CN102579422B - 黄酮类化合物在制备抗代谢性疾病药物中的用途 - Google Patents
黄酮类化合物在制备抗代谢性疾病药物中的用途 Download PDFInfo
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Abstract
本发明属医药技术领域,涉及式(I)结构化合物的用途,具体涉及所述化合物(5aR,10aS)-5a,10a-二氢-1,3,8,10a-四羟基-2,5a-二(3-甲基-2-丁烯基)-11H-苯并呋喃[3,2-b][1]苯并吡喃-11-酮在治疗代谢性疾病中的用途。该化合物从黑桑中分离得到。实验证实,该化合物具有很强的促进脂肪细胞分化、增加糖尿病小鼠的胰岛素敏感性、降低血糖和血脂的作用,可进一步制成胰岛素增敏剂、降糖药物以及降脂药物应用于医药领域。
Description
技术领域
本发明属医药技术领域,涉及黄酮类化合物新的药物用途,具体涉及从黑桑中分离得到的黄酮类化合物的用途。尤其涉及化合物(5aR,10aS)-5a,10a-二氢-1,3,8,10a-四羟基-2,5a-二(3-甲基-2-丁烯基)-11H-苯并呋喃[3, 2-b][1]苯并吡喃-11-酮在提高胰岛素敏感性、治疗糖尿病和高脂血症方面的用途。
背景技术
近年来,由于生活水平的提高、饮食结构的改变、日趋紧张的生活节奏以及少动多坐的生活方式等诸多因素,全球糖尿病发病率增长迅速,糖尿病已经成为继肿瘤、心脑血管疾病之后第三大严重威胁人类健康的疾病。据世界卫生组织预计,到2025年,全球成人糖尿病患者人数将增至3亿。
2型糖尿病占总糖尿病的90%,其主要发病机制是胰岛素抵抗、胰岛β细胞功能衰竭和胰岛素分泌障碍。2型糖尿病病人多伴随有肥胖、高甘油三脂或高胆固醇血症,高血脂是胰岛素抵抗和胰岛β细胞功能紊乱的主要原因之一。糖尿病可导致多种急性和慢性并发症,如酮症酸中毒、心脑血管疾病、肾病等,对人类健康构成严重威胁。目前常用的降糖药有:胰岛素、磺脲类药物、非磺脲类胰岛素促分泌剂、双胍类降糖药、胰岛素增敏剂等,这几类降糖药作用快、疗效好、但毒副作用强,对肝、肾等器官损害,部分糖尿病人对胰岛素表现明显的抗药性。糖尿病为终身性疾病,需长期服药,因此,发现新的安全有效的抗糖尿病药物是目前社会的迫切需要。
脂肪组织是餐后葡萄糖吸收的主要部位,分化的脂肪细胞能高水平表达葡萄糖载体4(Glut4)。Glut4是一种糖蛋白,具有在胰岛素的作用下将葡萄糖转运至脂肪细胞内的功能。增加Glut4蛋白的表达量能增加脂肪组织对葡萄糖的转运,改善对胰岛素刺激的葡萄糖摄取的抵抗。糖尿病患者机体中Glut4表达减少、移位障碍,是胰岛素抵抗的主要原因,因此,寻找促进脂肪细胞分化、提高Glut4表达、增加胰岛素敏感性而促进葡萄糖转运的药物对治疗2型糖尿病具有重要的临床意义。我国有丰富的天然药物资源和悠久的应用中草药的历史,并且各少数民族在与疾病的斗争中积累了宝贵的民族药,这些都成为药物发现的重要源泉。
黑桑(Morus nigra Linn.)为桑科(Moraceae)桑属植物,原产伊朗,后传入我国,现在新疆喀什、阿克苏地区广泛栽培。黑桑在维吾尔医药中早已应用,俗称“药桑”,根皮和茎枝具有降血压、抗衰老、消炎止痛等功效。结构如式(I)所示的化合物桑根醇F(sanggenol F)是从黑桑中分离得到的(参考文献:傅大煦等,《黑桑的化学成分研究》,中草药,2005, 36 (9), 1296-1299)。另有文献报道,Fukai T. 等从桑属植物华桑(Morus cathayana Hemsl.)中首次分离得到如式(I)所示的化合物sanggenol F(Phytochemistry, 1997,
47(2), 273-280)。未见该化合物的生物活性研究报道。
发明内容
本发明的目的是提供黄酮类化合物新的药物用途,尤其涉及化合物(5aR,10aS)-5a,10a-二氢-1,3,8,10a-四羟基-2,5a-二(3-甲基-2-丁烯基)-11H-苯并呋喃[3, 2-b][1]苯并吡喃-11-酮在提高胰岛素敏感性、治疗糖尿病和高脂血症方面的用途。
本发明所述黄酮类化合物是从黑桑中分离得到的天然化合物。该黄酮类化合物具有如下式(I)的结构,
