CN115385795B - 白鹤灵芝萘醌类单体白鹤灵芝素-c的制备方法及应用 - Google Patents
白鹤灵芝萘醌类单体白鹤灵芝素-c的制备方法及应用 Download PDFInfo
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Abstract
本发明公开了一种白鹤灵芝萘醌类单体白鹤灵芝素‑C的制备方法及应用,具体为:取白鹤灵芝药材粉碎,加乙酸乙酯加热回流,提取液减压回收溶剂,加入硅胶拌样,干燥,300目硅胶装柱,用正己烷‑乙酸乙酯梯度洗脱,收集10:1流分,减压浓缩,得总萘醌,总萘醌用甲醇溶解,与强碱性苯乙烯系阴离子交换树脂搅拌,静置反应,将吸附样品的离子交换树脂倒入玻璃柱,先用甲醇洗脱,然后用10%醋酸甲醇洗脱,收集10%醋酸甲醇洗脱液,减压回收溶剂,即得高纯度白鹤灵芝素‑C。该方法简单易行,收率高,制得的白鹤灵芝素‑C产品纯度不低于95%。且本发明通过研究发现,白鹤灵芝素‑C对HepG2、HeLa细胞的IC50分别为49.19μmol/L、35.21μmol/L;对金黄色葡萄球菌和结核杆菌均有较好的抑制作用。
Description
技术领域
本发明涉及一种白鹤灵芝萘醌类单体白鹤灵芝素-C的制备方法及应用,具体涉及一种采用反相柱色谱从壮药白鹤灵芝药材中富集白鹤灵芝总萘醌,再经由强碱性苯乙烯系阴离子交换树脂制备高纯度白鹤灵芝素-C的方法及应用,属于天然药物化学技术领域。
背景技术
白鹤灵芝为爵床科白鹤灵芝属植物Rhinacanthus nasutus(L.)Kurz的干燥枝、叶,别名癣草,主产于云、桂、贵等地深山,是壮族等少数民族秘传的珍贵药材,壮药名Go’gyak(棵绛),清热毒、杀虫、止痒;主治能晗能累(湿疹)、痂(疥癣)、额哈(毒蛇咬伤)等,具有清热疏肝、杀虫止痒、收敛止血等功效。白鹤灵芝叶披针形对生生长,叶片呈黄绿色,花冠颜色为白色,像嘴唇类型,花冠可以长在枝顶、叶腋这两个部位,放眼望去犹如白鹤成群结对的在一望无垠的天空中翱翔,且药效有如灵芝,故中药界人士命名为“白鹤灵芝”,植物形态见附图1。
药理活性报道白鹤灵芝具有抗病毒、抗肿瘤、抑菌、降血脂、抗凝血等多种作用。白鹤灵芝含有多种化学成分,主要含有20余种类胡桃醌酯类衍生物的萘醌以及黄酮、异黄酮、香豆素、挥发油等(白鹤灵芝萘醌类化合物结构式见附图2)。萘醌类化合物是从白鹤灵芝醇提物中分离得到的主要活性成分,化学结构以胡桃醌酯类衍生物及其甲氧基衍生物为主醌类化合物具有广泛的药理活性,包括抗炎、抑菌、抗病毒、抗肿瘤等活性,其中较为显著的是萘醌类化合物的抗肿瘤活性。目前,已从白鹤灵芝中分离鉴定出包括rhinacanthin-A~V及rhinacanthone共20个萘醌类化合物,其中主要为α-(1,4)萘醌19个,和β-(1,2)萘醌1个,其中白鹤灵芝素-C为主要报道的活性物质。
白鹤灵芝素-C可通过抑制前列腺素E2 和肿瘤坏死因子而治疗风湿性关节炎,还可以抑制NO 和PGE2 释放抑制炎症的发生。白鹤灵芝素-C对人宫颈癌细胞系HeLa 及其MDR1 过表达亚系Hvr100-GFP 在体外评估显示较好的抗细胞增殖活性。白鹤灵芝素-C,-D,-N对抗原诱导的TNF-α 和IL-4 释放的活性筛选,结果显示白鹤灵芝素-C可很好的用于治疗过敏及过敏相关疾病。白鹤灵芝素-C还可诱导HMGB-1 重组蛋白损害RCT-C 的神经保护和免疫抑制作用,减轻SAH 发病机制中的脑细胞凋亡,并通过干扰MRP2 和P-gp功能来增强阿霉素的细胞毒性。白鹤灵芝素-C对调节脂多糖淀粉样β 肽或干扰素γ 诱发的神经元和神经胶质细胞也具有保护作用。另有研究表明白鹤灵芝素-C 可有效清除超氧化物和抑制白蛋白糖化使其在各种慢性疾病,尤其是糖尿病并发症中的治疗作用合理化。
