CN114057764A - 具有抗炎活性的乌药烷型二聚倍半萜及其制备方法和用途 - Google Patents
具有抗炎活性的乌药烷型二聚倍半萜及其制备方法和用途 Download PDFInfo
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- CN114057764A CN114057764A CN202111486837.8A CN202111486837A CN114057764A CN 114057764 A CN114057764 A CN 114057764A CN 202111486837 A CN202111486837 A CN 202111486837A CN 114057764 A CN114057764 A CN 114057764A
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Abstract
本发明属于植物化学和药物领域,涉及具有抗炎活性的乌药烷型二聚倍半萜sarcglabralides A–C及其制备方法和用途,还涉及含有作为活性药物成分的sarcglabralides A–C的药物组合物,以及sarcglabralides A–C的制药用途。本发明的乌药烷型二聚倍半萜sarcglabralides A–C具有较好的抗炎活性,可以用于治疗炎性疾病。
Description
技术领域
本发明属于植物化学和药物技术领域,具体而言,涉及三个具有抗炎活性的乌药烷型二聚倍半萜sarcglabralides A–C,含有其中任一种或两种或三种组合的药物组合物,还涉及化合物sarcglabralides A–C的制备方法,及其在制备用于抗炎药物中的应用。
背景技术
炎症是具有血管***的活体组织对内源性或外源性刺激所做出的一种主动防御反应。正常生理条件下,适度可控的炎症可帮助机体清除和修复损伤。在病理条件下,不可控和过度的炎症又会导致组织和器官的损伤。长期持续的慢性炎症对人体健康有许多危害,如:诱导癌症的发生—幽门螺旋杆菌感染性炎症、EB病毒感染性炎症、肝炎病毒炎症分别与胃癌、鼻咽癌和肝癌相关;危及心血管健康—血管中脂肪斑块引发的慢性炎症能形成血栓最终导致肺动脉高压、慢性阻塞性肺疾病、肺气肿和心脏病等;诱发阿尔茨海默氏症—随着年龄增大,炎症反应导致免疫***的调控机制发生紊乱,增加早老年痴呆的发生;此外,长期过度的炎症反应还能引起糖尿病及其并发症、帕金森氏病、黄斑变性和骨关节炎等。随着城镇化、老龄化进程的不断加快和生活方式的改变、炎性疾病已成为影响全球人群健康的重要威胁之一,正在全球范围蔓延并且已演变成严重危害人类健康和社会经济可持续发展的重要公共卫生问题。
炎症反应涉及到一系列生理病理变化:如受损组织毛细血管通透性增高,花生四烯酸代谢产物及血小板活化因子的释放,炎症因子(IL-1、 IL-6、TNF-α、组胺、5-羟色胺)的释放等,这些生理病理变化组成了炎症反应网络。NO(一氧化氮)在炎症反应中起到关键调节作用,尤其是在炎症反应的发生和信号传导方面。NO是一氧化氮合酶(NOS)催化L-精氨酸生成后,作用到自生细胞,或扩散到邻近细胞,结合到其目的受体(转录因子、蛋白激酶等),从而发挥一系列调节作用。在免疫性炎症进程中,体内NO在高浓度状态下,能激活NF-κB,诱导促炎症细胞因子TNF-α、 IL-1β等的产生,IL-1和TNF-α的产生又能激活iNOS(诱导型一氧化氮合酶),促进机体产生更多的NO,使细胞因子的分泌以及其NO自生表达得以持续,使炎症反应更持久,更剧烈。故在炎症反应中抑制NO的生成能使炎症症状得到改善。
目前,炎症的治疗主要为甾体类(糖皮质激素类:如***、强的松、氢化可的松等)和非甾体类(NSAIDS:如阿司匹林、布洛芬、吲哚美辛等)化学合成药,它们都具有多种副作用,如:胃肠道反应、心脏毒性、肝毒性、肾毒性和免疫功能障碍等。因此,继续寻找新的抗炎先导化合物,研究开发具有疗效好、副作用小的抗炎药物,是必要且迫切的。
天然产物在自然界中经过长期而漫长的进化过程,其化学结构的新颖性和生物活性的多样性是药物研发的重要资源之一,从天然产物中寻找具有抗炎活性的先导化合物有着巨大的潜力。
发明内容:
