用硅胶、凝胶、聚酰胺柱层析的方法从构棘根乙醇提取物中分离出17个单体化合物,其中有3个Xanthone、11个黄酮、2个三萜。通过1H-NMR、13C-NMR、HMBC、HSQC、HR-MS技术及文献对照分别表征为：Isocudraniaxanthone B (I-1)、1,6,7-trihydroxy-4-(1,1-dimethylallyl)-3-methoxy xanthone (I-2)、Gerontoxanthones H (I-3)、桂木生黄素(Ⅰ-4)、环桂木黄素(I-5)、Cudraflavone A(I-6)、柚皮素(Ⅰ-7)、香橙素(Ⅰ-8)、山萘酚(Ⅰ-9)、桑色素(Ⅰ-10)、槲皮素(Ⅰ-11)、山萘酚-7-O-葡萄糖苷(Ⅰ-12)、槲皮素-7-0-葡萄糖苷(Ⅰ-13)、4-(乙氧基甲基)苯酚(Ⅰ-14)、β-谷甾醇(Ⅰ-15)、(13α,14p,17a,20R)-7,24-二烯-3-羟基羊毛甾烷(Ⅰ-16)、(13a,14p,17α,20R)-7,24-二烯-3-乙酰酯羊毛甾烷(Ⅰ-17)。其中化合物Ⅰ-2为新化合物,Ⅰ-14首次从桑科发现。
2、通过硅胶柱层析、聚酰胺柱层析、单晶衍射等方法首次对构棘果化学成分进行了研究,从中分离出9个单体化合物,其中苯并吡喃异黄酮5个,分别表征为染料木素(I-19)、Alpinumisoflavone (I-20)4'-O-methylalpinmumisoflavone (I-21)、4'-O-methylderrone (I-22) isoderrone (I-23)。异黄酮Ⅰ-22、Ⅰ-23为首次从本属分离得到。同时还培养了Ⅰ-21、Ⅰ-23的单晶,晶体结构显示化合物Ⅰ-21、Ⅰ-23均属单斜晶系,空间群为P2(1)/c,晶体以分子间氢键、分子内氢键、π-π堆积作用和范德华力构成三维超分子建筑结构。此外,还对含量较高的异黄酮isoderrone5-位、7位羟基进行了甲基、乙基、异戊烯基的衍生化修饰,得到了5个新的苯并吡喃异黄酮衍生物(Ⅰ-23a～Ⅰ-23e)。
3、以天然橙皮素(Ⅱ-1)和柚皮苷(Naringin)为原料,通过酸水解,选择性甲基、异戊烯基、苯乙酮基、吲哚甲醛基的取代分别合成了橙皮素衍生物(Ⅱ-2、Ⅱ-3)和柚皮苷衍生物(Ⅲ-1-Ⅲ-9),然后分别与盐酸羟胺、盐酸甲氧胺、盐酸苄氧胺反应,高产率的合成得到了3个E-橙皮素肟(Ⅱ-1a～Ⅱ-3a)、6个E橙皮素肟醚(Ⅱ-1b～Ⅱ-3c)、9个E-柚皮素肟(Ⅲ-1a～Ⅲ-9a)和13个E-柚皮素肟醚(Ⅲ-1b～Ⅲ-9b, Ⅲ-1c～Ⅲ-6c)。并通过红外、核磁、高分辨质谱等分析手段对所合成的化合物进行了结构表征。
4、从丰富易得的柚皮苷(Naringin)出发,通过酸水解得到了柚皮素(Ⅲ-1)。分别以橙皮素(Ⅱ-1)和柚皮素(Ⅲ-1)为母体,通过4-位羰基与水合肼作用合成了中间体橙皮素腙(Ⅱ-4)和柚皮素腙(Ⅲ-10),进而与各种不同类型的醛缩合,设计合成了28个新型N-苄叉二氢黄酮腙(Ⅱ-4a～Ⅱ-4n、Ⅲ-10a～Ⅲ-10n)。该合成方法原料易得、操作简捷、产物活性显著,可为进一步开发利用天然二氢黄酮资源、设计抗肿瘤药物提供新的思路。
5、利用MTT法对分离得到的Xanthone、异黄酮、isoderrone衍生物进行了体外抗肿瘤活性研究。初步的结果显示Xanthone(Ⅰ-1,Ⅰ-3)、异黄酮(Ⅰ-23)对胃癌细胞SGC-7901有较弱的抗细胞增殖活性；7-O-烷基化修饰不能增强底物isoderrone的细胞活性。同时,还对所合成得到的二氢黄酮肟类衍生物(Ⅱ-1a～Ⅱ-3c, Ⅲ-1a～Ⅲ-9b)也进行了对胃癌细胞SGC-7901活性的研究,结果显示二氢黄酮肟比前体对胃癌细胞SGC-7901的细胞活性有了显著地增强。二氢黄酮4位肟基的存在是关键因素,而当肟基转化成肟醚时其活性显著降低。此外,采用胃癌细胞SGC-7901对N-苄叉二氢黄酮腙类衍生物(Ⅱ-4a～Ⅱ-4n,Ⅲ-10a～Ⅲ-10n)体外抑制肿瘤细胞增长活性试验,发现N-苄叉橙皮素腙的活性比柚皮素腙活性高。其中化合物Ⅱ-4c,Ⅱ-4e,Ⅱ-4h, Ⅱ-4n与顺铂具有相近的抗肿瘤活性,对应的IC50值分别为10.6μM、6.9μM、9.8μM、9.6μM。
综上所述,构棘根化学成分以Xanthone、黄酮、黄酮醇为主,而构棘果则以异黄酮为主。经化学合成的部分二氢黄酮肟(29个新化合物)和部分N-苄叉二氢黄酮腙(28个新化合物)对胃癌细胞SGC-7901显示出显著的抑制作用。初步的抗肿瘤活性测试及构效关系研究可为进一步的设计合成新抗肿瘤药物提供参考。
Natural flavonoids were popular for the biological activities of antioxidant, antivirus, antitumor and so on. At present, study of isolation, elucidation, structure modification and physiological activities of flavonoids is one of focus topics in chemical and medical fields.
