CN102349886B - 苯代萘型木脂素类化合物在制备抗辐射药物中的应用 - Google Patents
苯代萘型木脂素类化合物在制备抗辐射药物中的应用 Download PDFInfo
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Abstract
本发明涉及医药技术领域。苯代萘型木脂素类成分为牡荆属植物的主要特征性成分之一，现代药理试验表明，苯代萘型木脂素类化合物具有镇痛、抗炎、抗菌和抗氧化等多种药理活性。本发明提供了苯代萘型木脂素类化合物新的医药用途，经药效学研究表明，苯代萘型木脂素类化合物VNL、Vitedoin A、Vitedoamine A和Vitrofolal F均可显著提高辐射损伤人淋巴母细胞(AHH-1)的活力，增加辐射损伤小鼠存活率和存活时间，具有良好的抗辐射活性，因此可用于制备抗辐射药物或食品。本发明为寻求抗辐射药物或食品提供了一种新的来源。
Description
技术领域
本发明涉及医药技术领域，具体涉及是以牡荆属植物为原料制备的苯代萘型木脂素类化合物6-羟基-4β-(4-羟基-3-甲氧基苯基)-3α-羟甲基-7-甲氧基-3，4-二氢-2-萘醛(VNL)、VitedoinA、Vitedoamine A和Vitrofolal F在制备抗辐射药物或食品中的应用。
背景技术
随着核技术在工农业和医学生命科学等方面的广泛应用，以及世界核军备竞赛的加剧，核能源在给人类带来益处的同时，核辐射也对人类造成了极大的伤害。当今面临的核辐射损伤主要来源为战争核辐射(包括核武器、贫铀武器所致的辐射)与非战争核辐射(包括核泄漏、民用放射源、医疗照射、职业照射、宇航人员受到的空间辐射等)。
辐射损伤指由电离辐射所致的急性，迟发性或慢性的机体组织损害(史国兵，安哗，赵庆春.中药预防与治疗核辐射损伤的研究进展.中草药[J]，2008，39(12)：附1-4)。辐射损伤最早是发生电离、激发及生成自由基，随着发生一系列生物化学反应，包括DNA的损伤、代谢过程的改变、细胞死亡、组织损伤，直到机体死亡(黄德娟，刘罗发，王彩霞，黄德超，朱业安，朱茫.抗辐射植物抗损伤作用研究进展.中国辐射卫生[J]，2010，19(1)：126-128)。其远期效应则包括若干年乃至数十年后的致癌及遗传后代的基因畸变等。因此，无论是从提供战时防护的角度还是和平时期对在放射性环境条件下的工作人员提供预防保护，或是应对突发性核事故的急救措施，开发高效、低毒、使用方便的抗辐射药物都是十分必要的。
马鞭草科牡荆属(Vitex L.)植物全世界约有250种(裴鉴，陈守良.中国植物志[M]65(1).北京：科学出版社，1982：131)，主要分布于热带和温带地区。我国有14种，7变种，3变型，主产长江以南地区，少数种类向西北经秦岭至西藏高原，向东北经华北至辽宁等地亦有分布，资源丰富。该属多种植物具有较高的药用价值，其中较为常用的有单叶蔓荆Vitex trifolia L.var.simplicifolia Cham.，蔓荆V.trifolia L.，黄荆V.negundo L.，牡荆V.negundo var.cannabifolia(Sieb.et Zucc.)Hand.-Mazz.以及穗花牡荆V.agnus-castus L.，它们的叶、果实、根等多个部位都作药用。黄荆分布于我国20余省市，其中以四川盆地和秦巴山区资源最为丰富，黄荆果实、叶、枝及根均可入药，各药用部位的功效略有偏重：果实—祛风解表，止咳平喘，理气消食止痛；叶—解表散热，化湿和中，杀虫止痒；枝条—祛风解表，消肿止痛；根—解表止咳，祛风除湿，理气止痛(国家中医药管理局《中华本草》编委会.中华本草[M].上海科学技术出版社，1999(6)：596-598)。此外，在印度的阿育吠陀医学Ayurvedic Medicine中，黄荆子(果实)可用于治疗类风湿性关节炎。牡荆为黄荆的变种，用途与黄荆相似。牡荆叶具有解表化湿，祛痰平喘，解毒的功效，早在《五十二病方》中即有用来治疗淋病的记载，其后《肘后方》记载其治疗蛇伤；牡荆果实—化湿祛痰，止咳平喘，理气止痛，主治咳嗽气喘；茎—祛风解表，消肿止痛；根—祛风解表，除湿止痛。蔓荆子为本属植物单叶蔓荆或蔓荆的干燥成熟果实，为常用中药，已收入《中国药典》，具有疏散风热，清利头目的功效。穗花牡荆的果实提取物在欧洲被广泛用来治疗雌激素失调及经前期综合症(Lauritzen C，Reuter HD，Repges R，Bohnert KJ，Schmidt U.Treatment of premenstrual tension syndrome with Vitexagnus-castus controlled，double-blind study versus pyridoxine.Phytomedicine，1997，4(3)：183-189)。国内外已有不少文献报道了牡荆属植物化学成分和药理方面的研究，尤其是穗花牡荆、单叶蔓荆和黄荆，由于它们在药理作用和临床应用方面表现出多种明显的活性，已引起国内外学者的广泛关注。