有鉴于此,本发明的目的在于三个新的乌药烷型二聚倍半萜天然产物,即化合物sarcglabralide A、sarcglabralide B和sarcglabralide C,以及该三个化合物作为活性成分在制备治疗抗炎药物中的应用,为炎性疾病的治疗提供疗效好、副作用小的天然产物。
本发明的目的可以通过以下技术方案来实现。
在第一方面,本发明提供了乌药烷型二聚倍半萜,即化合物 sarcglabralides A、B和C,其分别具有下述式I、Ⅱ和Ⅲ所示的结构式:
在第二方面,本发明提供了用于治疗炎性疾病的药物组合物,其包含作为活性药物成分的乌药烷型二聚倍半萜化合物sarcglabralides A、B 或C或其组合,或其药学上可接受的衍生物,以及药学上可接受的载体、佐剂和赋形剂。
在第三方面,本发明涉及乌药烷型二聚倍半萜化合物sarcglabralides A、B或C或其药学上可接受的衍生物在制备用于治疗炎性疾病的药物中的应用。
在第四方面,本发明提供了制备乌药烷型二聚倍半萜化合物 sarcglabralidesA、B或C的方法,包括以下步骤:
1)将草珊瑚属(Sarcandra)植物材料干燥、粉碎,采用有机溶剂提取后脱溶,得到草珊瑚属植物材料提取物;
2)对所述草珊瑚属植物材料提取物依次采用柱层析、中压分离凝胶及半制备高压液相色谱得到化合物sarcglabralides A–C。
在优选的实施方案中,有机溶剂包括石油醚、氯仿、二氯甲烷、乙酸乙酯、丙酮、乙醇、甲醇、正丁醇、乙腈和甲酸中的至少一种。
与现有技术相比,本发明具有明显的有益效果。具体而言,本发明的乌药烷型二聚倍半萜sarcglabralides A–C,具有显著的抗炎活性,可以用于治疗炎性疾病。
附图说明
图1为本发明乌药烷型二聚倍半萜化合物sarcglabralides A–C的化学结构式。
图2为本发明化合物乌药烷型二聚倍半萜sarcglabralides A–C确定绝对构型的ECD(电子圆二色谱)计算结果图。
具体实施方式
为了便于理解本发明,下面将对本发明进行更全面的描述,并给出了本发明的优选实施方案。但是,本发明可以以许多不同的形式来实现,并不限于本文所描述的实施方案。相反,提供这些实施方案的目的是使对本发明公开内容的理解更加透彻全面。
除非另有定义,本文所使用的所有的技术和科学术语与本发明所属技术领域的技术人员通常理解的含义相同。在本发明的说明书中所用的术语只是为了描述具体的实施方案的目的,并非旨在限制本发明的范围。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
根据第一方面,本发明提供了乌药烷型二聚倍半萜化合物 sarcglabralides A、B和C,其结构式分别如下式I、Ⅱ和Ⅲ所示:
根据本发明的第二方面,本发明提供了用于治疗炎性疾病的药物组合物,其包含作为活性药物成分的乌药烷型二聚倍半萜化合物 sarcglabralides A、B或C或其药学上可接受的衍生物,以及药学上可接受的载体、佐剂或赋形剂。
在本发明药物组合物的实施方案中,炎性疾病包括但不限于:皮肤炎症、风湿性疾病、心血管疾病及自身免疫病等。
在本发明药物组合物的实施方案中,作为活性成分的乌药烷型二聚倍半萜可以是化合物sarcglabralides A–C中的任一种、任意两种或三种。
本领域技术人员应当理解,本发明的化合物sarcglabralides A–C的药学上可接受的衍生物,例如化合物sarcglabralides A–C的盐、溶剂化物或水合物也可以用于本发明的药物组合物中。
药学上可接受的盐可以是例如药学上可接受的加碱成盐。
药学上可接受的加碱成盐包括衍生自诸如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝等无机碱的盐。衍生自药学上可接受的无毒有机碱的盐包括伯胺、仲胺和叔胺的盐,包括天然存在的取代胺、环胺和碱性离子交换树脂,例如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺以及乙醇胺和三乙醇胺。
因此,在本发明药物组合物的实施方案中,活性药物成分可以是sarcglabralides A–C中的任一种化合物、任意两种或三种的混合物或其碱加成盐、溶剂化物、水合物等衍生物。
