CN107056867A - 灵芝三萜化合物、其药用组合物及其应用 - Google Patents
灵芝三萜化合物、其药用组合物及其应用 Download PDFInfo
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- CN107056867A CN107056867A CN201710289165.9A CN201710289165A CN107056867A CN 107056867 A CN107056867 A CN 107056867A CN 201710289165 A CN201710289165 A CN 201710289165A CN 107056867 A CN107056867 A CN 107056867A
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- cyclopenta
- phenanthren
- pentamethyl
- methyl
- compound
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- Organic Chemistry (AREA)
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Abstract
本发明公开了一种三萜化合物，其药用组合物及其应用。所述化合物具有通式(I)所示的化学式，其具有抑制醛糖还原酶的活性，具有很广阔的应用前景。
Description
技术领域
本发明涉及三萜类化合物，具体涉及从真菌中提取的三萜类化合物及其作为醛糖还原酶抑制剂的用途。
背景技术
灵芝(Ganoderma lucidum(Leyss.ex Fr.)Karst.)隶属于真菌门(Eumycota)、担子菌亚门(Basidiomycotina)、层菌纲(Hymenomycetes)、非褶菌目(Aphyllophorales)、灵芝科(Gamodermataceae)、灵芝属(Ganoderma)类。《中华本草》中记录“其性甘；味平；无毒；归肺、心、脾、肾经。益气血；安心神；健脾胃。主治虚劳、心悸、失眠、头晕、神疲乏力、久咳气喘、冠心病、矽肺、肿瘤。”《中国药典》中将灵芝收录为中药材，其中的灵芝多糖、三萜、核苷、生物碱、氨基酸多肽、微量元素等成分是其药效物质的主要基础，以三萜和多糖为其中主要活性成分。现代药理研究表明，灵芝三萜类化合物具有保肝、抗肿瘤、抗HIV-4及HIV-4蛋白酶活性、抗组织胺释放、抑制血管紧张素、抗氧化等作用。
代谢综合征主要表现为胰岛素抵抗，中心肥胖，提高血压和血脂，并已经成为世界性的疾病。目前虽然有一些临床治疗代谢综合征的药物比如胰岛素、他汀类以及贝特类药物，但是由于其副作用以及治疗功效不够理想等仍然是这类治疗药物面临很多问题。醛糖还原酶(aldose reductase，AR)存在于人体神经、红细胞、晶状体、视网膜等组织器官中，在多元醇通路中催化血液中的葡萄糖生成山梨醇，是多元醇通路的关键限速酶。当血糖浓度维持在正常生理水平时，它并不激活，对葡萄糖的亲和力较低，此时葡萄糖很少转化为山梨醇。在高血糖状况下(如糖尿病)，己糖激酶被饱和，这时醛糖还原酶激活，促使体内的葡萄糖转化为山梨醇。然而，山梨醇脱氢酶(sorbitol dehydrogenase，SDH)的活力并未相应地成比例增加，山梨醇转化为果糖的效率没有提高。山梨醇本身由于极性强不易通过细胞膜，在细胞内会形成蓄积，使细胞膜的通透性发生改变，并使细胞中Na+-K+-ATP酶活性下降，造成肌醇丧失，导致细胞代谢与功能的损害。由于眼睛和神经细胞等组织内醛糖还原酶的含量较高，糖尿病病人体内高血糖的环境使这一通路很容易被打开，造成对这些组织的病理损害，如糖尿病、白内障、神经病变、肾脏病变、视网膜病变、动脉粥样硬化等糖尿病并发症(diabetes control and complications，DCC)糖尿病并发症严重威胁着糖尿病人的生存质量，阻断或减弱醛糖还原酶活性的药物可以用来预防或推迟糖尿病并发症的发生。1970年代以来，醛糖还原酶抑制剂的研究成为治疗糖尿病药物研究的热点，已有一些种类进入临床试验或上市销售，但是好多药物有已经由于临床试验存在问题而退出。目前可供临床使用的醛糖还原酶抑制剂依然很少在我们的长期研究中，从峨眉山赤芝的子实体乙酸乙酯粗提物中分离到具有醛糖还原酶抑制活性的化合物。这些化合物表现出了和阳性药依帕司他相似的活性，为醛糖还原酶抑制剂药物开发提供先导化合物。
发明内容
本发明以灵芝为研究对象，对其提取物进行了分离纯化，得到新的三萜以及杂萜类化合物，对这些化合物进行了结构鉴定和生物活性研究，发现这些化合物具有很好的醛糖还原酶抑制活性，有潜在的药用价值。
为此，本发明提供一种通式(I)所示的化合物或其药用盐：
其中，碳8和碳9之间为双键，或者碳7与碳8之间和碳9与碳11之间为双键；
R1为＝O，α-OH或β-OH，
R2为-H或-OH，
R3为H、＝O或β-OH，
R4为-H或＝O，
R5为-H、β-OH或β-OCOCH3，
R6为-H、α-OH、β-OH、＝O或α-OCOCH3，
R7为-CH(CH3)CH2C(O)CH2CH(CH3)COOCH3、
-CH(CH3)CH2C(O)CH2CH(CH3)COOH、
-CH(CH3)CH2CH(OH)CH＝C(CH3)COOH、
-(CH3)C＝CHC(O)CH2CH(CH3)COOCH3、
-CH(CH3)CH2CH2CH(OH)C(CH3)(OH)CH3、
-CH(CH3)CH2CH2CH＝C(CH2OH)COOH、
-CH(CH3)CH2CH2CH＝C(CH3)COOH、
-CH(CH3)CH2CH2CH(R9)C(CH2R8)(OH)CH3，
R8为-OH、
R9为α-OH或
优选的，化合物为如下式(I-1)到(I-7)的化合物：
| R1 | R2 | R3 | R4 | R5 | R6 | |
| 1 | β-OH | OH | ＝O | β-OCOCH3 | ＝O | CH3 |
| 2 | β-OH | H | β-OH | H | α-OH | H |
| 3 | β-OH | H | β-OH | H | β-OH | CH3 |
| 4 | ＝O | H | β-OH | H | ＝O | CH3 |
| 5 | ＝O | H | ＝O | β-OCOCH3 | ＝O | H |
| R1 | R2 | R3 | |
| 6 | ＝O | COCH3 | α-OH |
| 7 | β-OH | H | β-OH |
| R1 | R2 | R3 | R4 | |
| 10 | ＝O | H | CH2OH | COOH |
| 11 | α-OH | α-OCOCH3 | COOH | CH3 |
| 12 | ＝O | α-OCOCH3 | COOH | CH3 |
| R1 | R2 | |
| 13 | α-OH | C |
| 14 | α-OH | A |
| 15 | β-A | OH |
| 16 | α-OH | B |
化合物1-17的结构式如下：
具体实施方式
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
HPLC分析仪为Agilent 1200分析型液相色谱仪。HPLC的条件如下：以色谱甲醇将样品配制为10mg/ml的溶液，上样量为每次15ul，色谱柱为Kromasil 10×250mm C18半制备柱，柱温为25℃，210nm波长进行HPLC制备。
实施例1
制备灵芝的提取物
将灵芝子实体剪碎，称重2500克。用10L体积百分含量95％乙醇的水溶液回流提取3次，每次1小时。合并提取液，减压浓缩干燥得到170克提取物。
进一步将提取物用蒸馏水600ml溶解，用等体积的正己烷萃取三次，弃去有机相。再用等体积乙酸乙酯萃取水相三次，弃去水相，合并乙酸乙酯萃取液。用旋转蒸发仪蒸干乙酸乙酯获得浸膏49g，记作GS。
实施例2
化合物的制备
灵芝粗提物乙酸乙酯层GS通过硅胶柱色谱分离，以正己烷:乙酸乙酯体系(正己烷:乙酸乙酯的体积比为1:0，50:1，30:1，20:1，15:1，10:1，4:1，2:1)，二氯甲烷:甲醇体系(二氯甲烷:甲醇的体积比为1:0,100:1,50:1,30:1,10:1,5:1)依次进行梯度洗脱，每个梯度洗涤4个保留体积，每个保留体积一个馏分。根据薄层层析色谱行为分析，合并相似流分,在正己烷:乙酸乙酯(体积比为1:0)体系得到馏分GS-1；在正己烷:乙酸乙酯(体积比为100:1～30:1)中得到馏分GS-2～5；在正己烷:乙酸乙酯(体积比为20:1)中得到馏分GS-6，GS-7；在正己烷:乙酸乙酯(体积比为10:1)中得到馏分GS-8；在二氯甲烷:甲醇(体积比为1:0)中得到馏分GS-9～10；在二氯甲烷:甲醇(体积比为50:1)中得到馏分GS-11～13；在二氯甲烷:甲醇(体积比为20:1)中得到馏分GS-14在二氯甲烷:甲醇(体积比为30:1)中得到馏分GS-15；在二氯甲烷:甲醇(体积比为20:1,10:1,1:0)中得到馏分GS-16。共得到16个馏分，将各馏分冷冻干燥。
