CN102731277A - 二萜类化合物豆荚甲素—己素、其制备方法及其在制备药物中的用途 - Google Patents
二萜类化合物豆荚甲素—己素、其制备方法及其在制备药物中的用途 Download PDFInfo
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Abstract
本发明涉及医药技术领域,具体而言,涉及一类从Lobophytum属软珊瑚Lobophytum cristatum Tixier-Durivault中分离得到的6个结构新颖的二萜类化合物豆荚甲素、乙素、丙素、丁素、戊素和己素,其制备方法及其在制备治疗II型糖尿病药物中的应用。本发明的豆荚甲素、乙素、丙素、丁素、戊素和己素的结构式如下所示。该类化合物经过生物活性测试可作为蛋白酪氨酸磷酸酯酶1B(PTP1B)抑制剂和胰岛素增敏剂,它们可用于制备治疗II型糖尿病、肥胖症及其并发症的药物。
Description
技术领域
本发明涉及医药技术领域,具体而言,涉及一类从豆荚软珊瑚属软珊瑚(Lobophytum cristatum)中分离得到的6个结构新颖的二萜类化合物豆荚甲素、乙素、丙素、丁素、戊素或己素;本发明还涉及该类化合物的制备方法;以及该类化合物作为蛋白酪氨酸磷酸酯酶1B(PTP1B)抑制剂和胰岛素增敏剂,在制备治疗II型糖尿病、肥胖症及其并发症的药物中的用途。
背景技术
糖尿病(diabetes mellitus)是一组由遗传和环境因素相互作用而引起的临床综合症。目前,一般将糖尿病分为两类,I型糖尿病(胰岛素依赖型糖尿病,insulin-dependent diabetes mellitus,IDDM)与II型糖尿病(非胰岛素依赖型糖尿病,non-insulin-dependent diabetes mellitus,NIDDM)。糖尿病中90%以上是II型糖尿病。
II型糖尿病的特点是胰岛素敏感组织如骨骼肌、肝、脂肪组织对胰岛素作用的抵抗。蛋白酪氨酸磷酸酯酶(PTPases)在平衡细胞内胰岛素作用通路中相关蛋白酪氨酸磷酸化水平中的作用越来越受到重视,成为治疗II型糖尿病的新途径。PTPase包括一大族跨膜(受体型)和胞内(非受体型)酶,参与调控一系列重要生命过程。目前,对PTPase在胰岛素通路中受体或受体后环节影响正常胰岛素作用的研究,主要集中在LAR-PTPase、SHPTP-2、PTP1B。
PTP1B是最早被纯化和确定生物学特性的PTPase,全长大约50KD。早期研究证明能在体外有效地将胰岛素受体去磷酸化;随后发现PTP1B在所有胰岛素敏感组织中高表达;最近有研究表明,PTP1B直接与激活状态的IR相互作用;PTP1B能够负调控胰岛素信号转导通路并主要作用于胰岛素受体。更重要的实验证据来自PTP1B基因敲除小鼠。Elchebly等报道,运用同源重组的方法产生的PTP1B基因敲除的小鼠生长正常,有生殖力,对胰岛素敏感性显著增强,而且这一增强作用与肝脏和骨骼肌中胰岛素受体及胰岛素 受体底物1磷酸化水平的增强相关[Elchebly M.等.Science,283,1544-1548]。令人惊奇的是,PTP1B基因敲除的小鼠对食物诱导的体重增加和胰岛素抵抗也有抵抗作用。Klaman等运用大致相同的方法产生的PTP1B基因敲除的小鼠也得到同样的结果,而且发现PTP1B基因敲除的小鼠之所以对食物诱导的体重增加有抵抗作用,是由于脂肪细胞体积的减少,而脂肪细胞的数量并不改变。PTP1B基因敲除的小鼠基本代谢水平和总体能量消耗升高[Klaman L.D.等.Molecular and Cellular Biology,20(15):5479-5489]。这些实验更加有力地证明了PTP1B在胰岛素敏感性、能量消耗和脂肪储存方面的重要作用,从而更加明确了它是治疗II型糖尿病和肥胖症的一个潜在药物作用靶点。