合适的药物赋形剂是本领域技术人员众所周知的。药用载体或赋形剂是一种或多种固体、半固体和液体稀释剂、填料以及药物制品辅剂,包括但不仅限于填充剂(稀释剂)、润滑剂(助流剂或抗粘着剂)、分散剂、湿润剂、粘合剂、增溶剂、抗氧剂、抑菌剂、乳化剂、崩解剂等。粘合剂包括糖浆、***胶、明胶、山梨醇、黄芪胶、纤维素及其衍生物(如微晶纤维素、羧甲基纤维素钠、乙基纤维素或羟丙甲基纤维素等)、明胶浆、糖浆、淀粉浆或聚乙烯吡咯烷酮等;填充剂包括乳糖、糖粉、糊精、淀粉及其衍生物、纤维素及其衍生物、无机钙盐(如硫酸钙、磷酸钙、磷酸氢钙、沉降碳酸钙等)、山梨醇或甘氨酸等;润滑剂包括微粉硅胶、硬脂酸镁、滑石粉、氢氧化铝、硼酸、氢化植物油、聚乙二醇等;崩解剂包含淀粉及其衍生物(如羧甲基淀粉钠、淀粉乙醇酸钠、预胶化淀粉、改良淀粉、羟丙基淀粉、玉米淀粉等)、聚乙烯吡咯烷酮或微晶纤维素等;湿润剂包括十二烷基硫酸钠、水或醇等;抗氧剂包括亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、二丁基苯酸等;抑菌剂包括0.5%苯酚、0.3%甲酚、 0.5%三氯叔丁醇等;乳化剂包括聚山梨酯-80、没酸山梨坦、卵磷酯、豆磷脂等;增溶剂包括吐温-80、胆汁、甘油等。
本发明的乌药烷型二聚倍半萜用作药物时,可以直接施用,或者以药物组合物的形式施用。在本发明的药物组合物中,按药物组合物总重量计,药物组合物可以含有0.1–99%的sarcglabralides A、B或C,优选为 0.5–90%。
乌药烷型二聚倍半萜化合物Sarcglabralides A、B或C或其药学上可接受的衍生物例如碱加成盐的“有效量”是指,足以实现所需生物学效果的量。应当理解,有效剂量会取决于接受者的年龄、性别、健康状况和体重。通常,有效量由施用治疗的人例如治疗医师来决定。
本发明的药物组合物可以以单位体重服用量的形式施用。所有以乌药烷型二聚倍半萜sarcglabralides A–C或其药学上可接受的衍生物例如碱加成盐为有效成分的药物组合物采用制药和食品领域公认的方法制备成各种剂型,例如液体制剂(注射剂、混悬剂、乳剂、溶液剂、糖浆剂等)、固体制剂(片剂、胶囊剂、颗粒剂、冲剂等)、喷剂、气雾剂等。本发明的药物组合物可经注射(静脉注射、静脉滴注、肌肉注射、腹腔注射、皮下注射)和口服、舌下给药、粘膜透析等给药途径进行炎性疾病的治疗。
根据第三方面,本发明提供了本发明的乌药烷型二聚倍半萜化合物sarcglabralides A–C或其药学上可接受的衍生物在制备用于治疗炎性疾病的药物中的用途。
在本发明的实施方案中,炎性疾病包括但不限于:皮肤炎症、风湿性疾病、心血管疾病及自身免疫病等。
根据第四方面,本发明提供了制备乌药烷型二聚倍半萜化合物 sarcglabralidesA–C的方法,包括以下步骤:
1)将草珊瑚属(Sarcandra)植物材料干燥、粉碎,采用有机溶剂浸提后脱溶,得到草珊瑚属植物提取物;
2)对所述草珊瑚属植物提取物依次采用柱层析、中压色谱分离凝胶及半制备高效液相色谱,得到sarcglabralides A–C。
在具体实施方案中,草珊瑚属植物材料可以是草珊瑚属植物的各部位,例如根、茎、枝叶或果实,或全株植物。在本发明的实施方案中,草珊瑚属植物材料可以是草珊瑚(S.glabra)、海南草珊瑚(S.hainanensis) 植物的各部位(例如根、茎、枝叶或果实)或全株。在本发明优选的实施方案中,草珊瑚植物材料来自草珊瑚(S.glabra)。
在本发明的实施方案中,步骤1)提取所用有机溶剂包括石油醚、氯仿、二氯甲烷、乙酸乙酯、丙酮、乙醇、甲醇、正丁醇、乙腈、和甲酸中的至少一种,优选,有机溶剂为甲醇、乙酸乙酯或95%乙醇。
在本发明的实施方案中,提取方法可以是有机溶剂冷浸提取、加热回流提取或超声提取等。
在本发明的实施方案中,用有机溶剂对草珊瑚属植物材料进行提取次数为至少1次,例如2、3、4次,优选3次。
在本发明的实施方案中,有机溶剂与干燥的草珊瑚属植物材料的体积比为1:1到5:1,例如1:1、2:1、3:1、4:1、5:1,以及上述任意两个比例之间的比例,例如1.5:1、2.5:1、3.5:1、4.5:1等,优选为3:1。
在本发明的具体实施方案中,步骤2)具体包括:
在本发明的具体实施方案中,在步骤2)中,所述柱层析包括正相硅胶柱层析、反相硅胶柱层析(例如RP-18)、凝胶柱层析(例如Sephadex LH-20)、中压色谱分离凝胶(例如MCIGel CHP20P)和制备或半制备高效液相色谱(HPLC)。
在本发明的具体实施方案中,在步骤2)中,柱层析所用洗脱剂包括石油醚、氯仿、二氯甲烷、乙酸乙酯、丙酮、乙醇、甲醇、正丁醇、乙腈、水和甲酸中的一种或任意两种的组合;正相硅胶柱层析采用石油醚和乙酸乙酯按体积比从1:0到0:1梯度洗脱,例如1:0、50:1、25:1、10:1、 5:1、0:1;或正相硅胶柱层析采用氯仿和甲醇按体积比从100:1到1:1梯度洗脱,例如100:1、50:1、30:1、10:1、1:1;反相RP-18柱层析采用甲醇和水按体积比从2:8到1:0梯度洗脱;凝胶柱层析,例如Sephadex LH-20 凝胶柱层析,采用甲醇、氯仿-甲醇(v:v 1:1)洗脱;中压色谱分离凝胶(MCI Gel)采用甲醇和水按体积比从2:8到1:0梯度洗脱;制备或半制备HPLC 采用乙腈和水按体积比从2:8到6:4梯度洗脱。
下面结合实施例对本发明的优选实施方式进行详细说明。需要理解的是以下实施例的给出仅是为了起到说明的目的,并不是用来限制本发明的保护范围。本领域的技术人员在不背离本发明的宗旨和精神的情况下,可以对本发明进行各种修改和替换,所有这些修改和替换都落入了本发明权利要求书请求保护的范围内。
下述实施例中所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,均可通过商业途径获得。
Agilent UPLC/Q-Tof液质联用仪测定;紫外光谱(UV)在甲醇中用ShimazuUV-2401PC紫外光谱仪测定;HPLC分析和制备用Agilent 1260 型或1100型高效液相色谱仪,色谱柱为AgilentZORBAX-SB-C18层析在下述实施例中,1H,13C NMR和2D NMR谱在BrukerDRX-500核磁共振仪上测定;电喷雾电离质谱(ESI-MS)由Waters XevoTQ-S三重四极杆串联质谱联用仪或Bruker HTC/Esquire液相-离子阱色谱质谱联用仪测定;高分辨质谱(HR-ESI-MS)由柱(5μm;4.6×150mm)或Agilent ZORBAX-SB-C18层析柱(5μm;9.4×250mm);柱层析用正相硅胶 (200–300目)及薄层层析板均为青岛海洋化工厂产品;薄层层析通过10% FeCl3-乙醇溶液观察其斑点;Sephadex LH-20为GE Healthcare公司产品;反相材料Rp-8及Rp-18为Merck公司产品。MCI Gel CHP20P为日本三菱化学产品。
实施例1:化合物sarcglabralides A–C的制备方法一
草珊瑚(S.glabra)根(干燥),粉碎后用乙酸乙酯在室温下按有机溶剂和植物材料的体积比为3:1,冷浸提取4次,2天/次,合并提取液后减压蒸馏得到膏状提取物。膏状提取物经硅胶柱层析,用石油醚-乙酸乙酯梯度洗脱(40:1→1:1,v/v),得到6个组分(Fr.1–Fr.6)。将收集得到的Fr.4部分经过RP-18反相柱层析,用甲醇-水梯度洗脱(2:8→1:0,v/v),得到6 个组分Fr.4.1–Fr.4.6。Fr.4.3采用凝胶柱层析(Sephadex LH-20),以氯仿:甲醇(1:1,v/v)为洗脱剂,然后通过半制备高效液相色谱(HPLC),以乙腈 -水为流动相,采用等度洗脱的方法(乙腈浓度45%,v/v)进行制备可得到 sarcglabralideA和sarcglabralideB。Fr.4.5采用正相硅胶柱层析,以氯仿 -甲醇(30:1,v/v)进行洗脱得到sarcglabralideC。