对GS-7利用ODS反相硅胶柱进一步分离。用体积百分含量为10％，20％，30％，40％，50％，70％，90％的甲醇水溶液依次进行洗脱,每个洗脱体系洗3个保留体积，每个保留体积为500ml。根据薄层层析色谱行为，照射254nm紫外灯判断不同馏分，在体积百分含量为20％～40％的甲醇水溶液中得到馏分GS-7-1～3；在体积百分含量为50％的甲醇水溶液系统中得到馏分GS-7-4；在体积百分含量为60％的甲醇水溶液系统中得到馏分GS-7-5～6；在体积百分含量为70％，90％的甲醇水溶液系统中得到馏分GS-7-7；共得到7个子馏分，将各个馏分冷冻干燥。
对GS-7-3馏分进一步进行HPLC制备。以体积百分含量40％乙腈的酸水(此处的酸水为体积百分含量为0.01％三氟乙酸的水溶液)溶液为洗脱剂进行HPLC制备，流速为2ml/min，收集25min的色谱峰，得到化合物1；收集28min的色谱峰，得到化合物2；收集31min，35min的色谱峰，分别得到化合物3、4。对GS-7-4以体积百分含量40％乙腈的酸水(此处的酸水为体积百分含量为0.01％三氟乙酸的水溶液)溶液为洗脱剂进行HPLC制备，流速为2ml/min，收集20min的色谱峰，得到化合物5；收集23.4min的色谱峰，得到化合物6；收集28和30min的色谱峰，分别得到化合物7、8。对GS-7-5以体积百分含量42％乙腈酸水(此处的酸水为体积百分含量为0.01％三氟乙酸的水溶液)溶液为洗脱剂进行HPLC制备，流速为2ml/min，分别收集23，27.2min的色谱峰得到化合物9、10。对GS-7-4以体积百分含量45％乙腈的酸水(此处的酸水为体积百分含量为0.01％三氟乙酸的水溶液)溶液为洗脱剂进行HPLC制备，流速为2ml/min，收集23.2min的色谱峰，得到化合物11；收集27.3min的色谱峰，得到化合物12。
通过薄层色谱分析还发现GS-9中活性物质含量较高，因此对GS-9利用ODS反相硅胶柱分离。用体积百分含量为20％,40％，50％,70％,90％甲醇的水溶液依次进行洗脱，每个洗脱体系洗1500ml。根据薄层层析色谱行为，照射254nm紫外灯判断不同馏分，在体积百分含量为20％的甲醇水溶液中得到馏分GS-9-1～3；在体积百分含量为40％的甲醇水溶液系统中得到馏分GS-9-4～6；在体积百分含量为50％的甲醇水溶液系统中得到馏分GS-9-7～8；在体积百分含量为70％的甲醇水溶液系统中得到馏分GS-9-9～10；在体积百分含量为90％的甲醇水溶液系统中得到馏分GS-9-11。共得到11个子馏分,将各个馏分冷冻干燥。
通过薄层色谱分析发现GS-9-6中活性物质含量较高，因此对GS-9-6进一步进行HPLC分离制备。以体积百分含量82％甲醇的酸水(此处的酸水为体积百分含量为0.01％三氟乙酸的水溶液)溶液为洗脱剂进行HPLC制备，流速为2ml/min，收集15min的色谱峰，得到化合物13；收集19min的色谱峰，得到化合物14；收集23min，27min的色谱峰，分别得到化合物15、16；收集30min的色谱峰，分别得到化合物17。
实施例3
化合物1-17的确认
对制备得到的17个化合物分别进行核磁共振、红外、质谱检测，确定各化合物的结构。
其中所使用的核磁共振仪为Varian Mercury-500和-600兆赫，红外色谱仪为Nicolet IS5FT-IR，质谱仪为Bruker APEX III 7.0T和APEX II FT-ICR。
经确认，化合物1、6、8、10、13、14、15为新化合物，均含有三萜骨架I。
1、6、8、10、13、14、15的NMR的碳谱和氢谱确认数据如表1-2所示。
化合物1(Lucidenic acid R)
化合物1结构如下：
碳8和碳9之间为双键
R1为β-OH，R2为-OH，R3为＝O，R4为＝O，R5为β-OCO CH3，R6为＝O，
R7为-CH(CH3)CH2C(O)CH2CH(CH3)COOH，
(6R)-6-((3S,4R,5R,10S,12S,13R,14R,17R)-12-乙酰氧基-3-羟基-4-(羟基甲基)-4,10,13,14-四甲基-7,11,15-三氧代-2,3,4,5,6,7,10,11,12,13,14,15,16,17-十四氢-1H-环戊[a]菲-17-基)-2-甲基-4-氧代庚酸
(6R)-6-((3S,4R,5R,10S,12S,13R,14R,17R)-12-acetoxy-3-hydroxy-4-(hydroxymethyl)-4,10,13,14-tetramethyl-7,11,15-trioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-c yclopenta[a]phenanthren-17-yl)-2-methyl-4-oxoheptanoic acid
化合物6(Lucidenic acid Q)
化合物6结构如下：
其中，碳8和碳9之间为双键，
R1为＝O，R2为-H，R3为＝O，R4为＝O，R5为β-OCO CH3，R6为＝O，
R7为-CH(CH3)CH2CH(OH)CH＝C(CH3)COOH，
(4R,6R,E)-6-((5R,10S,12S,13R,14R,17R)-12-乙酰氧基-4,4,10,13,14-五甲基-3,7,11,15-四氧代-2,3,4,5,6,7,10,11,12,13,14,15,16,17-十四氢-1H-环戊[a]菲-17-基)-4-羟基-2-甲基庚-2-烯酸
(4R,6R,E)-6-((5R,10S,12S,13R,14R,17R)-12-acetoxy-4,4,10,13,14-pentamethyl-3,7,11,15-tetraoxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-4-hydroxy-2-methylhept-2-enoic acid
化合物8(Methyl ganoderate P)
化合物8结构如下：
其中，碳8和碳9之间为双键，
R1为β-OH，R2为-H，R3为α-OH，R4为＝O，R5为β-OCO CH3，R6为＝O，
R7为-(CH3)C＝CHC(O)CH2CH(CH3)COOCH3
甲基(Z)-6-((3S,5R,7S,10S,12S,13R,14R)-12-乙酰氧基-3,7-二羟基-4,4,10,13,14-五甲基-11,15-二氧代-2,3,4,5,6,7,10,11,12,13,14,15,16,17-十四氢-1H-环戊[a]菲-17-基)-2-甲基-4-氧代庚-5-烯酸酯
methyl(Z)-6-((3S,5R,7S,10S,12S,13R,14R)-12-acetoxy-3,7-dihydroxy-4,4,10,13,14-pentamethyl-11,15-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-4-oxohept-5-enoate
化合物10(Lucidenic acid S)
化合物10结构如下：
其中，碳7与碳8之间和碳9与碳11之间为双键，
R1为＝O，R2为-H，R3为H，R4为-H，R5为-H，R6为-H，
R7为-CH(CH3)CH2CH2CH＝C(CH2OH)COOH
(R,Z)-2-(羟基甲基)-6-((5R,10S,13R,14R,17R)-4,4,10,13,14-五甲基-3-氧代-2,3,4,5,6,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)庚-2-烯酸
(R,Z)-2-(hydroxymethyl)-6-((5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-3-oxo-2,3,4,5,6,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)hept-2-enoic acid
化合物13(Ganolucinin A)
化合物13结构如下：
其中，碳7与碳8之间和碳9与碳11之间为双键，
R1为＝O，R2为-H，R3为H，R4为-H，R5为-H，R6为-H，
R7为-CH(CH3)CH2CH2CH(R9)C(CH2R8)(OH)CH3,
R8为
R9为α-OH,
(2R,3S,6R)-2,3-二羟基-2-甲基-6-((5R,10S,13R,14R,17R)-4,4,10,13,14-五甲基-3-氧代-2,3,4,5,6,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)庚基(2Z,5E)-2-(2-(2,5-二羟基苯基)-2-氧代亚乙基)-6,10-二甲基十一-5,9-二烯酸酯
(2R,3S,6R)-2,3-dihydroxy-2-methyl-6-((5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethy l-3-oxo-2,3,4,5,6,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)heptyl(2Z,5E)-2-(2-(2,5-dihydroxyphenyl)-2-oxoethylidene)-6,10-dimethylundeca-5,9-dienoate