PTP1B选择性抑制剂的研究取得了一定的进展,但大多局限于一些肽类或非肽类化合物,例如基于PTP1B去磷酸化的底物序列设计的抑制剂EEDE(F2PMP)M(Ki=7.2nM)、Glu-F2PMP-F2PMP(IC50=40nM),虽然这些肽类抑制剂具有较强的抑制活性及较高的选择性,但它们是肽类磷酸化合物的事实使其很难成为药物候选化合物。最近,一系列非肽类非磷酸化合物类PTP1B抑制剂被报道,它们具有一定的选择性,更重要的是,其中一些化合物对降低ob/ob小鼠血浆中葡萄糖和胰岛素水平有显著作用。这是第一例药理学的直接证据,证明PTP1B抑制剂具有抗糖尿病活性[Malamas,M.S.等.J.Med.Chem.,2000,43,1293-1310]。这些无疑为寻找新的小分子非肽类有机化合物作为高效、高选择性PTP1B抑制剂提供了机遇。
发明内容
文献检索表明,从豆荚软珊瑚属软珊瑚Lobophytum cristatum中分离得到的豆荚甲素、乙素、丙素、丁素、戊素或己素是结构新颖的二萜类化合物。经体外抗蛋白酪氨酸磷酸酯酶1B(PTP1B)活性筛选实验表明,豆荚甲素、乙素、丙素、丁素、戊素或己素对PTP1B具有显著的抑制活性。
因此,本发明的一个目的是提供一类从豆荚软珊瑚属软珊瑚Lobophytum cristatum中分离得到的结构新颖二萜类化合物豆荚甲素、乙素、丙素、丁素、戊素或己素。
本发明的另一目的是提供上述豆荚甲素、乙素、丙素、丁素、戊素或己素的制备方法。
本发明的又一目的是提供上述豆荚甲素、乙素、丙素、丁素、戊素或己素在制备药物中的用途。具体地,包括其在制备蛋白酪氨酸磷酸酯酶1B(PTP1B)抑制剂的药物中的用途;在制备胰岛素增敏剂的药物中的用途;从而在制备治疗II型糖尿病、肥胖症及其并发症的药物中的用途。
本发明提供的豆荚甲素、乙素、丙素、丁素、戊素或己素具有如下的化学结构式:其中,“ ”表示该位置手性碳的构型为R型或S型。
上述的6个化合物为结构新颖的化合物,分别命名为豆荚甲素、乙素、丙素、丁素、戊素和己素。
本发明还提供了上述的二萜类化合物豆荚甲素、乙素、丙素、丁素、戊素和己素的制备方法,具体地,是从豆荚软珊瑚属软珊瑚L.cristatum中提取分离化合物豆荚甲素、乙素、丙素、丁素、戊素和己素的方法,步骤如下:
步骤1)-提取:
将软珊瑚Lobophytum cristatum用酮溶剂提取,所得提取液浓缩后得粗浸膏;将该粗浸膏溶于水中,混悬均匀后用乙醚萃取,所得萃取液浓缩后得到乙醚浸膏;
步骤2)-分离:
将步骤1)中得到的乙醚浸膏进行硅胶柱层析,以石油醚/乙醚进行梯度洗脱;其中,体积比为95∶5的石油醚/乙醚的洗脱部分,经进一步硅胶柱层析,以体积比为98∶2的石油醚/乙醚洗脱,分离出豆荚丙素和丁素;体积比为90∶10的石油醚/乙醚洗脱部分,经进一步硅胶柱层析,以体积比为95∶5的 石油醚/乙醚洗脱后采用填料为ODS-C18反相材料、流动相为甲醇/水的半制备高效液相色谱分离得到豆荚甲素、乙素、戊素和己素;
在步骤1)中,所述酮溶剂为丙酮,所述的提取是采用超声提取。
在所述步骤2)中,所述石油醚/乙醚梯度洗脱是以石油醚/乙醚的体积比为100∶0→95∶5→90∶10→80∶20→50∶50→20∶80→0∶100进行梯度洗脱。
本发明对所得豆荚甲素、乙素、丙素、丁素、戊素和己素进行了蛋白酪氨酸磷酸酯酶1B抑制活性实验,表明其对PTP1B有明显的抑制活性,因而其为PTP1B抑制剂和胰岛素增敏剂。因此,本发明还提供了豆荚甲素、乙素、丙素、丁素、戊素和己素在制备治疗II型糖尿病、肥胖症及其并发症的药物中的用途。
本发明还提供一种药物组合物,其含有一种或多种治疗有效量的所述的二萜类化合物豆荚甲素、乙素、丙素、丁素、戊素或己素作为有效成分,并含有常规药用载体。
具体实施方式
下面结合实施例对本发明作进一步阐述,但本发明不限于此。