SarcglabralideA的物理常数和波谱数据:黄色胶状物; UV(MeOH)λmax(logε)216(2.93)nm;CD(MeOH)λmax(Δε) 225(3.50)nm;IR(KBr)νmax 3440,2925,2853,1720,1632,1454,1384,1263, 1128cm-1;1H NMR(CDCl3,600MHz)δ2.06(1H,dt,J=9.1,5.2Hz,H-1), 0.83(1H,m,H-2α),1.72(1H,m,H-2β),1.67(1H,o,H-3),4.26(1H,s,H-9), 1.34(3H,s,H3-13),1.06(3H,s,H3-14),1.58(1H,m,H-15α),2.64(1H,dd,J =14.6,3.7Hz,H-15β),1.67(1H,o,H-1′),0.64(1H,td,J=8.9,5.5Hz, H-2′α),1.17(1H,m,H-2′β),1.70(1H,o,H-3′),1.82(1H,o,H-5′),1.91(1H, d,J=12.8Hz,H-6′α),1.80(1H,d,J=12.8Hz,H-6′β),2.83(1H,dd,J= 13.5,3.8Hz,H-9′),6.55(1H,s,H-13′a),5.70(1H,s,H-13′b),0.91(3H,s, H3-14′),4.07(1H,d,J=11.0Hz,H-15′a),3.93(1H,d,J=11.0Hz,H-15′b), 6.88(1H,q,J=7.1Hz,H-3″),1.82(3H,d,J=7.1Hz,H3-4″),1.85(3H,s, H3-5″),6.12(1H,s,H-1″′),3.47(3H,s,MeO-1″′),3.77(3H,s,MeO-12);13CNMR(CDCl3,150MHz)δ31.9(C-1,d),9.5(C-2,t),27.2(C-3,d),92.6 (C-4,s),90.2(C-5,s),148.1(C-6,s),143.1(C-7,s),198.1(C-8,s),81.2(C-9, d),54.8(C-10,s),63.3(C-11,s),173.0(C-12,s),25.6(C-13,q),14.3(C-14, q),33.2(C-15,t),27.1(C-1′,d),10.8(C-2′,t),29.3(C-3′,d),78.7(C-4′,s), 53.1(C-5′,d),33.2(C-6′,t),57.7(C-7′,s),95.9(C-8′,s),50.0(C-9′,d),41.5 (C-10′,s),143.5(C-11′,s),167.6,(C-12′,s),126.6(C-13′,t),23.8(C-14′,q), 69.4(C-15′,t),168.0(C-1″,s),128.4(C-2″,s),138.2(C-3″,d),14.6(C-4″, q),12.3(C-5″,q),121.2(C-1″′,d),54.1(MeO-1″′,q),53.3(MeO-12,q)。 HRESIMS m/z 727.2537[M+Cl]-(calcd.for C38H44O12Cl,727.2527)。
Sarcglabralide B的物理常数和波谱数据:黄色胶状物; UV(MeOH)λmax(logε)220(3.13)nm;CD(MeOH)λmax(Δε) 223(14.8),333(–1.04)nm;IR(KBr)νmax 3446,2928,2854,1714,1643, 1441,1381,1263,1132cm-1;1H NMR(CDCl3,500MHz)δ2.03(1H,dt,J= 8.6,5.0Hz,H-1),0.73(1H,m,H-2α),0.81(1H,m,H-2β),2.28(1H,ddd,J= 8.6,5.9,3.6Hz,H-3),4.23(1H,s,H-9),1.33(3H,s,H3-13),1.02(3H,s,H3-14),1.40(1H,t,J=14.3Hz,H-15α),3.31(1H,dd,J=14.6,3.1Hz, H-15β),1.58(1H,m,H-1′),0.61(1H,td,J=8.9,5.5Hz,H-2′α),1.14(1H,m, H-2′β),1.69(1H,m,H-3′),1.76(1H,s,H-5′),1.92(1H,d,J=11.5Hz, H-6′α),1.75(1H,d,J=11.5Hz,H-6′β),2.42(1H,dd,J=13.9,3.0Hz,H-9′), 6.56(1H,s,H-13′a),5.72(1H,s,H-13′b),0.86(3H,s,H3-14′),4.06(1H,d,J =11.0Hz,H-15′a),3.89(1H,d,J=11.0Hz,H-15′b),6.87(1H,q,J=7.1Hz, H-3″),1.81(3H,d,J=7.1Hz,H3-4″),1.84(3H,s,H3-5″),2.23(1H,q, H-2″′),3.77(3H,s,MeO-12);3.18(1H,s,5-OH),3.42(1H,d,J=4.0Hz, 9-OH);13C NMR(CDCl3,125MHz)δ29.9(C-1,d),7.7(C-2,t),27.1(C-3, d),89.4(C-4,s),78.6(C-5,s),150.3(C-6,s),141.3(C-7,s),198.1(C-8,s), 80.9(C-9,d),54.6(C-10,s),63.3(C-11,s),173.0(C-12,s),25.7(C-13,q), 13.7(C-14,q),31.7(C-15,t),27.1(C-1′,d),10.9(C-2′,t),29.3(C-3′,d),78.7 (C-4′,s),52.8(C-5′,d),32.9(C-6′,t),57.4(C-7′,s),96.7(C-8′,s),50.1(C-9′, d),41.3(C-10′,s),142.9(C-11′,s),167.6,(C-12′,s),127.1(C-13′,t),24.1(C-14′,q),69.4(C-15′,t),168.0(C-1″,s),128.4(C-2″,d),138.2(C-3″,d), 14.6(C-4″,q),12.3(C-5″,q),169.3(C-1″′,s),22.2(Me-2″′,q),53.3 (MeO-12,q)。HRESIMS m/z715.2723[M+Na]+(calcd.for C38H44O12Na, 715.2725)。
Sarcglabralide C的物理常数和波谱数据:黄色胶状物; UV(MeOH)λmax(logε)214(3.24)nm;CD(MeOH)λmax(Δε) 260(5.93),212(–9.53),343(–1.58)nm;IR(KBr)νmax 3440,2955,2924, 1738,1636,1437,1382,1241,1126cm-1;1H NMR(CDCl3,600MHz)δ2.05 (1H,m,H-1),0.98(1H,m,H-2α),0.28(1H,m,H-2β),1.83(1H,o,H-3), 3.91(1H,s,H-6),3.93(1H,s,H-9),1.88(3H,s,H3-13),1.01(3H,s,H3-14), 2.59(1H,dt,J=16.5,5.1Hz,H-15α),2.75(1H,d,J=16.5Hz,H-15β),1.58 (1H,o,H-1′),0.72(1H,td,J=8.7,6.0Hz,H-2′α),1.28(1H,m,H-2′β),1.43 (1H,td,J=8.6,3.6Hz,H-3′),1.75(1H,dd,J=13.8,5.8Hz,H-5′),2.41(1H, dd,J=18.4,5.8Hz,H-6′α),2.72(1H,dd,J=18.4,13.8Hz,H-6′β),1.83 (1H,o,H-9′),4.81(1H,s,H-13′a),4.81(1H,s,H-13′b),0.86(3H,s,H3-14′), 4.06(1H,d,J=11.6Hz,H-15′a),3.75(1H,d,J=11.6Hz,H-15′b),2.13 (3H,s,H3-2″),2.09(3H,s,H-2″′),3.78(3H,s,MeO-12);13C NMR(CDCl3,150MHz)δ25.5(C-1,d),16.0(C-2,t),24.8(C-3,d),142.4(C-4,s),131.7 (C-5,s),40.9(C-6,d),131.4(C-7,s),200.5(C-8,s),80.4(C-9,d),51.3 (C-10,s),148.0(C-11,s),170.6(C-12,s),20.6(C-13,q),15.3(C-14,q),25.4 (C-15,t),25.8(C-1′,d),12.0(C-2′,t),28.2(C-3′,d),77.2(C-4′,s),60.7 (C-5′,d),23.0(C-6′,t),171.5(C-7′,s),93.3(C-8′,s),55.9(C-9′,d),44.8 (C-10′,s),123.7(C-11′,s),172.3,(C-12′,s),55.2(C-13′,t),26.5(C-14′,q), 71.6(C-15′,t),170.7(C-1″′,s),20.6(C-2″′,q),52.8(MeO-12,q)。HRESIMS m/z 659.2465[M+Na]+(calcd.for C35H40O11Na,659.2463)。