化合物14(Ganolucinin B)
化合物14结构如下：
其中，碳7与碳8之间和碳9与碳11之间为双键，
R1为＝O，R2为-H，R3为H，R4为-H，R5为-H，R6为-H，
R7为-CH(CH3)CH2CH2CH(R9)C(CH2R8)(OH)CH3,
R8为
R9为-OH,
(2R,3S,6R)-2,3-二羟基-2-甲基-6-((5R,10S,13R,14R,17R)-4,4,10,13,14-五甲基-3-氧代-2,3,4,5,6,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)庚基(2E,5E)-2-(2-(2,5-二羟基苯基)亚乙基)-6,10-二甲基十一-5,9-二烯酸酯
(2R,3S,6R)-2,3-dihydroxy-2-methyl-6-((5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethy l-3-oxo-2,3,4,5,6,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)hept yl(2E,5E)-2-(2-(2,5-dihydroxyphenyl)ethylidene)-6,10-dimethylundeca-5,9-dienoate
化合物15(Ganolucinin C)
化合物15结构如下：
其中，碳7与碳8之间和碳9与碳11之间为双键，
R1为＝O，R2为-H，R3为H，R4为-H，R5为-H，R6为-H，
R7为-CH(CH3)CH2CH2CH(R9)C(CH2R8)(OH)CH3,
R8为-OH,
R9为
(2R,3R,6R)-1,2-二羟基-2-甲基-6-((5R,10S,13R,14R,17R)-4,4,10,13,14-五甲基-3-氧代-2,3,4,5,6,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)庚an-3-基(2Z,5E)-2-(2-(2,5-二羟基苯基)亚乙基)-6,10-二甲基十一-5,9-二烯酸酯
(2R,3R,6R)-1,2-dihydroxy-2-methyl-6-((5R,10S,13R,14R,17R)-4,4,10,13,14-pentameth yl-3-oxo-2,3,4,5,6,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)he ptan-3-yl(2Z,5E)-2-(2-(2,5-dihydroxyphenyl)ethylidene)-6,10-dimethylundeca-5,9-dienoate
表1 1H(500MHz)and 13C(125MHz)NMR(1,6，8，10)(CDCl3)
表2 1H(500MHz)and 13C(125MHz)NMR(13-15)(CDCl3)
化合物2(Ganoderic acid C)
化合物2结构如下
其中，碳8和碳9之间为双键，
R1为β-OH，R2为-H，R3为β-OH，R4为＝O，R5为-H，R6为α-OH，
R7为-CH(CH3)CH2C(O)CH2CH(CH3)COOH
(6R)-2-甲基-4-氧代-6-((3S,5R,7S,10S,13R,14R,15S,17R)-3,7,15-三羟基-4,4,10,13,14-五甲基-11-氧代-2,3,4,5,6,7,10,11,12,13,14,15,16,17-十四氢-1H-环戊[a]菲-17-基)庚酸
(6R)-2-methyl-4-oxo-6-((3S,5R,7S,10S,13R,14R,15S,17R)-3,7,15-trihydroxy-4,4,10,13,14-pentamethyl-11-oxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)heptanoic acid
化合物3(Methyl Ganoderate K)
化合物3结构如下
其中，碳8和碳9之间为双键，
R1为β-OH，R2为-H，R3为H，R4为＝O，R5为β-OCOCH3，R6为＝O，
R7为-CH(CH3)CH2C(O)CH2CH(CH3)COOCH3，
甲基(6R)-6-((3S,5R,7S,10S,12S,13R,14R,17R)-12-乙酰氧基-3,7-二羟基-4,4,10,13,14-五甲基-11,15-二氧代-2,3,4,5,6,7,10,11,12,13,14,15,16,17-十四氢-1H-环戊[a]菲-17-基)-2-甲基-4-氧代庚酸酯
methyl(6R)-6-((5R,7S,10S,13R,14R,15R,17R)-7,15-dihydroxy-4,4,10,13,14-pentamethyl-3,11-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-4-oxoheptanoate
化合物4(Methyl lucidenate F)
化合物4结构如下
其中，碳8和碳9之间为双键，
R1为＝O，R2为-H，R3为β-OH，R4为＝O，R5为-H，R6为β-OH，
R7为-CH(CH3)CH2C(O)CH2CH(CH3)COOCH3
甲基(6R)-6-((5R,7S,10S,13R,14R,15R,17R)-7,15-二羟基-4,4,10,13,14-五甲基-3,11-二氧代-2,3,4,5,6,7,10,11,12,13,14,15,16,17-十四氢-1H-环戊[a]菲-17-基)-2-甲基-4-氧代庚酸酯
methyl(6R)-6-((5R,7S,10S,13R,14R,15R,17R)-7,15-dihydroxy-4,4,10,13,14-pentamethyl-3,11-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-4-oxoheptanoate
化合物5(Ganoderic acid F)
化合物5结构如下
其中，碳8和碳9之间为双键，
R1为＝O，R2为-H，R3为＝O，R4为＝O，R5为β-OCOCH3，R6为＝O，
R7为-CH(CH3)CH2C(O)CH2CH(CH3)COOH
(6R)-6-((5R,10S,12S,13R,14R,17R)-12-乙酰氧基-4,4,10,13,14-五甲基-3,7,11,15-四氧代-2,3,4,5,6,7,10,11,12,13,14,15,16,17-十四氢-1H-环戊[a]菲-17-基)-2-甲基-4-氧代庚酸
(6R)-6-((5R,10S,12S,13R,14R,17R)-12-acetoxy-4,4,10,13,14-pentamethyl-3,7,11,15-tetr aoxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-4-oxoheptanoic acid
化合物7(Ganoderic acidθ)
化合物7结构如下
其中，碳8和碳9之间为双键，
R1为β-OH，R2为-H，R3为＝O，R4为＝O，R5为β-OH，R6为＝O，
R7为-CH(CH3)CH2CH(OH)CH＝C(CH3)COOH
(6R,E)-6-((3S,5R,10S,12S,13R,14R,17R)-3,12-二羟基-4,4,10,13,14-五甲基-7,11,15-三氧代-2,3,4,5,6,7,10,11,12,13,14,15,16,17-十四氢-1H-环戊[a]菲-17-基)-4-羟基-2-甲基庚-2-烯酸
(6R,E)-6-((3S,5R,10S,12S,13R,14R,17R)-3,12-dihydroxy-4,4,10,13,14-pentamethyl-7,11,15-trioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-4-hydroxy-2-methylhept-2-enoic acid
化合物9(Lucidumol A)
化合物9结构如下
其中，碳8和碳9之间为双键，
R1为＝O，R2为-H，R3为＝O，R4为-H，R5为-H，R6为-H，
R7为-CH(CH3)CH2CH2CH(OH)C(CH3)(OH)CH3,
(5R,10S,13R,14R,17R)-17-((2R,5S)-5,6-二羟基-6-甲基庚烷-2-基)-4,4,10,13,14-五甲基-1,2,5,6,10,11,12,13,14,15,16,17-十二氢-3H-环戊[a]菲-3,7(4H)-二烷
(5R,10S,13R,14R,17R)-17-((2R,5S)-5,6-dihydroxy-6-methylheptan-2-yl)-4,4,10,13,14-p entamethyl-1,2,5,6,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3,7(4H)-dione
化合物11(Ganoderic acid T-Q)
化合物11结构如下
其中，碳7与碳8之间和碳9与碳11之间为双键，
R1为＝O，R2为-H，R3为H，R4为-H，R5为-H，R6为α-OCOCH3，