(I)
本发明所述的式(I)结构的化合物,尤其是化合物(5aR,10aS)-5a,10a-二氢-1,3,8,10a-四羟基-2,5a-二(3-甲基-2-丁烯基)-11H-苯并呋喃[3, 2-b][1]苯并吡喃-11-酮,经实验证实,其具有很强的促进脂肪细胞分化、增加Glut4蛋白的表达量而增加胰岛素敏感性和促进葡萄糖转运的作用,并具有降低血脂的功效,可进一步作为胰岛素增敏剂、降糖药物、降脂药物应用于医药领域。
本发明的黄酮类化合物是从黑桑中分离得到的天然化合物,通过如下方法制备:
将黑桑Morus nigra Linn.的茎枝粉碎后,用有机溶剂或/和水提取制备总提取物,所用的有机溶剂可采用醇类,如乙醇,甲醇等,其中优选95%(体积比)乙醇,将总提取物溶于水后,用石油醚萃取,取石油醚相,回收溶剂后干燥即得石油醚提取物;
将石油醚提取物进行硅胶柱色谱分离, 分别用石油醚、石油醚-丙酮梯度洗脱,其中石油醚-丙酮4∶1洗脱部分进行硅胶柱色谱分离, 以氯仿-乙醚(5∶1) 洗脱, 然后再进行ODS柱色谱分离,以甲醇-水梯度洗脱,得到化合物 (5aR,10aS)-5a,10a-二氢-1,3,8,10a-四羟基-2,5a-二(3-甲基-2-丁烯基)-11H-苯并呋喃[3, 2-b][1]苯并吡喃-11-酮,用波谱方法鉴定其结构,如式()的结构。
本发明式()的化合物进行了体外脂肪细胞分化、葡萄糖转运和体内db/db小鼠糖代谢、脂代谢相关实验,结果表明,所述化合物(I)具有很强的促进脂肪细胞分化、增强胰岛素刺激的脂肪细胞葡萄糖转运而增加胰岛素敏感性的作用,并具有降血脂的作用,可作为胰岛素增敏剂、降血糖、降血脂药物及应用于医药领域。
进一步,本发明式(I)的化合物(5aR,10aS)-5a,10a-二氢-1,3,8,10a-四羟基-2,5a-二(3-甲基-2-丁烯基)-11H-苯并呋喃[3, 2-b][1]苯并吡喃-11-酮可作为药物的有效成分,制备抗代谢性疾病的药物。所述的药物是胰岛素增敏剂,降血糖药物或降血脂药物。
附图说明
图1为实施例2中本发明化合物(I)对3T3-L1前脂肪细胞分化作用的影响。
图2为实施例3中本发明化合物(I)对胰岛素刺激的葡萄糖转运的影响。
图3为实施例4中本发明化合物(I)对db/db小鼠口服糖耐量(OGTT)的影响。
图4为实施例4中本发明化合物(I)对db/db小鼠OGTT曲线下面积的影响。
图5为实施例5中本发明化合物(I)对db/db小鼠胰岛素耐量(ITT)的影响。
图6为实施例5中本发明化合物(I)对db/db小鼠ITT曲线下面积的影响。
图7为实施例6中本发明化合物(I)对db/db小鼠脂肪组织基因aP2、C/EBPα、PPARg和Glut4表达水平的影响。
图8为实施例7中本发明化合物(I)对db/db小鼠血清甘油三酯(TG)、胆固醇(TC)水平的影响。
图1至图8中,* p < 0.05 and
** p < 0.01(与对照组相比)。
具体实施方式
下面结合具体实施实例对本发明作进一步阐述,但不限制本发明。
实施例 1 从黑桑中提取本发明化合物(I)
(1)提取:黑桑干燥茎枝粉碎后得粗粉2 公斤, 95%含水乙醇室温浸提三次,分别得到提取液8升、6升、4升,合并提取液,减压浓缩至干,得到浸膏204克。将此浸膏溶于水悬浮,用石油醚萃取,回收溶剂浓缩至干,得石油醚提取物47克。
(2)分离:将石油醚提取物47克进行硅胶柱色谱分离, 分别用石油醚、石油醚-丙酮(30∶1→20∶1→10∶1→9∶1→6∶1→4∶1)梯度洗脱,每个梯度用量3000毫升,收集流份,得到组分1~17份。石油醚-丙酮4∶1洗脱得到组分15~17,其中组分15(800毫克)经硅胶柱色谱分离, 氯仿-乙醚(5∶1) 洗脱700毫升, 得到组分15.1~15.3;将组分15.2(450毫克)进行ODS柱色谱分离, 甲醇-水(7∶3→8∶2→9∶1) 梯度洗脱, 每个梯度用量500毫升,收集流份,甲醇-水(8∶2)流份得到化合物 (I)(5aR,10aS)-5a,10a-二氢-1,3,8,10a-四羟基-2,5a-二(3-甲基-2-丁烯基)-11H-苯并呋喃[3, 2-b][1]苯并吡喃-11-酮 201毫克。