Novel structures of prenylated flavonoids isolated from Cudrania genus have been reported and displayed anti-inflammatory, hepatorrotective, anti-peroxidation and anti-tumor activities. Cudrania cochinchinensis is one of a shrub of Cudrania genus. Its roots have been applied for the treatment of digestive apparatus tumor, especially gastric carcinoma, and were also used as Chinese folk medicine "Chuan-po-shi" against tuberculosis, gonorrhea, rheumatism, mumps, jaundice, boils, scabies, bruising, and dysmenorrhea. Cudrania cochinchinensis fruits had physiological effects for the treatment of shernia, dypepsia and urination. However, there were only a few of literatures reported the chemical components from roots of Cudrania cochinchinensis, and the fruits phytochemical constituents and its biological effect of this plant has not yet been investigated. To take full use of rich resources of this plant and compare the chemical components differences, the chemical constituents from Cudrania cochinchinensis roots and fruits were investigated systematically in this paper. Moreover, aboundant flavanones contained in peels of pomelo and citrus with effects of lower cholesterol, antimicrobial resistance, resistance to atherosclerosis, antioxidation, antitumor and so on. In order to enhance the pharmacological activities of natural flavanones and exploit antitumor medicines with effective effects and low toxicity, flavanones derivatives of oximes and hydrozones were synthesized using hesperitin and naringin as starting materials. In addition, the cytotoxity against human cancer cell SGC-7901of all synthesized compounds were also assayed by MTT method.
1. Seventeen compounds including three xanthons, ten flavonoids, two triterpenes, one sterol and one phenolic were isolated from roots of Cudrania cochinchinensis by silica gel column and polyamide column chromatography. Sructures of the compounds were elucidated on the basis of spectral data (MS,1H-NMR,13C-NMR, HMBC and HSQC) and by the comparison of spectroscopic data with the reported values in the literatures. They are isocudraniaxanthone B (Ⅰ-1),1,6,7-trihydroxy-4-(1,1-dimethylallyl)-3-methoxyxanthone (Ⅰ-2), gerontoxanthones H (Ⅰ-3), artocarpesin (Ⅰ-4), cycloartocarpesin (Ⅰ-5), cudraflavone A(Ⅰ-6), naringenin (Ⅰ-7), aromadendrin (Ⅰ-8), kaempferol (Ⅰ-9), morin (Ⅰ-10), quercetin (Ⅰ-11), kaempferol-7-O-β-Dglucopyranoside (Ⅰ-12), quercetin-7-O-β-D-glucopyranoside (Ⅰ-13),4-ethoxymethylphenol (Ⅰ-14), B-sitosterol (Ⅰ-15),(13α,14β,17a,20R)-lanosta-7,24-diene-3β-ol (Ⅰ-16),13α,14β,17α,20R-lanosta-7,24-diene-3β-O-aceta (Ⅰ-17). Among them, Ⅰ-2was a new prenylated xanthone,Ⅰ-14was first founded in Morus family.