R7为-CH(CH3)CH2CH2CH＝C(CH3)COOH
(R,E)-6-((5R,10S,13R,14R,15S,17R)-15-乙酰氧基-4,4,10,13,14-五甲基-3-氧代-2,3,4,5,6,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)-2-甲基庚-2-烯酸
(R,E)-6-((5R,10S,13R,14R,15S,17R)-15-acetoxy-4,4,10,13,14-pentamethyl-3-oxo-2,3,4,5,6,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylhept-2-enoic acid
化合物12(Ganoderic acid X)
化合物12结构如下
其中，碳7与碳8之间和碳9与碳11之间为双键，
R1为α-OH，R2为-H，R3为H，R4为-H，R5为-H，R6为α-OCOCH3，
R7为-CH(CH3)CH2CH2CH＝C(CH3)COOH，
(R,E)-6-((3R,5R,10S,13R,14R,15S,17R)-15-乙酰氧基-3-羟基-4,4,10,13,14-五甲基-2,3,4,5,6,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)-2-甲基庚-2-烯酸
(R,E)-6-((3R,5R,10S,13R,14R,15S,17R)-15-acetoxy-3-hydroxy-4,4,10,13,14-pentameth yl-2,3,4,5,6,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methy lhept-2-enoic acid
化合物16(Ganoleuconin M)
化合物16结构如下
其中，碳7与碳8之间和碳9与碳11之间为双键，
R1为＝O，R2为-H，R3为H，R4为-H，R5为-H，R6为-H，
R7为-CH(CH3)CH2CH2CH(R9)C(CH2R8)(OH)CH3,
R8为
R9为-OH，
(2R,3S,6R)-2,3-二羟基-2-甲基-6-((5R,10S,13R,14R,17R)-4,4,10,13,14-五甲基-3-氧代-2,3,4,5,6,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)庚基(2Z,5E)-2-(2-(2,5-二羟基苯基)亚乙基)-6,10-二甲基十一-5,9-二烯酸酯
(2R,3S,6R)-2,3-dihydroxy-2-methyl-6-((5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethy l-3-oxo-2,3,4,5,6,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)hept yl(2Z,5E)-2-(2-(2,5-dihydroxyphenyl)ethylidene)-6,10-dimethylundeca-5,9-dienoate
化合物17(Ganoleuconin P)
化合物17结构如下
其中，碳8和碳9之间为双键，
R1为＝O，R2为-H，R3为＝O，R4为-H，R5为-H，R6为-H，
R7为-CH(CH3)CH2CH2CH(R9)C(CH2R8)(OH)CH3,
R8为
R9为α-OH,
(2R,3S,6R)-2,3-二羟基-2-甲基-6-((5R,10S,13R,14R,17R)-4,4,10,13,14-五甲基-3,7-二氧代-2,3,4,5,6,7,10,11,12,13,14,15,16,17-十四氢-1H-环戊[a]菲-17-基)庚基(2Z,5E)-2-(2-(2,5-二羟基苯基)亚乙基)-6,10-二甲基十一-5,9-二烯酸酯。
(2R,3S,6R)-2,3-dihydroxy-2-methyl-6-((5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethy l-3,7-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)heptyl(2Z,5E)-2-(2-(2,5-dihydroxyphenyl)ethylidene)-6,10-dimethylundeca-5,9-dienoate。
本发明化合物1-17的理化性质如下：
化合物1
Lucidenic acid S(1):白色粉末，[α]25 D+32.99(c 0.1,CH2Cl2),UV(MeOH)λmax(logε)215(6.12),255(3.47)nm；CD(c 1.85×10-3M,MeOH)λmax(Δε)230(+3.5),316(-0.7)nm；IR(neat)νmax 3401,2966,2927,2849,1711,1462,1376,1267,1113,1006,737cm-1；正离子模式HRTOFMS m/z[M+H]+559.3266(计算值C32H47O8,559.3265)。
化合物2
Ganoderic acid C(2):白色粉末,UV(MeOH)λmax(logε)220(4.12),254(2.47)nm；IR(neat)νmax 3511,3456,1703,1705,1654,1640,1337,1203,1106,1066cm-1；1HNMR(CDCl3,500MHz)δH 4.76(1H,dd,J＝7.8,8.3Hz),4.51(1H,dd,J＝7.6,10Hz),1.26(3H,s),1.24(3H,s),1.17(3H,d，J＝6.9,Hz)，1.02(3H,s)，0.98(3H,s)，0.86(3H,s)；正离子模式HRTOFMS m/z[M+H]+519.3325(计算值C30H47O7,519.3322)。
化合物3
Methyl Ganoderate K(3):白色粉末；[α]25 D+68.0(c 0.1,CH2Cl2)；UV(CHCl3)λmax(logε)254(2.04)nm；IR(dry film)νmax 3435,2968,2933,2875,1732,1679,1583,1462,1373,1232,1043,758cm-1；1HNMR(CDCl3,500MHz)δH 0.92(m,H-1α),2.61(ddd,J＝3.6,7.2,13.6,H-1β),1.65(m,H-2),3.19(dd,J＝5.2,10.8,H-3),0.89(m,H-5),2.24(m,H-6α),1.68(m,H-6β),4.79(t,J＝-8.8,H-7),5.6(s,H-12),2.12(dd,J＝9.6,19.6,H-16α),2.68(dd,J＝8.0,19.2,H-16β),2.47(m,H-17),0.95(s,H-18),1.25(s,H-19),2.44(m,H-20),0.96(d,J＝-5.6,H-21),2.28(dd,J＝8.4,16,H-22α),2.43(m,H-22β),2.45(m,H-24α),2.83(dd,J＝8.8,17.6,H-24β),2.95(m,H-25),1.17(d,J＝7.2,H-27),1.02(s,H-28),0.84(s,H-29),1.48(s,H-30),2.25(s,H-CH3CO),3.66(s,H-CH3)；13C NMR(CDCl3,125MHz)δC 34.4(C-1),27.4(C-2),78.2(C-3),38.6(C-4),49.1(C-5),36.7(C-6),66.2(C-7),155.8(C-8),142.9(C-9),38.5(C-10),192(C-11),79.5(C-12),49.6(C-13),60.6(C-14),216.2(C-15),37.9(C-16),45.2(C-17),12(C-18),18.6(C-19),28.2(C-20),21.9(C-21),47.9(C-22),207.4(C-23),46.6(C-24),34.6(C-25),176.1(C-26),17.1(C-27),28(C-28),15.4(C-29),24(C-30),170.4(C-CH3CO),20.9(C-CH3CO),51.9(C-OCH3)；正离子模式HRTOFMS m/z[M+H]+589.3379(计算值C28H39O6,589.3370)。
化合物4