用Varian Mercury 400型核磁共振仪测定1H和13C-NMR;用Finnigan-MAT-95型质谱仪测定MS(EIMS及HREIMS);用Perkin-Elmer241MC型偏光计测定旋光值;所使用的硅胶为青岛海洋化工厂生产;各种溶剂均由国药集团试剂有限公司生产,均为分析纯。
如无特殊说明,以下实施例中涉及到的液/液之间比值均为体积比。
实施例1:二萜类化合物豆荚甲素、乙素、丙素、丁素、戊素和己素的制备
(1)提取:将干重为210.0g的中国南海豆荚软珊瑚属软珊瑚Lobophytum cristatum用丙酮(3000ml)超声提取3次,提取液合并后减压浓缩得到粗浸膏,将所得粗浸膏混悬于500ml水中。以乙醚(1000ml)萃取该混悬液3次,所得萃取液合并后减压浓缩得到乙醚浸膏5.4g。
(2)分离:乙醚浸膏5.4g经200-300目硅胶柱层析,用石油醚/乙醚(100∶0→95∶5→90∶10→80∶20→50∶50→20∶80→0∶100)进行梯度洗脱,每个梯度的洗脱液用量为1000ml。其中,石油醚/乙醚(90∶10)洗脱液浓缩物得625.3mg,该部分经硅胶柱层析,用石油醚/乙醚95∶5洗脱,继而经半制备高效液 相色谱分离,填料为ODS-C18反相材料,用甲醇/水98∶2洗脱,分别得到豆荚甲素11.7mg,豆荚乙素10.6mg,豆荚戊素7.7mg和豆荚己素8.5mg;石油醚/乙醚(95∶5)洗脱液浓缩物得274.1mg,该部分经硅胶柱层析,用石油醚/乙醚(98∶2)洗脱,得到豆荚丙素9.0mg和豆荚丁素8.8mg。
豆荚甲素(Lobophytumi nA)的理化性状如下:无色油状物;[α]D 25+116(c1.10,CHCl3);1H NMR(CDCl3,300MHz)δ6.02(1H,s,H-14),δ5.78(1H,d,J=15.9Hz,H-5),δ5.18(1H,dd,J=15.9,9.9Hz,H-6),δ5.10(1H,m,H-1),δ4.76(1H,brs,H-16b),δ4.74(1H,brs,H-16a),δ2.51(1H,dd,J=15.4,3.9Hz,H-12b),δ2.36(1H,m,H-8b),δ2.26(1H,m,H-9b),δ2.20(1H,m,H-9a),δ2.11(3H,s,H3-20),δ2.07(3H,m,H-3a,H-3b,H-11),δ2.05(1H,m,H-12a),δ2.04(1H,m,H-7),δ1.97(1H,m,H-8a),δ1.85(3H,s,H3-19),δ1.55(1H,m,H-2b), 1.49(3H,s,H3-17), 1.38(1H,m,H-2a), 0.87(3H,d,J=6.7,H3-18);13CNMR(见表1);HREIMS m/z 286.2281.
豆荚乙素(Lobophytumin B)的理化性状如下:无色油状物;[α]D 25+46.6(c 1.10,CHCl3);1H NMR(CDCl3,300MHz)δ5.78(1H,d,J=16.0Hz,H-5),δ5.16(1H,dd,J=15.9,9.8Hz,H-6),δ5.10(1H,m,H-1),δ4.76(1H,brs,H-16b),δ4.74(1H,brs,H-16a),δ2.51(1H,m,H-12b),δ2.36(1H,m,H-8b),δ2.26(1H,m,H-9b),δ2.26(2H,d,J=6.6Hz,H2-14),δ2.20(1H,m,H-9a),δ2.11(3H,s,H3-20),δ2.07(3H,m,H-3a,H-3b,H-11),δ2.05(1H,m,H-12a),δ2.04(1H,m,H-7),δ1.97(1H,m,H-8a),δ1.55(1H,m,H-2b),δ1.49(3H,s,H3-17),δ1.38(1H,m,H-2a),δ0.89(3H,d,J=7.0,H3-19),δ0.88(3H,d,J=7.0,H3-20),δ0.87(3H,d,J=6.7,H3-18);13C NMR(见表1);HREIMS m/z288.2447.