目前对白鹤灵芝的研究主要集中在规范化种植(GAP)、质量控制技术方面,药理活性主要集中在降血脂、降血糖及对非酒精性脂肪肝的保护作用。对白鹤灵芝的有效活性成分和指标性成分方面的研究比较欠缺,在白鹤灵芝素-C的制备方法方面的研究也较少。检索到相关的文献如申请号为201110304675.1的中国专利,公开了一种高纯度白鹤灵芝素 C的制备方法,但是本申请人经过研究发现按照该专利申请中所述的制备方法进行制备白鹤灵芝素 C并不能得出其所描述的纯度不低于 95%这样的产品纯度,而且该公开的技术方案中,也没有相关的附图、数据等对所制的白鹤灵芝素C进行表征。而在白鹤灵芝素-C的制备方法方面,目前尚未见有采用反相柱色谱富集白鹤灵芝总萘醌,再经由强碱性苯乙烯系阴离子交换树脂制备高纯度白鹤灵芝素-C的方法报道。
发明内容
本发明的目的在于克服现有制备分离技术的缺陷,提供一种采用反相柱色谱快速富集白鹤灵芝总萘醌,再经由强碱性苯乙烯系阴离子交换树脂制备高纯度白鹤灵芝素-C的方法及应用。该制备方法工艺步骤简单,收率高,制得的白鹤灵芝素-C产品纯度不低于95%。
为实现上述目的,本发明采用如下技术方案:
一种白鹤灵芝萘醌类单体白鹤灵芝素-C的制备方法,包括如下步骤:
(1)称取白鹤灵芝药材全草粉碎,加6~10倍量的乙酸乙酯加热回流3~4次,每次1小时,提取液减压回收溶剂,反相柱色谱分离,加入1~1.6倍量硅胶200目拌样,干燥;10~15倍量300目硅胶装柱,用正己烷:乙酸乙酯为洗脱溶剂进行梯度洗脱,收集10:1流分,流分减压浓缩得白鹤灵芝萘醌类富集物即总萘醌;
(2)总萘醌用甲醇溶解,与强碱性苯乙烯系阴离子交换树脂搅拌,静置反应1~2h,将吸附样品的离子交换树脂倒入玻璃柱,先用2~4 柱体积的甲醇洗脱,然后用2~4 柱体积的10%醋酸甲醇洗脱,收集10%醋酸甲醇洗脱液,减压回收溶剂,即得高纯度白鹤灵芝素-C。
上述白鹤灵芝萘醌类单体白鹤灵芝素-C的制备方法,步骤(1)中利用反相硅胶色谱柱进行富集白鹤灵芝总萘醌,采用正己烷:乙酸乙酯为洗脱溶剂进行梯度洗脱是按照正己烷:乙酸乙酯体积比20:1→1:1进行梯度洗脱,收集流分为10:1流分。
上述的白鹤灵芝萘醌类单体白鹤灵芝素-C的制备方法,所述步骤(2)是通过强碱性苯乙烯系阴离子交换树脂对白鹤灵芝素萘醌类富集物即总萘醌中的白鹤灵芝素C进行分离。
所述的白鹤灵芝萘醌类单体白鹤灵芝素-C的制备方法,制备得到的白鹤灵芝素-C产品的纯度不低于95%。
另一方面,本发明还公开了所述的白鹤灵芝萘醌类单体白鹤灵芝素-C在制备抗人肝癌HepG2细胞和/或人宫颈癌HeLa细胞药物中的应用以及白鹤灵芝素-C在制备金黄色葡萄球菌抑制剂和/或结核杆菌抑制剂中的应用。