Methyl lucidenate F(4):淡黄色针状物(MeOH)；[α]25 D+120.0°(c 0.05,CHCl3)；UV(MeOH)λmax 251,224nm；IR(KBr)νmax 2956,1747,1701,1680,1641,1456,1386,754cm-1；1HNMR(CDCl3,500MHz)δ3.68(3H,s,O CH3),2.89(1H,ddd,J＝13.5,9.0,6.5Hz,H-1β),2.88(1H,d,J＝16.5Hz,H-12α),2.84(1H,dd,J＝18.2,9.0Hz,H-16),2.77(1H,d,J＝16.5Hz,H-12β),2.70(1H,dd,J＝15.0,13.5Hz,H-6β),2.62(1H,ddd,J＝16.0,9.8,6.2Hz,H-2β),2.48(1H,ddd,J＝15.5,9.0,6.0Hz,H-2α),2.48(1H,dd,J＝13.5,2.5Hz,H-6α),2.40(1H,ddd,J＝16.0,9.0,7.5Hz,H-23),2.32(1H,dd,J＝15.0,2.5Hz,H-5),2.27(1H,ddd,J＝16.0,9.0,7.5Hz,H-23),2.12(1H,dt,J＝9.0,8.0Hz,H-17),1.95(1H,dd,J＝18.0,8.0Hz,H-16),1.78(1H,dddd,J＝14.0,9.0,5.0,5.0Hz,H-22),1.75(1H,ddd,J＝14.0,9.0,5.5Hz,H-22),1.28(3H,s,H-19),1.14(3H,s,H-29),1.12(3H,s,H-30),0.96(3H,d,J＝6.2Hz,H-21),0.86(3H,s,H-18)；正离子模式HRTOFMS m/z[M+H]+471.2744(计算值C28H39O6,471.2747)。
化合物5
Ganoderic acid F(5):[α]25 D+113(c 0.4,CHCl3)；UV(MeOH)λmax(logε)254(2.04)nm；IR(KBr)νmax 1750,1700cm-1，1H NMR(CDCl3,500MHz)，δH 0.99(3H，d，J＝6.3Hz，21-CH3)，1.12(3H，s，31-CH3)，1.14(3H，s，30-CH3)，1.22(3H，d，J＝6.9Hz，27-CH3)，1.34(3H，s，19-CH3)，1.80(3H，s，32-CH3)，2.25(3H，s，OCO CH3)，5.68(IH，s，12-CH)。HREIMS m/z 569.2579[M]+(计算值C32H41O9,569.2575)。
化合物6
Lucidenic acid Q(6):黄色粉末，[α]25 D+132.98(c 0.1,CH2Cl2)；UV(MeOH)λmax(logε)248(2.34)nm；CD(c 1.01×10-3M,CH2Cl2)λmax(Δε)230(+16.4),254(-2.9),283(+7.9),310(-6.8)nm；IR(neat)νmax 3466,3060,2978,1748,1698,1460,1425,1388,1235,1176,1124,1044,736cm-1；正离子模式HRTOFMS m/z[M+H]+571.2904(计算值C32H43O9,571.2907)。
化合物7
Ganoderic acidθ(7):黄色针晶(MeOH–H2O),[α]25 D+71.3(c 0.1,MeOH)；UV(MeOH)λmax(logε)212(4.08),251(3.75)nm；IR(neat)νmax 3404,1747,1685,1653；1H NMR(CDCl3,500MHz)δH 1.10(m,H-1α),2.72(m,H-1β),1.73(m,H-2),3.22(dd,J＝8.9,7.2,H-3α),1.55(dd,J＝14.5,2.2,H-5),2.72(m,H-6α),2.57(dd,J＝14.5,2.2,H-6β),4.51(s,H-12α),2.75(dd,J＝18.0,9.8,H-16α),2.63(m1.69,H-16β),1.99(dd,J＝18.0,8.2,H-17),0.62(s,H3-18),1.37(s,H3-19),1.78(m,H-20),1.15(,J＝6.5,H3-21),1.46(m,H-22),1.62(m,H-22),4.54(ddd,J＝13.8,8.9,4.8,H-23),6.52(d,J＝8.9,H-24),1.87(s,H3-27),1.05(s,H3-28),0.89(s,H3-29),1.68(s,H3-30)；13C NMR(CDCl3,150MHz)δC 33.2(C-1),26.7(C-2),76.8(C-3),40(C-4),51.2(C-5),36.4(C-6),199.5(C-7),146.2(C-8),151(C-9),38.8(C-10),201.4(C-11),77.6(C-12),49.5(C-13),57.5(C-14),207.6(C-15),36.7(C-16),45.5(C-17),10.6(C-18),17.6(C-19),29.4(C-20),21.3(C-21),41.8(C-22),66.5(C-23),142.2(C-24),129(C-25),175(C-26),12.6(C-27),27.4(C-28),15.2(C-29),20.1(C-30)。正离子模式HRTOFMS m/z[M+H]+531.2954(计算值C30H43O8,531.2958)。
化合物8
Lucidenic acid R(8):白色粉末，[α]25 D-162.47(c 0.1,MeOH)；UV(MeOH)λmax(logε)259(4.10)nm；CD(c8.9×10-4M,MeOH)λmax(Δε)228(+0.94),254(-0.51),280(-0.16),302(-0.95)nm；IR(neat)νmax 3420,2939,2927,1747,1689,1450,1347,1232,1038cm-1；正离子模式HRTOFMS m/z[M+H]+589.3015(计算值C32H45O10,589.3013)。
化合物9
Lucidumol A(9):无色针晶[α]25 D+35°(C 0.2,EtoH)IR(KBr)νmax 3500，1710，1650cm-1.UV(MeOH)λmax(logε)251(4.0)nm。1H NMR(CDCl3,500MHz)δH 1.83(m,H-1α),2.11(m,H-1β),2.47(ddd,H-2α),2.71(ddd,H-2β),3.22(dd,J＝11.0，5.1,H-3α),2.15(dd,J＝14.5，3.2,H-5α),2.34(dd,J＝15.8，3.2,H-6α),2.55(dd,J＝15.8，14.5,H-6β),4.8(t,J＝9.3,H-7),2.32(m,H-11),1.81(m,H-12),2(m,H-15α),1.38(m,H-15β),2.07(m,H-16α),1.69(m,H-16β),1.47(m,H-17),0.69(s,H-18),1.34(s,H-19),1.43(m,H-20),0.94(d,J＝6.2,H-21),1.05(m,H-22α),1.8(m,H-22β),1.59(,H-23),3.3(d,J＝1O.1,H-24),1.17(s,H-26),1.22(s,H-27),1.1(s,H-28),1.2(s,H-29),0.94(s,H-30)；13C NMR(CDCl3,125MHz)δC 35.3(C-1),34.4(C-2),214.8(C-3),47.2(C-4),50.3(C-5),37.1(C-6),198.2(C-7),139.5(C-8),162.3(C-9),39.4(C-10),23.8(C-11),30.1(C-12),44.9(C-13),47.4(C-14),28.6(C-15),31.8(C-16),49.1(C-17),15.9(C-18),24.9(C-19),36.6(C-20),18.9(C-21),33.4(C-22),28.6(C-23),79.5(C-24),73.2(C-25),23.2(C-26),26.5(C-27),25.3(C-28),21.2(C-29),17.9(C-30)。正离子模式HRTOFMS m/z[M+H]+473.3628(计算值C30H48O4,473.3631)。
化合物10
Methyl ganoderate P(10):白色粉末，[α]25 D+37.99(c 0.1,CH2Cl2)；UV(MeOH)λmax(logε)247(5.04)nm；CD(c 1.95×10-3M,CH2Cl2)λmax(Δε)257(+10.5),285(-2.8)nm；IR(neat)νmax 3476,2996,2940,2884,1732,1691,1607,1441,1372,1233,1137,1052cm-1；正离子模式HRTOFMS m/z[M+H]+587.3218(计算值C33H47O9,587.3220)。
化合物11