2. The ethanol extract of Cudrania cochinchinensis fruits was separated by silica column chromatography, the structures were elucidated based on spectroscopic and X-ray diffraction. Five known benzopyranisoflavones were isolated and elucidated as genistein (Ⅰ-19), alpinumisoflavone (Ⅰ-20),4'-O-methylalpinmumisoflavone (Ⅰ-21),4'-O-methylderrone (Ⅰ-22), isoderrone (Ⅰ-23). Compounds Ⅰ-22, Ⅰ-23were isolated from this genus for the first time and obtained two crystals of Ⅰ-21and Ⅰ-23. Crystal structures showed compound Ⅰ-21and Ⅰ-23belong to monoclinic system, space group for P2(1)/c,3D-supramolecular structures were accumulated by hydrogen bond, π-π and van der waals force. Futhermore, using isoderrone as material, five new benzopyranylisoflavones (Ⅰ-23a～Ⅰ-23e) were synthesised by the mothods of modification Ⅰ-23at5-OH and7-OH with methyl, ethyl and isopentene.
3. Derivatives of hesperitin (Ⅱ-2, Ⅱ-3) and naringenin (Ⅲ-2～Ⅲ-9) were synthesized by the steps of hydrolysis, selective methylation, selective O-prenylation or substituted by other groups using natural hesperitin and naringin as starting materials. Three new E-hesperitin oximes (Ⅱ-1a～Ⅱ-3a), six E-hesperitin oxime ethers (Ⅱ-1b～Ⅱ-3c) and nine novel E-naringenin oximes (Ⅲ-1a～Ⅲ-9a), thirteen E-naringenin oxime ethers (Ⅲ-1b～Ⅲ-9c) were synthesiszed by reacting flavanone derivatives(Ⅱ-1～Ⅱ-3, Ⅲ-1～Ⅱ-9) with hydroxylamine hydrochloride, methoxylamine hydrochloride and benzyloxygen amine hydrochloride respectively. The structures of these prducts were characterizated by IR,1H NMR,13C NMR and HR-ESI-MS.
4. Intermediate hesperitin hydrazone (Ⅱ-4) and naringenin hydrazone (Ⅲ-10) were generated by reactions of hydrolysis in acidic condition and then reacted with hydrazine hydrate using natural hesperitin (Ⅱ-1) and naringin as starting materials. Novel twenty eight N-benzylidene flavanone hydrazones and analogues (Ⅱ-4a～Ⅱ-4n, Ⅲ-10a～Ⅲ-10n) were synthesised by the reaction of Ⅱ-4and Ⅲ-10with various aldehydes respectively. The synthetic route have the advantages of easy availability of starting materials, simple operation and good activities. In addition, it also can provide a new way for further exploitation and utilization of natural flavanone resources and development of antineoplastic drugs.
5. In vitro anti-tumor activities of xanthone, benzopyran isoflavones and isodrrrone derivatives were assayed against BEL-7404(human liver carcinoma) and SGC-7901(human gastric carcinoma) cell lines by MTT method. The results indicated that compounds Ⅰ-1, Ⅰ-3and Ⅰ-23displayed moderate anti-proliferative activity against human cancer cell line SGC-7901, and7-O-alkylation of isoderrone derivatives showed weaker activity than the parent compound. Meanwhile, the anti-proliferative activities of flavanone oximes (Ⅱ-1a～Ⅱ-3c, Ⅲ-1a～Ⅲ-9b) were also investigated against SGC-7901. The results revealed that the cytotoxicity of flavanone oximes increased dramatically compared with its precursor. And the oxime group fused at C-4of flavanones was the key factor to anti-tumor activities. For example, compounds Ⅱ-1a, Ⅱ-2a, Ⅱ-3a, Ⅲ-7a, Ⅲ-9a showed obvious cytotoxicities. However, the inhibition activities were decreased significantly when converted oximes to oxime ethers. Moreover, the cytotoxity against human cancer cell SGC-7901of the synthesized N-Benzylidene flavanone hydrazones (Ⅱ-4a～Ⅱ-4n, Ⅲ-10a～Ⅲ-10n) were also evaluated. The results showed N-Benzylidene hesperitin hydrazones displayed better activities than N-Benzylidene naringenin hydrazones. Compounds Ⅱ-4c, Ⅱ-4e, Ⅱ-4h, Ⅱ-4n had similar cytotoxicity to cisplatin's against SGC-7901, and the corresponding IC50values were10.6μM,6.9μM,9.8μM and9.6μM respectively.
In conclusion, prenylated isoflavones were the main compoents in Cudrania cochinchinensis fruits from the present investigation. It is different with prenylated flavonoids isolated from roots of this plant. Furhtermore, some of falvanone oximes (twenty-nine new compounds) and N-Benzylidene flavanone hdrazone derivatives (twenty-eight new compounds) showed obvious activities against SGC-7901, the relationship between structure and biological activity could be helpful in designing more potent anti-cancer agents for therapeutic use.
引文
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