豆荚丙素(Lobophytumin C)的理化性状如下:无色油状物;[α]D 25-36.6(c 0.45,CHCl3);1H NMR(CDCl3,300MHz)δ5.13(1H,m,H-14),δ4.80(1H,brs,H-18b),δ4.74(1H,brs,H-18a),δ4.71(1H,brs,H-16b),δ4.44(1H,brs,H-16a),δ2.31(1H,m,H-3b),δ2.13(2H,m,H2-13),δ2.08(2H,m,H2-12),δ2.01(1H,m,H-3a),δ1.95(1H,m,H-7),δ1.81(1H,m,H-5),δ1.69(3H,s,H3-19),δ1.62(3H,s,H3-20),δ1.61(2H,m,H2-8),δ1.59(1H,m,H-6b),δ1.58(2H,m,H2-2),δ1.53(1H,m,H-9b),δ1.51(1H,m,H-9a),δ1.45(1H,m,H-1b),δ1.27(1H,m,H-6a),δ1.26(1H,m,H-1a),δ0.76(3H,s,H3-17);13C NMR(见 表1);HREIMS m/z 272.2488.
豆荚T素(Lobophytumin D)的理化性状如下:无色油状物;[α]D 25+7.2(c0.48,CHCl3);1H NMR(CDCl3,300MHz)δ5.32(1H,brs,H-3),δ5.13(1H,m,H-14),δ4.80(1H,brs,H-18b),δ4.74(1H,brs,H-18a),δ2.13(2H,m,H2-13),δ2.09(1H,m,H-2b),δ2.07(2H,m,H2-12),δ1.96(1H,m,H-2a),δ1.95(1H,m,H-7),δ1.91(1H,m,H-5),δ1.78(1H,m,H-6b),δ1.70(3H,s,H3-19),δ1.62(3H,s,H3-20),δ1.61(3H,s,H3-16),δ1.56(2H,m,H2-8),δ1.35(2H,m,H2-9),δ1.45(1H,m,H-1b),δ1.19(1H,m,H-1a),δ1.15(1H,m,H-6a),δ0.90(3H,s,H3-17); 13C NMR(见表1);HREIMS m/z 272.2488.
豆荚戊素(Lobophytumin E)的理化性状如下:无色油状物;[α]D 25+61.5(c 0.53,CHCl3);1H NMR(CDCl3,300MHz)δ6.03(1H,s,H-14),δ4.72(1H,brs,H-16b),δ4.69(1H,brs,H-16a),δ2.52(1H,m,H-3b),δ2.44(1H,dd,J=15.2,2.6Hz,H-12b),δ2.41(1H,m,H-5),δ2.32(1H,m,H-1),δ2.26(1H,m,H-3a),δ2.13(3H,s,H3-20),δ2.09(1H,m,H-12a),δ1.91(1H,m,H-2b),δ1.86(3H,s,H3-19),δ1.85(1H,m,H-8b),δ1.72(1H,m,H-11),δ1.63(1H,m,H-7),δ1.60(1H,m,H-8a),δ1.59(1H,m,H-2a),δ1.52(1H,m,H-6),δ1.00(3H,s,H3-17),δ0.85(3H,d,J=6.2,H3-18);13C NMR(见表1);HREIMS m/z 286.2296.