Ganoderic acid T-Q(11)：白色粉末，[α]25 D+57.99(c 0.1,CH2Cl2)；UV(MeOH)λmax(logε)251(3.04)nm；1H NMR(CDCl3,500MHz)δH 2.75(ddd,J＝5.7.14.6,14.6,H-l),5.51(m,H-7),5.37(d,J＝5.6,H-11),5.06(dd,J＝4.6,9.4),H-15),0.66(s,CH3-18),1.09(s,CH3-19),0.9(d,J＝6.3,CH3-21),6.82(t,J＝6.9,H-24),1.81(s,CH3-27),0.98(,J＝s,CH3-28),1.07(s,CH3-29),1.16(s,CH3-30),2.07(s,OAC)；13C NMR(CDCl3,125MHz)δC 36.6(C-1),37.48(C-2),216.59(C-3),47.42(C-4),50.39(C-5),23.63(C-6),121.04(C-7),140.37(C-8),145(C-9),37.25(C-10),116.92(C-11),37.99(C-12),44.06(C-13),51.31(C-14),77.23(C-15),36.97(C-16),48.85(C-17),16(C-18),22.44(C-19),35.92(C-20),18.16(C-21),34.62(C-22),25.92(C-23),144.53(C-24),126.76(C-25),172.1(C-26),12.04(C-27),18.24(C-28),25.4(C-29),22.14(C-30),171.21(AcCO),21.4(AcMe)。正离子模式HRTOFMS m/z[M+H]+511.3430(计算值C32H47O5,511.3424)。
化合物12
Ganoderic acid X(12)：白色粉末；UV(乙腈)λmax(logε)218(4.12),234(4.07),243(4.06)；1H NMR(CDCl3,600MHz)δH 6.83(1H,t,H-24),5.46(1H,m,H-7),5.33(1H,m,H-11),5.05(1H,t,H-15),3.43(1H,m,H-3),2.30and 2.07(2H,m,H-12),2.22and 2.08(2H,m,H-23),2.10and 1.70(2H,m,H-16),2.07(3H,s,H-32),1.99(2H,m,H-6),1.97and 1.68(2H,m,H-2),1.82(3H,s,H-27),1.75and 1.68(2H,m,H-1),1.67(1H,t,H-17),1.50and1.11(2H,m,H-22),1.48(1H,t,H-5),1.39(1H,m,H-20),1.00(3H,s,H-28),0.97(6H,s,H-29and H-19),0.92(3H,s,H-30),0.90(3H,d,H-21),0.64(3H,s,H-18)；13C NMR(CDCl3,125MHz)δC171.9(C-26),171.2(C-31),146.0(C-9),145.1(C-24),140.2(C-8),126.6(C-25),121.29(C-7),115.6(C-11),77.41(C-15),76.1(C-3),51.40(C-14),48.85(C-17),44.11(C-13),42.92(C-5),37.97(C-12),37.34(C-10),37.32(C-4),37.03(C-16),35.96(C-20),34.65(C-22),29.89(C-1),28.18(C-29),25.93(C-23),25.56(C-2),22.95(C-6),22.78(C-30),22.65(C-19),21.42(C-32),18.50(C-28),18.17(C-21),15.95(C-18),12.03(C-27).正离子模式HRTOFMS m/z[M+H]+511.3591(计算值C32H47O5,513.3580)。
化合物13
Ganolucinin A(13):黄色油状液体，[α]25 D+18.00(c 0.1,MeOH)；UV(MeOH)λmax(logε)239(5.12),377(2.10)nm；CD(c 1.02×10-3M,MeOH)λmax(Δε)234(+3.18),280(+0.17),306(-0.14)nm；IR(neat)νmax 3425,2965,2934,1712,1645,1592,1452,1378,1301,1265,1183,1076,1002,792,737cm-1；正离子模式HRTOFMS m/z[M+H]+829.5258(计算值C51H73O9,829.5255)。
化合物14
Ganolucinin B(14):黄色油状液体，[α]25 D+18.00(c 0.1,MeOH)；UV(MeOH)λmax(logε)236(5.12),294(1.95),nm；CD(c 1.02×10-3M,MeOH)λmax(Δε)234(+3.15),280(+0.14),310(-0.11)nm；IR(neat)νmax 3407,2935,2834,1722,1645,1400,1328,1301,1269,1153,1076,1001,760,649cm-1；正离子模式HRTOFMS m/z[M+H]+799.5509(计算值C51H75O7,799.5507)。
化合物15
Ganolucinin C(15):黄色油状液体，[α]25 D+19.00(c 0.1,MeOH)；UV(MeOH)λmax(logε)236(5.12),294(1.95)nm；CD(c 1.02×10-3M,MeOH)λmax(Δε)237(+3.14),276(+0.17),306(-0.21)nm；IR(neat)νmax 3380,2934,2814,1723,1630,1466,1423,1301,1229,1163,1073,999,647cm-1；正离子模式HRTOFMS m/z[M+H]+799.5511(计算值C51H75O7,799.5507)。
化合物16
Ganoleuconin M(16)：淡黄色油状液体，[α]25D+9.00(c 0.1,MeOH)；UV(MeOH)200(3.50),254(3.40),377(2.00)；IR(neat)νmax 3452,2925,2849,1719,1700,1635,1460,1423,1345,1301,1234,1190,1128,1023,1000,649cm-1；1H NMR(CDCl3,500MHz)δH2.26(m,H-1α),1.78(m,H-1β),2.8(dt,J＝14.5,9,H-2α),2.34(m,H-2β),1.55(m,H-5),2.05(m,H-6α),2.23(m,H-6β),5.39(d,J＝5.8,H-7),5.5(d,J＝6.5,H-11α),2.21(m,H-12α),2.1(m,H-12β),1.93(m,H-15α),1.29(m,H-15β),1.65(m,H-16α),1.35(m,H-16β),1.54(m,H-17),0.58(s,H-18),1.21(s,H-19),1.48(m,H-20),0.91(d,J＝6.5,H-21),1.63(m,H-22α),1.05(m,H-22β),1.62(m,H-23α),1.46(m,H-23β),3.44(d,J＝10.2,H-24),4.42(d,J＝11.1,H-26α),4.19(d,J＝11.1,H-26β),1.15(s,H-27),0.86(s,H-28),1.13(s,H-29),1.09(s,H-30),3.65(dd,J＝16.1,8.5,H-1’α),3.59(dd,J＝16.1,8.5,H-1‘β),5.97(t,J＝8.5,H-2'),2.25(m,H-4'),2.08(m,H-5'),5.04(m,H-6'),1.97(m,H-8'),2.14(m,H-9'),5.04(m,H-10'),1.68(s,H-12'),1.61(s,H-13'),1.53(s,H-14'),6.64(d,J＝1.5,H-3″),6.61(dd,J＝8.2,1.5,H-5″),6.73(d,J＝8.2,H-6″)；13C NMR(CDCl3,125MHz)δC 36.8(C-1),35(C-2),217.2(C-3),47.6(C-4),51.1(C-5),23.8(C-6),120.1(C-7),143(C-8),144.6(C-9),37.9(C-10),117.3(C-11),37.3(C-12),43.9(C-13),50.4(C-14),28(C-15),31.6(C-16),50.8(C-17),15.9(C-18),22.6(C-19),36.6(C-20),18.8(C-21),33.7(C-22),26.8(C-23),77.2(C-24),74.1(C-25),69.2(C-26),22.2(C-27),25.5(C-28),25.6(C-29),21(C-30),31.9(C-1'),140.2(C-2'),131.5(C-3'),34.5(C-4'),28.2(C-5'),124.4(C-6'),136.8(C-7'),39.8(C-8'),27.6(C-9'),122.5(C-10'),131.4(C-11'),25.9(C-12'),17.9(C-13'),16.3(C-14'),170.4(C-15'),149.4(C-1″),124(C-2″),117.4(C-3″),149(C-4″),115.1(C-5″),117.1(C-6″)。正离子模式HRTOFMS m/z[M+H]+815.5456(计算值C51H74O8,815.5456)。
化合物17