(3)化合物(I)的理化性质及光谱数据如下述:分子式为C25H26O7;其性状为黄色无定形粉末;比旋光:[a]20 D
+165.6°(c 1.03, Me2CO);电子轰击质谱(质荷比):438 [M]+;核磁共振氢谱(500 MHz)数据(化学位移:ppm,偶合常数:Hz, 溶剂:氘代丙酮):δ 11.91(1H,s,OH-5),9.12(2H,br s,OH-7, 4′),7.35(1H,d,J = 8.2 Hz,H-6′),7.03(1H,br s,OH-3), 6.52(1H,dd,J = 1.6,8.2 Hz,H-5′),6.40(1H,d,J = 1.6 Hz,H-3′),5.92(1H,s,H-8), 5.25(1H,br t,J = 7.0 Hz,H-2″),5.19(1H,br t,J = 7.0 Hz,H-10),3.23 (2H,br d,J = 7.0 Hz,H2-1″),3.12(1H,br dd,J = 8.8,14.7 Hz,H-9a), 2.78(1H,br dd,J = 6.1,14.7 Hz,H-9b),1.73, 1.623(各3H,br s,H3-4″, 5″),1.615, 1.52 (各3H,br s,H3-12, 13);核磁共振碳谱(100 MHz)数据(化学位移:ppm,溶剂:氘代丙酮):d 188.2 s(C-4),166.6 s(C-7),162.7 s(C-5),161.6 s(C-8a),161.3 s(C-2¢),161.2 s(C-4¢),136.5 s(C-11),131.4 s(C-3¢¢),125.6 d(C-6¢),123.3 d(C-2¢¢),121.4 s(C-1¢),118.7 d(C-10),109.7 d(C-5¢),109.1 s(C-6),102.6 s(C-3),100.2 s(C-4a),99.5 d(C-3¢),95.3 s(C-8),91.8 s(C-2),31.9 t(C-9),25.8 q(C-13,5¢¢),21.5 t(C-1¢¢),18.1 q(C-12),17.8 q(C-4¢¢)。
实施例 2 本发明化合物(I)对3T3-L1前脂肪细胞分化的影响(油红染色法)
将3T3-L1细胞接种于48孔板,用含10% NCS(小牛血清)的高糖H-DMEM培养基培养。2天后改用含125 μM IBMX(3-异丁基-1-甲基黄嘌呤)、1μM Dex(地塞米松)、20 μg/ml Insulin(胰岛素)的10% FBS(胎牛血清)培养基诱导分化,并加入不同浓度的化合物(I)。分化2天后,分化细胞的培养基改用含20 μg/ml Insulin、10%的FBS和不同浓度化合物(I)的高糖H-DMEM培养基,每2天换液一次,连续换三次。细胞分化8天后弃培养基,用PBS(磷酸盐缓冲盐水)洗一次,每孔小心加入300 µl的10%福尔马林(终浓度为4%甲醛),37℃孵育15分钟。弃10%福尔马林,用PBS洗两次,吸干PBS,油红O 染色30分钟,弃上清,加入300 µl的PBS,拍照。结果证实本发明化合物(I)可剂量依赖性的增加3T3-L1细胞内脂滴的含量, 能明显促进3T3-L1细胞向脂肪细胞分化(如图1所示)。
实施例 3本发明化合物(I)对已分化3T3-L1脂肪细胞葡萄糖转运的影响
将3T3-L1细胞接种于48孔板,分化培养方法与油红染色法相同,细胞分化8天后,弃去培养基,用无血清DMEM洗一遍,1ml/孔,加入含有0.1% BSA (牛血清清蛋白)的DMEM,300 µl/孔。37℃温育3-5h。弃去培养基,用HRP buffer洗一遍,加入HRP buffer(提前37℃温育,含有10 ng/ml 胰岛素),200 µl/孔,37℃温育15min。补加HRP buffer(含有2-deoxy-d-[1,2-3H]-glucose,终浓度稀释2000倍),100µl/孔,37℃温育10min。弃去板中所有液体,用冰冷的HRP buffer(300 µl /孔)洗一遍,吸掉,加入HRP buffer (400-500 μl/孔)再洗一遍,弃去。加入HRP buffer(含有0.1-0.5% TritonX-100),200μl/孔,过夜裂解。加入闪烁液 800µl/孔,检测。结果证实本发明化合物(I)能够剂量依赖性促进胰岛素刺激的葡萄糖转运而增强胰岛素的敏感性,其浓度为10 μM时,作用略强于降糖药物罗格列酮(Rosiglitazone)(如图2所示)。