实施例2:化合物sarcglabralidesA–C的制备方法二
草珊瑚(S.glabra)全株(干燥),粉碎后用95%乙醇按有机溶剂和植物材料的体积比为2:1加热回流提取3次,每次2小时,合并提取液后减压蒸馏回收至小体积(乙醇浓度约为25%-30%),再过LS-700B大孔树脂柱,先用5个柱体积蒸馏水洗脱除去糖,再用75%乙醇洗脱,回收乙醇溶剂得到膏状提取物。膏状经MCI柱层析,用甲醇-水梯度洗脱(3:7、5:5、8:2, v/v),每个梯度4~6个柱体积,得到3个组分(Fr.1–Fr.3)。将收集得到的 Fr.2部分采用正相硅胶柱层析(硅胶用量与样品的质量比为20:1),以石油醚-乙酸乙酯为洗脱剂进行梯度洗脱(每个梯度3~5个柱体积),得到六个部分即:Fr.2.1(石油醚:乙酸乙酯=1:0,v/v)、Fr.2.2(石油醚:乙酸乙酯=50:1,v/v)、Fr.2.3(石油醚:乙酸乙酯=25:1,v/v)、Fr.2.4(石油醚:乙酸乙酯=10:1,v/v)、Fr.2.5(石油醚:乙酸乙酯=5:1,v/v);Fr.2.6(石油醚:乙酸乙酯=0:1,v/v);Fr.2.5采用凝胶柱层析(Sephadex LH-20),以氯仿:甲醇(1:1,v/v)为洗脱剂,然后通过半制备高效液相色谱(HPLC),以乙腈-水为流动相,采用梯度洗脱的方法(乙腈浓度20%→60%,v/v)进行制备得到sarcglabralide A、sarcglabralide B和sarcglabralide C。
实施例3:化合物sarcglabralidesA–C的制备方法三
草珊瑚(S.glabra)枝叶(干燥),粉碎后用甲醇在室温下按有机溶剂和植物材料的体积比为5:1,冷浸提取3次,2天/次,合并提取液后减压蒸馏得到膏状提取物。合并提取液后减压蒸馏回收溶剂得浸膏,浸膏过中压色谱分离凝胶(MCI Gel)柱层析,用甲醇-水梯度洗脱(2:8、5:5、8:2, 10:0,v/v),每个梯度4~6个柱体积,得到3个组分(Fr.1–Fr.,4)。将收集得到的Fr.2部分采用正相硅胶柱层析(硅胶用量与样品的质量比为20:1),以氯仿-甲醇为洗脱剂进行梯度洗脱(100:1→1:1,v/v),得到五个部分得到 5个组分Fr.2.1–Fr.2.5。;Fr.2.4采用凝胶柱层析(Sephadex LH-20),以氯仿:甲醇(1:1,v/v)为洗脱剂,然后通过半制备高效液相色谱(HPLC),以乙腈-水为流动相,采用梯度洗脱的方法(乙腈浓度30%→55%,v/v)进行制备得到sarcglabralide A、sarcglabralide B和sarcglabralide C。
实施例4:化合物sarcglabralides A–C的制备方法四
海南草珊瑚(S.hainanensis)全株(干燥),粉碎后用甲醇在室温下按有机溶剂和植物材料的体积比为4:1,超声波提取2次,合并提取液后减压蒸馏得到膏状提取物。膏状提取物经硅胶柱层析,用石油醚-乙酸乙酯梯度洗脱(1:0→0:1,v/v),得到8个组分(Fr.1–Fr.8)。将收集得到的Fr.5部分经过中压色谱分离凝胶(MCI Gel)柱层析,用甲醇-水梯度洗脱(2:8→10:0, v/v),得到5个组分Fr.5.1–Fr.5.5。将Fr.5.2采用凝胶柱层析(SephadexLH-20),以甲醇为洗脱剂,然后通过半制备高效液相色谱(HPLC),以乙腈-水为流动相,采用梯度洗脱的方法(乙腈浓度30%→45%,v/v)进行制备可得到sarcglabralide A–C。
实施例5:SarcglabralidesA–C的抗炎活性