豆荚己素(Lobophytumin F)的理化性状如下:无色油状物;[α]D 25+52.2(c 0.43,CHCl3);1H NMR(CDCl3,300MHz)δ4.73(1H,brs,H-16b),δ4.69(1H,brs,H-16a),δ2.53(1H,m,H-3b),δ2.44(1H,m,H-5),δ2.43(1H,dd,J=15.3,2.7Hz,H-12b),δ2.32(1H,m,H-1),δ2.27(1H,m,H-3a),δ2.24(2H,d,J=6.6Hz,H-14),δ2.13(1H,m,H-12),δ2.12(1H,m,H-12a),δ1.92(1H,m,H-2b),δ1.82(1H,m,H-8b),δ1.74(1H,m,H-11),δ1.63(1H,m,H-7),δ1.60(1H,m,H-8a),δ1.55(1H,m,H-2a),δ1.46(1H,m,H-6),δ0.99(3H,s,H3-17),δ0.90(3H,d,J=6.5,H3-20),δ0.89(3H,d,J=6.5,H3-19),δ0.84(3H,d,J=6.4,H3-18);13C NMR(见表1);HREIMS m/z 288.2459.
表1豆荚甲素、乙素、丙素、丁素、戊素和己素的13C NMR数据
实施例2:二萜类化合物豆荚甲素、乙素、丙素、丁素、戊素和己素的PTP1B抑制活性实验
测试原理:对硝基苯磷酸(p-Nitrophenyl phosphate,pNPP)是碱性磷酸酶的可溶性底物,在人源蛋白酪氨酸磷酸酶1B(hPTP1B)的催化下,它脱去一个磷酸根,生成黄色可溶产物对硝基苯酚(p-Nitrophenol),该产物在410nM处有光吸收,通过检测410nM处光吸收的增加可以检测碱性磷酸酶(在本文中特指人源蛋白酪氨酸磷酸酶1B(hPTP1B))的活性。
对硝基苯磷酸 对硝基苯酚
标准的测活体系:10mM Tris.Cl(Tris(hydroxymethyl)aminomethane hydrochloride,即三(羟甲基)氨基甲烷盐酸盐)(pH 7.6)、10mM pNPP、2%DMSO(dimethyl sulphoxide,即二甲基亚砜)和100nM hPTP1B。
测试方法:用于筛选的蛋白酪氨酸磷酸酯酶PTP1B是从大肠杆菌中表达并纯化的GST(glutathione S-transferases,即谷胱甘肽S-转移酶)融合蛋白。采用紫外适用底物pNPP,观察不同化合物对重组的PTP1B活性的抑制作用,以初步评价化合物的药用效果。临用前将样品溶于DMSO配成适当浓度,如3倍稀释或7倍稀释度的样品溶液,设置三复孔,取2μL样品溶液加入96孔板,然后加入88μL测试混合物(assay mix)(测试缓冲液(assay buffer)78μL、10×pNPP(2685μM)10μL),再加入10μL PTP1B。将96孔板置于VERSAmax上动态检测波长为410nm处的Vmax值,时间为3分钟,其动力学曲线一级反应的斜率作为酶的活性指标。通过下面的公式计算样品的抑制率(%):
抑制率(%)=[1-Vmax(待测样品)/Vmax(空白对照)]×100%
实验结果的评判与解释:根据化合物浓度为10μg/ml时对酶活性的抑制率(%)来评价其对PTP1B的抑制活性。抑制率(%)高于50%时,按常规筛选(将抑制率高于50%的被检测化合物稀释成不同的浓度,依上述测试方法进行反应,所有试验均设置复孔)得出IC50,阳性对照正钒酸钠的IC50为2μM。实验结果如表2所示。
表2豆荚甲素、乙素、丙素、丁素、戊素和己素的PTP1B抑制活性
化合物 | 豆荚甲素 | 豆荚乙素 | 豆荚丙素 | 豆荚丁素 | 豆荚戊素 | 豆荚己素 |
IC50(μg/ml) | 3.45±0.03 | 4.44±1.22 | 1.69±0.11 | 2.11±0.23 | 3.02±0.75 | 6.88±0.30 |
结论:豆荚甲素、乙素、丙素、丁素、戊素和己素均对PTP1B显示不同程度的抑制活性。因此,豆荚甲素、乙素、丙素、丁素、戊素或己素可作为PTP1B抑制剂和胰岛素增敏剂,从而可将豆荚甲素、乙素、丙素、丁素、戊素或己素用于制备治疗II型糖尿病、肥胖症及其并发症的药物中。
Claims (9)
2.权利要求1所述的二萜类化合物豆荚甲素、乙素、丙素、丁素、戊素或己素的制备方法,其特征是,该方法包括以下步骤:
1)-提取:将软珊瑚Lobophytum cristatum用酮溶剂提取,所得提取液浓缩后得粗浸膏;将该粗浸膏溶于水中,混悬均匀后用乙醚萃取,所得萃取液浓缩后得到乙醚浸膏;
2)-分离:将步骤1)中得到的乙醚浸膏进行硅胶柱层析,以石油醚/乙醚进行梯度洗脱;其中,体积比为95∶5的石油醚/乙醚的洗脱部分,经进一步硅胶柱层析,以体积比为98∶2的石油醚/乙醚洗脱,分离出豆荚丙素和丁素;体积比为90∶10的石油醚/乙醚洗脱部分,经进一步硅胶柱层析,以体积比为95∶5的石油醚/乙醚洗脱后采用填料为ODS-C18反相材料、流动相为甲醇/水的半制备高效液相色谱分离得到豆荚甲素、乙素、戊素和己素。
3.根据权利要求2所述的制备方法,其特征是,在步骤1)中,所述的酮溶剂为丙酮。
4.根据权利要求2所述的制备方法,其特征是,在步骤1)中,所述的酮溶剂提取是采用超声提取。
5.根据权利要求2所述的制备方法,其特征是,在步骤2)中,所述石油醚/乙醚梯度洗脱是以石油醚/乙醚的体积比为100∶0→95∶5→90∶10→80∶20→50∶50→20∶80→0∶100进行梯度洗脱。
6.权利要求1所述的二萜类化合物豆荚甲素、乙素、丙素、丁素、戊素或己素在制备蛋白酪氨酸磷酸酯酶1B抑制剂的药物中的用途。
7.权利要求1所述的二萜类化合物豆荚甲素、乙素、丙素、丁素、戊素或己素在制备胰岛素增敏剂的药物中的用途。
8.权利要求1所述的二萜类化合物豆荚甲素、乙素、丙素、丁素、戊素或己素在制备治疗II型糖尿病、肥胖症或其并发症的药物中的用途。
9.一种药物组合物,其特征是,含有一种或多种治疗有效量的权利要求1所述的二萜类化合物豆荚甲素、乙素、丙素、丁素、戊素或己素作为有效成分,并含有常规药用载体。
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102731242A (zh) * | 2011-04-12 | 2012-10-17 | 中国科学院上海药物研究所 | 二萜化合物豆荚丙素或丁素及其在制备药物中的用途 |
CN107021942A (zh) * | 2016-02-01 | 2017-08-08 | 复旦大学 | 大别山五针松的树皮提取物及其制备方法和在制药中的用途 |
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CN108484542A (zh) * | 2018-05-16 | 2018-09-04 | 浙江医药高等专科学校 | 一种具有降血糖活性的叉甲基丁内酯二萜化合物及其制备方法与应用 |
CN109134184A (zh) * | 2017-06-16 | 2019-01-04 | 中国科学院上海药物研究所 | 二萜类化合物、其制备方法及用途 |
CN109125301A (zh) * | 2017-06-16 | 2019-01-04 | 中国科学院上海药物研究所 | 一种二萜类化合物在制备治疗糖尿病或肥胖症的药物中的用途 |
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---|---|---|---|---|
CN102731242A (zh) * | 2011-04-12 | 2012-10-17 | 中国科学院上海药物研究所 | 二萜化合物豆荚丙素或丁素及其在制备药物中的用途 |
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102731242A (zh) * | 2011-04-12 | 2012-10-17 | 中国科学院上海药物研究所 | 二萜化合物豆荚丙素或丁素及其在制备药物中的用途 |
Non-Patent Citations (2)
Title |
---|
SHI-YIE CHENG ET AL.: "Antiviral and anti-inflammatory Diterpenoids from the Soft Coral Sinularia gyrosa", 《JOURNAL OF NATURAL PRODUCTS》 * |
STEVEN E. POET ET AL.: "Three New Diterpenes from a Soft Coral Nephthea Species", 《AUSTRALIAN JOURNAL OF CHEMISTRY》 * |
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