Ganoleuconin P(17)：淡黄色油状液体，[α]25D+23.00(c 0.1,MeOH)；UV(MeOH)λmaxnm(logε)248(4.12),254(3.99),377(2.10)；IR(neat)νmax 3380,2930,2860,1725,1704,1642,1440,1403,1348,1301,1239,1167,1018,1000,745,649cm-1；1H NMR(CDCl3,500MHz)δH 2.12(m,H-1α),1.79(m,H-1β),2.69(dt,J＝14.6,8.9,H-2α),2.46(m,H-2β),1.45(m,H-5),2.33(m,H-6α),2.53(m,H-6β),2.11(m,H-11α),1.99(m,H-11β),1.79(m,H-12α),1.67(m,H-12β),1.99(m,H-15α),1.21(m,H-15β),2.32(m,H-16α),2.7(m,H-16β),2.15(m,H-17),0.67(s,H-18),0.94(s,H-19),1.8(m,H-20),0.95(d,J＝6.5,H-21),1.68(m,H-22α),1.13(m,H-22β),1.6(m,H-23α),1.45(m,H-23β),3.43(d,J＝10.2,H-24),4.41(d,J＝11.4,H-26α),4.19(d,J＝11.4,H-26β),1.11(s,H-27),1.08(s,H-28),1.12(s,H-29),1.34(s,H-30),3.65(dd,J＝16.1,8.5,H-1’α),3.6(dd,J＝16.1,8.5,H-1‘β),5.96(t,J＝8.5,H-2'),2.25(m,H-4'),2.07(m,H-5'),5.04(m,H-6'),1.98(m,H-8'),2.11(m,H-9'),5.05(m,H-10'),1.66(s,H-12'),1.57(s,H-13'),1.53(s,H-14'),6.63(d,J＝1.5,H-3″),6.6(dd,J＝8.2,1.5,H-5″),6.71(d,J＝8.2,H-6″)；13C NMR(CDCl3,125MHz)δC 35.5(C-1),34.5(C-2),215(C-3),47.4(C-4),50.5(C-5),37.3(C-6),198.5(C-7),163.3(C-8),139.7(C-9),39.6(C-10),25.1(C-11),30.2(C-12),47.9(C-13),45.1(C-14),26.6(C-15),32(C-16),49.1(C-17),16(C-18),24(C-19),36.6(C-20),19(C-21),33.7(C-22),26.7(C-23),77.4(C-24),74.2(C-25),69.2(C-26),21(C-27),25.9(C-28),21.5(C-29),18(C-30),31.9(C-1'),140.3(C-2'),131.5(C-3'),34.5(C-4'),28.8(C-5'),124.3(C-6'),136.7(C-7'),39.7(C-8'),27.6(C-9'),122.5(C-10'),131.4(C-11'),25.5(C-12'),17.9(C-13'),16.3(C-14'),170.3(C-15'),149.3(C-1″),124.3(C-2″),117.2(C-3″),149.1(C-4″),115.1(C-5″),117.2(C-6″)。正离子模式HRTOFMSm/z[M+H]+799.5508(计算值C51H74O7,799.5507)。
实施例4
式1-17所示化合物的体外抑制醛糖还原酶活性试验
准确称取实施例3所制备的式1-17所示17个化合物，用DMSO配制成20mM，供活性测试(终浓度范围在1-100μM，配制时溶于少量DMSO后，用蒸馏水稀释至相应浓度，控制DMSO的最终体积分数<0.1％)；依帕司他作为阳性对照(终浓度分别为20μM、10μM、5μM、2μM、1μM，配制时溶于少量DMSO后，用蒸馏水稀释至相应浓度，控制DMSO的最终体积分数<0.1％)。
实验步骤：在96孔板中依次加入以下试剂，不同组别的配比如下：
测试组：10μL化合物溶液+25μL浓度(0.1mM)的NADPH溶液+25μl PBS缓冲液+15μL醛糖还原酶稀释液
阳性对照组：10μL依帕司他溶液+25μL浓度(0.1mM)的NADPH溶液+25μl PBS缓冲液+15μL醛糖还原酶稀释液
空白组：25μL浓度(0.1mM)的NADPH溶液+35μLPBS缓冲液+15μL醛糖还原酶稀释液
背景组：25μL浓度(0.1mM)的NADPH溶液+60μL PBS缓冲液+15μL醛糖还原酶稀释液
将加完试剂的96孔板在室温放置10min使化合物和酶充分反应，之后除背景组外，其他三组各加入25μL 10mM D,L甘油醛溶液作为底物，在37℃恒温箱中反应30分钟，测定各孔在340nm的光密度。
对实验数据统计分析，计算各供试样品的IC50值结果如表4所示。可见，所示化合物均有一定的醛糖还原酶酶抑制活性，其中化合物9的抑制作用最强，与依帕司他效果相当。
表4 1-20的醛糖还原酶抑制活性检测结果
Claims (5)
1.一种具有化学式(I)的化合物或其药用盐：
其中，
碳8和碳9之间为双键，或者碳7与碳8之间和碳9与碳11之间为双键；
R1为＝O，α-OH或β-OH；
R2为-H或-OH；
R3为H、＝O或β-OH；
R4为-H或＝O；
R5为-H、β-OH或β-OCOCH3；
R6为-H、α-OH、β-OH、＝O或α-OCOCH3；
R7为-CH(CH3)CH2C(O)CH2CH(CH3)COOCH3、
-CH(CH3)CH2C(O)CH2CH(CH3)COOH、
-CH(CH3)CH2CH(OH)CH＝C(CH3)COOH、
-(CH3)C＝CHC(O)CH2CH(CH3)COOCH3、
-CH(CH3)CH2CH2CH(OH)C(CH3)(OH)CH3、
-CH(CH3)CH2CH2CH＝C(CH2OH)COOH、
-CH(CH3)CH2CH2CH＝C(CH3)COOH、
-CH(CH3)CH2CH2CH(R9)C(CH2R8)(OH)CH3；
R8为-OH、
R9为α-OH或
2.权利要求1所述的化合物或其药用盐在制备醛糖还原酶抑制剂中的应用。
3.权利要求1所述的化合物或其药用盐在制备醛糖还原酶抑制剂药物中的应用。
4.权利要求1所述的化合物或其药用盐在制备预防或治疗糖尿病并发症的药物、食品、保健品中的应用。
5.根据权利要求1所述的化合物或者其医学上可接受的盐，该化合物是选自：
(6R)-6-((3S,4R,5R,10S,12S,13R,14R,17R)-12-乙酰氧基-3-羟基-4-(羟基甲基)-4,10,13,14-四甲基-7,11,15-三氧代-2,3,4,5,6,7,10,11,12,13,14,15,16,17-十四氢-1H-环戊[a]菲-17-基)-2-甲基-4-氧代庚酸；
(4R,6R,E)-6-((5R,10S,12S,13R,14R,17R)-12-乙酰氧基-4,4,10,13,14-五甲基-3,7,11,15-四氧代-2,3,4,5,6,7,10,11,12,13,14,15,16,17-十四氢-1H-环戊[a]菲-17-基)-4-羟基-2-甲基庚-2-烯酸；
甲基(Z)-6-((3S,5R,7S,10S,12S,13R,14R)-12-乙酰氧基-3,7-二羟基-4,4,10,13,14-五甲基-11,15-二氧代-2,3,4,5,6,7,10,11,12,13,14,15,16,17-十四氢-1H-环戊[a]菲-17-基)-2-甲基-4-氧代庚-5-烯酸酯；
(R,Z)-2-(羟基甲基)-6-((5R,10S,13R,14R,17R)-4,4,10,13,14-五甲基-3-氧代-2,3,4,5,6,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)庚-2-烯酸；
(2R,3S,6R)-2,3-二羟基-2-甲基-6-((5R,10S,13R,14R,17R)-4,4,10,13,14-五甲基-3-氧代-2,3,4,5,6,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)庚基(2Z,5E)-2-(2-(2,5-二羟基苯基)-2-氧代亚乙基)-6,10-二甲基十一-5,9-二烯酸酯；
(2R,3S,6R)-2,3-二羟基-2-甲基-6-((5R,10S,13R,14R,17R)-4,4,10,13,14-五甲基-3-氧代-2,3,4,5,6,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)庚基(2E,5E)-2-(2-(2,5-二羟基苯基)亚乙基)-6,10-二甲基十一-5,9-二烯酸酯；
(2R,3R,6R)-1,2-二羟基-2-甲基-6-((5R,10S,13R,14R,17R)-4,4,10,13,14-五甲基-3-氧代-2,3,4,5,6,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)庚an-3-基(2Z,5E)-2-(2-(2,5-二羟基苯基)亚乙基)-6,10-二甲基十一-5,9-二烯酸酯；