本发明通过白鹤灵芝素-C药理活性实验研究发现,白鹤灵芝素-C对HepG2、HeLa细胞的IC50分别为49.19 μmol/L、35.21 μmol/L,能够抑制人肝癌HepG2细胞、人宫颈癌HeLa细胞的增殖,诱导人肝癌HepG2细胞、人宫颈癌HeLa细胞凋亡;白鹤灵芝素-C可用于制备抗人肝癌HepG2细胞和/或人宫颈癌HeLa细胞的药物。同时,白鹤灵芝素-C对金黄色葡萄球菌、枯草芽孢杆菌、大肠杆菌和结核杆菌这4种常见供试菌均表现出一定的生长抑制作用,其中白鹤灵芝素-C对金黄色葡萄球菌和结核杆菌均有较好的抑制作用,可用于制备金黄色葡萄球菌抑制剂和/或结核杆菌抑制剂。
本发明的有益效果为:
1、阴离子交换树脂广泛应用于许多化合物的分离纯化,白鹤灵芝素-C是一种负离子化合物,可以通过阴离子交换树脂进行富集,本发明白鹤灵芝萘醌类单体白鹤灵芝素-C的制备方法,采用常规的反相硅胶色谱柱进行白鹤灵芝萘醌类富集物,不仅简单方便,而且效率高,可以快速有效的富集得到白鹤灵芝总萘醌。本发明白鹤灵芝素-C的制备方法,采用反相柱色谱快速富集白鹤灵芝总萘醌,再经由强碱性苯乙烯系阴离子交换树脂制备高纯度白鹤灵芝素-C,工艺步骤简单易行,收率高,制得的白鹤灵芝素-C产品纯度不低于95%。
2、本发明通过实验研究发现,白鹤灵芝素-C对HepG2、HeLa细胞的IC50分别为49.19 μmol/L、35.21 μmol/L,白鹤灵芝素-C对金黄色葡萄球菌和结核杆菌均有较好的抑制作用;白鹤灵芝素-C可用于制备抗人肝癌HepG2细胞和/或人宫颈癌HeLa细胞的药物,可用于制备金黄色葡萄球菌和/或结核杆菌抑制剂。
附图说明
图1 壮药白鹤灵芝植物形态;
图2 白鹤灵芝萘醌类化合物结构式;
图3 实施例1中白鹤灵芝素萘醌类富集物(总萘醌)的HPLC色谱图;
图4 实施例1方法制得的白鹤灵芝素C(rhinacanthin-C)HPLC色谱图;
图5 白鹤灵芝素C(rhinacanthin-C)分子结构图;
图6 白鹤灵芝素-C液相色谱飞行时间质谱图(LC-TOF-MS)(负离子模式);
图7 实施例1方法制得的白鹤灵芝素-C 的1H NMR图谱;
图8 实施例1方法制得的白鹤灵芝素-C的 13C NMR图谱;
图9 实施例2中白鹤灵芝素萘醌类富集物(总萘醌)的HPLC色谱图;
图10 实施例2中白鹤灵芝总萘醌全波长(HPLC-DAD)等线吸收色谱图;
图11 实施例2方法制得的白鹤灵芝素C(rhinacanthin-C)的HPLC色谱图;
图12实施例2方法制得的白鹤灵芝素C全波长(HPLC-DAD)等线吸收色谱图。
具体实施方式
以下实施例仅用于说明本发明而不应将此理解为本发明上述主题的范围仅限于以下的实例。此外应理解,在阅读了本发明讲授的内容之后,本领域技术人员可以对本发明做各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。同时为了简单和清楚的目的,下文恰当的省略了公知技术的描述,以免那些不必要的细节影响对本技术方案的描述。
实施例1
一种白鹤灵芝萘醌类单体白鹤灵芝素-C的制备方法,包括如下步骤:
(1)将白鹤灵芝药材粉碎,取1kg,加入6倍量乙酸乙酯回流提取3次,每次1小时,提取液减压回收试剂,得浸膏9.76g,加入200目硅胶15g拌样,干燥,称取300目硅胶300g装柱(8×80 cm),用正己烷:乙酸乙酯(20:1→1:1)梯度洗脱,每个梯度洗脱4500mL,收集10:1馏分,馏分减压浓缩的白鹤灵芝素萘醌类富集物(总萘醌)1.43g;