实施例 4 本发明化合物(I)对db/db糖尿病小鼠口服糖耐量(OGTT)的影响
将8周龄的db/db小鼠按体重血糖分为两组:对照组(每天腹腔注射橄榄油,0.1ml/只)和给药组(每天腹腔注射橄榄油溶解的化合物(I),5 mg/kg, 0.1ml/只),每组6只,给药21天,第22天测口服糖耐量(OGTT):禁食12h,测对照组和给药组血糖、体重,根据体重灌胃葡萄糖(1g/kg)记为0时,灌胃后分别测60、90、120、150 min血糖。结果显示,给与本发明化合物(I)的db/db小鼠经口灌服葡萄糖后血糖低于对照组,曲线下面积明显小于对照组,说明本发明化合物(I)能提高db/db小鼠葡萄糖耐量(如图3和图4所示)。
实施例 5 本发明化合物(I)对db/db糖尿病小鼠胰岛素耐量(ITT)的影响
db/db小鼠给药18天(方法同上),第19天测胰岛素耐量(ITT):禁食6h,测对照组和给药组血糖、体重,根据体重腹腔注射胰岛素(1U/kg)记为0时,灌胃后分别测30、60、90、120 min血糖。结果显示,给与本发明化合物(I)的db/db小鼠在同样剂量胰岛素作用下,血糖明显低于对照组,说明本发明化合物(I)能提高db/db小鼠胰岛素敏感性(如图5和图6所示)。
实施例 6 本发明化合物(I)对db/db糖尿病小鼠脂肪组织基因表达水平的影响
db/db小鼠给与本发明化合物(I)三周后(方法同上),解剖,取脂肪组织,用TRIzol法抽提mRNA。100 mg组织加入1ml TRIzol,在旋涡震荡器上混匀后加入约1/5体积的氯仿,充分混匀后室温静置5 min;然后于4 °C,12000 rpm 离心15 min;将上清液转入1.5 ml离心管中,加入等体积的异丙醇,混匀后室温静置5 min;于4 °C,12000 rpm离心10 min;吸去上清液,向沉淀中加入2/5体积的70% 乙醇, 4 °C,12000 rpm离心15 min洗涤沉淀;吸去上清液,沉淀于室温自然晾干后加入适量RNase-free 的水,充分溶解沉淀;取1-2 ml稀释,测定OD 260, RNA浓度按以下公式计算:A260×40×稀释倍数(μg/μl)。用M-MLV逆转录酶把mRNA逆转录成cDNA,-80 °C冰箱保存待用。采用SYBR®Premix Ex
Taq™ II(Takara)对样品反转录产物进行实时荧光定量PCR分析。利用ABI 7500 Fast实时荧光定量PCR仪进行测定,同时做融解曲线判定引物质量,以β-actin为对照,计算aP2(脂肪组织脂肪酸结合蛋白)、C/EBPα(CAAT/ 增强子结合蛋白α)、PPARg(过氧化物体增殖剂活化受体g)和Glut4(葡萄糖载体4)的表达水平。结果显示,给与本发明化合物(I)的db/db小鼠脂肪细胞基因aP2、C/EBPα、PPARg和Glut4的表达明显高于对照组,说明本发明化合物(I)能提高db/db小鼠脂肪细胞基因aP2、C/EBPα、PPARγ和Glut4的表达, 在分子水平进一步证实本发明化合物(I)能促进脂肪细胞分化和葡萄糖的转运(如图7所示)。
实施例 7 本发明化合物(I)对db/db小鼠血清甘油三酯(TG)、胆固醇(TC)水平的影响
db/db小鼠给与本发明化合物(I)三周后(方法同上),尾静脉取血,离心,吸取上层血清,用甘油磷酸氧化酶-过氧化物酶法测血清TG含量,用胆固醇氧化酶-过氧化物酶法测血清TC含量。结果证实,本发明化合物(I)能降低db/db小鼠血清TG、TC的含量(如图8所示)。
上述实验结果表明,本发明化合物(I)具有明显促进脂肪细胞分化、提高Glut4的表达、增加胰岛素刺激的葡萄糖转运、提高糖尿病小鼠胰岛素敏感性、降低血糖、降低血脂的作用。因此,本发明化合物(I)可作为胰岛素增敏剂、降血糖药物和降血脂药物用于医药领域。
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