(6R)-2-甲基-4-氧代-6-((3S,5R,7S,10S,13R,14R,15S,17R)-3,7,15-三羟基-4,4,10,13,14-五甲基-11-氧代-2,3,4,5,6,7,10,11,12,13,14,15,16,17-十四氢-1H-环戊[a]菲-17-基)庚酸；
甲基(6R)-6-((3S,5R,7S,10S,12S,13R,14R,17R)-12-乙酰氧基-3,7-二羟基-4,4,10,13,14-五甲基-11,15-二氧代-2,3,4,5,6,7,10,11,12,13,14,15,16,17-十四氢-1H-环戊[a]菲-17-基)-2-甲基-4-氧代庚酸酯；
甲基(6R)-6-((5R,7S,10S,13R,14R,15R,17R)-7,15-二羟基-4,4,10,13,14-五甲基-3,11-二氧代-2,3,4,5,6,7,10,11,12,13,14,15,16,17-十四氢-1H-环戊[a]菲-17-基)-2-甲基-4-氧代庚酸酯；
(6R)-6-((5R,10S,12S,13R,14R,17R)-12-乙酰氧基-4,4,10,13,14-五甲基-3,7,11,15-四氧代-2,3,4,5,6,7,10,11,12,13,14,15,16,17-十四氢-1H-环戊[a]菲-17-基)-2-甲基-4-氧代庚酸；
(6R,E)-6-((3S,5R,10S,12S,13R,14R,17R)-3,12-二羟基-4,4,10,13,14-五甲基-7,11,15-三氧代-2,3,4,5,6,7,10,11,12,13,14,15,16,17-十四氢-1H-环戊[a]菲-17-基)-4-羟基-2-甲基庚-2-烯酸；
(5R,10S,13R,14R,17R)-17-((2R,5S)-5,6-二羟基-6-甲基庚烷-2-基)-4,4,10,13,14-五甲基-1,2,5,6,10,11,12,13,14,15,16,17-十二氢-3H-环戊[a]菲-3,7(4H)-二烷；
(R,E)-6-((5R,10S,13R,14R,15S,17R)-15-乙酰氧基-4,4,10,13,14-五甲基-3-氧代-2,3,4,5,6,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)-2-甲基庚-2-烯酸；
(R,E)-6-((3R,5R,10S,13R,14R,15S,17R)-15-乙酰氧基-3-羟基-4,4,10,13,14-五甲基-2,3,4,5,6,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)-2-甲基庚-2-烯酸；
(2R,3S,6R)-2,3-二羟基-2-甲基-6-((5R,10S,13R,14R,17R)-4,4,10,13,14-五甲基-3-氧代-2,3,4,5,6,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)庚基(2Z,5E)-2-(2-(2,5-二羟基苯基)亚乙基)-6,10-二甲基十一-5,9-二烯酸酯；
(2R,3S,6R)-2,3-二羟基-2-甲基-6-((5R,10S,13R,14R,17R)-4,4,10,13,14-五甲基-3,7-二氧代-2,3,4,5,6,7,10,11,12,13,14,15,16,17-十四氢-1H-环戊[a]菲-17-基)庚基(2Z,5E)-2-(2-(2,5-二羟基苯基)亚乙基)-6,10-二甲基十一-5,9-二烯酸酯。
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111302942A (zh) * | 2020-04-09 | 2020-06-19 | 中国热带农业科学院热带生物技术研究所 | 具有ptp1b抑制活性的化合物及其应用 |
| CN112028959A (zh) * | 2020-09-30 | 2020-12-04 | 云南民族大学 | 无柄灵芝中具有抗糖尿病活性的三萜化合物的制备方法及应用 |
| CN114019078A (zh) * | 2022-01-04 | 2022-02-08 | 宝枫生物科技（北京）有限公司 | 用于帕金森病诊断的生物标志物及其应用 |
| CN115806490A (zh) * | 2021-09-13 | 2023-03-17 | 深圳大学 | 具有激活ampk磷酸化的酚性杂萜化合物、药物组合物、制备方法以及应用 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103385931A (zh) * | 2012-05-12 | 2013-11-13 | 赵全成 | 一种降血糖的药物组合物 |
| CN104844675A (zh) * | 2014-12-22 | 2015-08-19 | 中国科学院微生物研究所 | 白肉灵芝三萜化合物、其药用组合物及其应用 |
| CN104873520A (zh) * | 2014-02-27 | 2015-09-02 | 天津药物研究院 | 一种11β-羟基类固醇脱氢酶抑制剂、药用组合物及其用途 |
| CN106074566A (zh) * | 2016-06-02 | 2016-11-09 | 广西医科大学 | 灵芝三萜类化合物的用途 |
-
2017
- 2017-04-27 CN CN201710289165.9A patent/CN107056867A/zh active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103385931A (zh) * | 2012-05-12 | 2013-11-13 | 赵全成 | 一种降血糖的药物组合物 |
| CN104873520A (zh) * | 2014-02-27 | 2015-09-02 | 天津药物研究院 | 一种11β-羟基类固醇脱氢酶抑制剂、药用组合物及其用途 |
| CN104844675A (zh) * | 2014-12-22 | 2015-08-19 | 中国科学院微生物研究所 | 白肉灵芝三萜化合物、其药用组合物及其应用 |
| CN106074566A (zh) * | 2016-06-02 | 2016-11-09 | 广西医科大学 | 灵芝三萜类化合物的用途 |
Non-Patent Citations (4)
| Title |
|---|
| CHUN-RU CHENG ETAL: "Cytotoxic triterpenoids from Ganoderma lucidum", 《PHYTOCHEMISTRY》 * |
| GLORIA CASTELLANO ETAL.: "Information entropy-based classification of triterpenoids and steroids from Ganoderma", 《PHYTOCHEMISTRY》 * |
| KAI WANG ETAL: "Lanostane Triterpenes from the Tibetan Medicinal Mushroom Ganoderma leucocontextum and Their Inhibitory Effects on HMG-CoA Reductase and α‑Glucosidase", 《JOURNAL OF NATURAL PRODUCTS》 * |
| 王晓良: "《应用分子药理学》", 30 September 2015 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111302942A (zh) * | 2020-04-09 | 2020-06-19 | 中国热带农业科学院热带生物技术研究所 | 具有ptp1b抑制活性的化合物及其应用 |
| WO2021204018A1 (zh) * | 2020-04-09 | 2021-10-14 | 中国热带农业科学院热带生物技术研究所 | 具有ptp1b抑制活性的化合物及其应用 |
| CN111302942B (zh) * | 2020-04-09 | 2022-03-01 | 中国热带农业科学院热带生物技术研究所 | 具有ptp1b抑制活性的化合物及其应用 |
| CN112028959A (zh) * | 2020-09-30 | 2020-12-04 | 云南民族大学 | 无柄灵芝中具有抗糖尿病活性的三萜化合物的制备方法及应用 |
| CN115806490A (zh) * | 2021-09-13 | 2023-03-17 | 深圳大学 | 具有激活ampk磷酸化的酚性杂萜化合物、药物组合物、制备方法以及应用 |
| CN114019078A (zh) * | 2022-01-04 | 2022-02-08 | 宝枫生物科技（北京）有限公司 | 用于帕金森病诊断的生物标志物及其应用 |
| CN114019078B (zh) * | 2022-01-04 | 2022-04-05 | 宝枫生物科技（北京）有限公司 | 用于帕金森病诊断的生物标志物的应用 |
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