(2)总萘醌用甲醇溶解,采用安捷伦1200高效液相制备色谱对白鹤灵芝素总萘醌进行HPLC分析,色谱柱C18(COSMOSIL C18-MS-II,2.5 μm×250 mm),流动相MeOH/0.2%TFA/H2O(82:18)等度洗脱,检测波长250 nm,进样量10 μL,流速为1mL/min,所得HPLC色谱图见附图3;总萘醌用甲醇溶解,与500g强碱性苯乙烯系阴离子交换树脂(AmberliteIRA-67)搅拌,静置反应1h,将吸附样品的离子交换树脂倒入玻璃柱(10×80 cm),先用3倍柱体积甲醇洗脱,然后用3倍柱体积的10%醋酸甲醇洗脱,收集10%醋酸甲醇洗脱液,减压回收溶剂,即得0.55g高纯度白鹤灵芝素-C橙红色油状液体,经HPLC检测,含量达95.7%,HPLC色谱图见附图4;经高分辨MS,化合物m/z 411.2080[M+H]+,分子式为C25H30O5,分子结构式见附图5;高分辨质谱图见附图6;1H NMR ( CDCl3,400 MHz) δ:8.09(1H,dd),7.74(1H,td),7.67(1H,td),8.06(1H,dd),2.69(2H,s),3.90(2H,s),1.01(6H,s),6.68(1H,t),2.15(2H,td),2.01(2H,t),5.19(1H,d),1.78(3H,s),1.58(3H,s),1.56(3H,d);13C NMR (101 MHz,CDCl3)δ:184.99,181.37,168.28,154.41,142.14,135.06,134.73,133.13,133.02,129.51,127.80,127.16,126.20,121.97,119.42,72.87,38.32,37.18,32.33,29.82,27.29,25.34,15.68,13.47,12.43。NMR核磁共振图见附图7、附图8。
实施例2
一种白鹤灵芝萘醌类单体白鹤灵芝素-C的制备方法,包括如下步骤:
(1)将白鹤灵芝药材粉碎,取2kg,加入8倍量乙酸乙酯回流提取4次,每次1小时,提取液减压回收试剂,得浸膏21.18g,加入200目硅胶25 g拌样,干燥,称取300目硅胶600g装柱(10×100 cm),用正己烷:乙酸乙酯(20:1→1:1)梯度洗脱,每个梯度洗脱6000 mL,收集10:1馏分,馏分减压浓缩的白鹤灵芝素萘醌类富集物(总萘醌)2.14g;
(2)总萘醌用甲醇溶解,采用安捷伦1200高效液相制备色谱对白鹤灵芝素总萘醌进行HPLC分析,色谱柱C18(COSMOSIL C18-MS-II,2.5 μm×250 mm),流动相MeOH/0.2%TFA/H2O(80:20)等度洗脱,检测波长250 nm,进样量10 μL,流速为1mL/min,所得HPLC色谱图见附图9、DAD全波长等线吸收图见附图10;总萘醌用甲醇溶解,与1000g强碱性苯乙烯系阴离子交换树脂(AmberliteIRA-67)搅拌,静置反应1h,将吸附样品的离子交换树脂倒入玻璃柱(10×80 cm),先用4倍柱体积甲醇洗脱,然后用4倍柱体积的10%醋酸甲醇洗脱,收集10%醋酸甲醇洗脱液,减压回收溶剂,即得0.96g高纯度白鹤灵芝素-C橙红色油状液体,经HPLC检测,含量达96.2%,HPLC色谱图见附图11、 DAD全波长等线吸收图见附图12。
实施例3
白鹤灵芝素-C药理活性筛选(试验中用的白鹤灵芝素-C为实施例2方法制得的白鹤灵芝素-C)
(1)MTT法白鹤灵芝素-C细胞活性筛选