一氧化氮(nitric oxide,NO)具有广泛而重要的生物学调控功能,在炎症、肿瘤及心血管***等均有重要作用。当免疫细胞遭受微生物内毒素、炎症介质等刺激时,会生成大量的诱导型一氧化氮合成酶(induced NO synthase,iNOS),产生NO进行免疫应答,因此抑制NO生成是化合物抗炎活性的直接指标。
将RAW264.7细胞接种至96孔板,用1μg/ml LPS进行诱导刺激,同时加入待测化合物(终浓度50μg/ml)处理,设置不含药物组和L-NMMA阳性药物组做对照。细胞过夜培养后取培养基检测NO生成,在570nm处测定吸光值。在剩余培养基中加入MTS进行细胞存活率检测,排除化合物对细胞的毒性影响。
NO生成抑制率(%)=(非药物处理组OD570nm–样品组OD570nm)/非药物处理组OD570nm×100%
IC50(半抑制浓度)按Reed&Muench法计算。
实验结果如表1和表2所示,sarcglabralidesA–C具有显著的抗NO 生成活性,它们的IC50值分别是16.60、13.43和17.19μM,是阳性对照药L-NMMA(41.33μM)的2.4–3.1倍。
表1.sarcglabralidesA–C对NO生成抑制率(%)
aL-NMMA为阳性对照药
表2.sarcglabralidesA–C抑制NO生成的IC50值
aL-NMMA为阳性对照药。
Claims (9)
2.一种用于治疗炎性疾病的药物组合物,其特征在于,包含作为活性药物成分的权利要求1所述的化合物sarcglabralidesA、B或C或其药学上可接受的衍生物,以及药学上可接受的载体、佐剂或赋形剂。
3.权利要求1所述的化合物乌药烷型二聚倍半萜或其药学上可接受的衍生物在制备用于治疗炎性疾病的药物中的应用。
4.制备权利要求1所述乌药烷型二聚倍半萜的方法,其特征在于,包括以下步骤:
1)将草珊瑚属(Sarcandra)植物材料干燥粉碎,采用有机溶剂提取后脱溶,得到草珊瑚属植物材料提取物;
2)对所述草珊瑚属植物材料提取物依次采用柱层析、半制备高效液相色谱,得到化合物sarcglabralides A–C。
5.根据权利要求4所述的方法,其特征在于,所述草珊瑚属植物材料是草珊瑚(S.glabra)或海南草珊瑚(S.hainanensis)的根、茎、枝叶、果实或全株。
6.根据权利要求4所述的方法,其特征在于,在步骤1)中,所述有机溶剂提取法包括有机溶剂室温冷浸法、有机溶剂加热回流法或超声法;所述有机溶剂和草珊瑚植物材料的体积比为1:1到5:1,优选3:1。
7.根据权利要求4所述的方法,其特征在于,在步骤1),中所述有机溶剂包括石油醚、氯仿、二氯甲烷、乙酸乙酯、丙酮、乙醇、甲醇、正丁醇和乙腈中的至少一种。优选地,所述有机溶剂包括乙酸乙酯、甲醇或95%乙醇。
8.根据权利要求4所述的方法,其特征在于,在步骤2)中,所述柱层析包括正相硅胶柱层析、反相硅胶柱层析、树脂柱层析、凝胶柱层析、中压色谱分离凝胶(MCI Gel)和制备或半制备高效液相色谱(HPLC)。
9.根据权利要求4所述的方法,其特征在于,在步骤2)中,柱层析所用洗脱剂包括石油醚、氯仿、二氯甲烷、乙酸乙酯、丙酮、乙醇、甲醇、正丁醇、乙腈、水和甲酸中的一种或两种以上的组合;正相硅胶柱层析采用石油醚和乙酸乙酯按体积比从1:0到0:1梯度洗脱;或正相硅胶柱层析采用氯仿和甲醇按体积比从100:1到1:1梯度洗脱;反相RP-18柱层析采用乙腈和水按体积比从2:8到1:0梯度洗脱;凝胶柱层析采用甲醇、氯仿与甲醇(1:1,v/v)洗脱;中压色谱分离凝胶(MCI Gel)采用甲醇和水按体积比从2:8到1:0梯度洗脱;制备或半制备HPLC采用乙腈和水按体积比从2:8到6:4梯度洗脱。
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CN116730957A (zh) * | 2023-08-11 | 2023-09-12 | 山东省食品药品检验研究院 | 一种乌药烷型倍半萜二聚体及其制备方法与应用 |
CN116730957B (zh) * | 2023-08-11 | 2023-10-20 | 山东省食品药品检验研究院 | 一种乌药烷型倍半萜二聚体及其制备方法与应用 |
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