取生长良好且贴壁生长至细胞瓶80 % - 90 %的HepG2、HeLa细胞,胰酶消化细胞,加入培养基终止消化,然后吹打细胞培养瓶使细胞均匀分散于细胞培养液中,将细胞悬液调整至2×104个/ mL,均匀种入96孔板中,每孔加入200 μL,孵育12 h后弃旧培养基,加入不同浓度的白鹤灵芝素-C,使白鹤灵芝素-C的终浓度为100 μmol/L、50 μmol/L、25 μmol/L、12.5 μmol/L、6.25 μmol/L,每组设置6个重复孔。孵育24 h后,每孔加入MTT溶液20 μL,在细胞培养箱中避光孵育4 h,弃去96孔板中的溶液,加入150 μL的DMSO,在570 nm和630nm处测定吸光度值,计算细胞的生长抑制率及IC50值。上述实验的结果为白鹤灵芝素-C对HepG2、HeLa细胞的IC50分别为49.19 μmol/L、35.21 μmol/L。可见,白鹤灵芝素-C能够抑制人肝癌HepG2细胞、人宫颈癌HeLa细胞的增殖,诱导人肝癌HepG2细胞、人宫颈癌HeLa细胞凋亡。
(2)最小抑菌浓度(MIC)测定
MH(B)营养肉汤分装后于121℃高压灭菌15 min,试验菌悬液用无菌水稀释,以比浊管调整菌液浓度为1×106 cfu.mL-1。分别将白鹤灵芝素-C用二甲基亚砜稀释成0.025、0.05、0.10、0.20、0.40、0.80、1.6、3.2 mg/mL共8个浓度梯度,参照NCCLS标准采用微量稀释法进行。用微量移液器吸取试验菌液0.1mL加入到含样品5.0 mL的试管中,迅速混匀,并立即计时。分别加入各菌液10 μL与供试液混合液0.1mL,加入含5.0 mL经灭菌的无菌水试管中,充分混匀,然后放置10 min。用微量移液器吸取各浓度供试液接种于灭菌平皿,倒入15mL的营养琼脂培养基(45℃),缓慢转动平皿,使其充分均匀,待琼脂凝固后翻转平皿,30℃湿盒孵育,48 h后观察结果,做活菌菌落计数。白鹤灵芝素-C对4种常见供试菌的最低抑菌浓度(MIC)的实验结果如表1所示,白鹤灵芝素-C对4种常见供试菌均均表现出一定的生长抑制作用,但抑制作用差异较大;其中白鹤灵芝素-C对金黄色葡萄球菌和结核杆菌均有较好的抑制作用。
Claims (1)
1.一种白鹤灵芝萘醌类单体白鹤灵芝素-C的制备方法,其特征在于,包括如下步骤:
(1)称取白鹤灵芝药材全草粉碎,加6~10倍量的乙酸乙酯加热回流3~4次,每次1小时,提取液减压回收溶剂,反相柱色谱分离,加入1~1.6倍量硅胶200目拌样,干燥;10~15倍量300目硅胶装柱,用正己烷:乙酸乙酯为洗脱溶剂进行梯度洗脱,收集10:1流分,流分减压浓缩得白鹤灵芝萘醌类富集物即总萘醌;
(2)总萘醌用甲醇溶解,与强碱性苯乙烯系阴离子交换树脂搅拌,静置反应1~2 h,将吸附样品的离子交换树脂倒入玻璃柱,先用2~4 柱体积的甲醇洗脱,然后用2~4 柱体积的10%醋酸甲醇洗脱,收集10%醋酸甲醇洗脱液,减压回收溶剂,即得高纯度白鹤灵芝素-C;
步骤(1)中采用正己烷:乙酸乙酯为洗脱溶剂进行梯度洗脱是按照正己烷:乙酸乙酯体积比20:1→1:1进行梯度洗脱,收集流分为10:1流分;
所述的白鹤灵芝萘醌类单体白鹤灵芝素-C的制备方法,制备得到的白鹤灵芝素-C产品的纯度不低于95%。
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