迄今为止，从该属植物中分离鉴定出数百种化学成分，主要类型有木脂素类、萜类(环烯醚萜、倍半萜、二萜和三萜)、黄酮类、植物甾类等(李春正，苏艳芳，靳先军.牡荆属植物化学成分及生物活性研究进展.中草药[J]，2005，36(6)：930-938)。其中，苯代萘型木脂素类成分为牡荆属植物的主要特征性成分之一。苯代萘型木脂素类化合物包括：6-羟基-4β-(4-羟基-3-甲氧基苯基)-3α-羟甲基-7-甲氧基-3，4-二氢-2-萘醛(VNL)、Vitedoin A、VitedoamineA、Vitedoamine B、Vitrofolals A-F、去四氢刺柏木脂体(detetrahydroconidendrin)和Vitexdoins A-E等(Ono M，Nishida Y，Masuoka C，Li JC，Okawa M，Ikeda T，Nohara T.Lignan derivatives and a norditerpene from the seeds of Vitex negundo.J.Nat.Prod.，2004，67(12)：2073-2075；Kawazoe K，Yutani A，Takaishi Y.Arylnaphthalenes norlignans from Vitex rotundifolia.Phytochemistry.1999，52(8)：1657-1659；Kawazoe K，Yutani A，Tamemoto K，Yuasa S，Shibata H，Higuti T，Takaishi Y.Phenylnaphthalene compounds from the subterranean part of Vitexrotundifolia and their antibacterial activity against methicillin-resistantStaphylococcus aureus.J.Nat.Prod.，2001，64：588-591；Zheng CJ，Huang BK，Han T，Zhang QY，Zhang H，Rahman K，Qin LP.Nitric oxide scavenging lignansfrom Vitex negundo seeds.J.Nat.Prod.，2009，72(9)：1627-1630)。现代药理试验表明，苯代萘型木脂素类化合物具有多种生物活性，其中6-羟基-4β-(4-羟基-3-甲氧基苯基)-3α-羟甲基-7-甲氧基-3，4-二氢-2-萘醛(VNL)具有镇痛活性(Zheng CJ，Tang WZ，Huang BK，Han T，Zhang QY，Zhang H，Qin LP.Bioactivity-guided fractionation for analgesic properties and constituents of Vitexnegundo L.seeds.Phytomedicine.2009，16：560-567)；6-羟基-4β-(4-羟基-3-甲氧基苯基)-3α-羟甲基-7-甲氧基-3，4-二氢-2-萘醛(VNL)和Vitexdoins A-E具有抗炎活性(Zheng CJ，Huang BK，Han T，Zhang QY，Zhang H，Rahman K，Qin LP.Nitric oxide scavenging lignans from Vitex negundo seeds.J.Nat.Prod.，2009，72(9)：1627-1630；Chawla AS，Sharma AK，Handa SS.A lignan from Vitex negundoseeds.Phytochemistry，1992，31(12)：4378-4379)；Vitrofolal C、Vitrofolal D和去四氢刺柏木脂体具有抗菌活性(Kawazoe K，Yutani A，Tamemoto K，Yuasa S，Shibata H，Higuti T，Takaishi Y.Phenylnaphthalene compounds from thesubterranean part of Vitex rotundifolia and their antibacterial activity againstmethicillin-resistant Staphylococcus aureus.J.Nat.Prod.，2001，64：588-591)；6-羟基-4β-(4-羟基-3-甲氧基苯基)-3α-羟甲基-7-甲氧基-3，4-二氢-2-萘醛(VNL)、Vitedoin A、Vitedoamine A、Vitrofolal E、Vitrofolal F和去四氢刺柏木脂体具有抗氧化活性(Ono M，Nishida Y，Masuoka C，Li JC，Okawa M，Ikeda T，Nohara T.Lignan derivatives and a norditerpene from the seeds of Vitex negundo.J.Nat.Prod.，2004，67(12)：2073-2075)等。
至今未见苯代萘型木脂素类化合物用于辐射损伤预防和治疗方面的报道。
发明内容
本发明的目的在于提供苯代萘型木脂素类化合物新的医药用途。
本发明提供了苯代萘型木脂素类化合物6-羟基-4β-(4-羟基-3-甲氧基苯基)-3α-羟甲基-7-甲氧基-3，4-二氢-2-萘醛(VNL)、Vitedoin A、Vitedoamine A和Vitrofolal F在制备抗辐射药物或食品中的应用。
本发明的苯代萘型木脂素类化合物是指：6-羟基-4β-(4-羟基-3-甲氧基苯基)-3α-羟甲基-7-甲氧基-3，4-二氢-2-萘醛(VNL)、Vitedoin A、Vitedoamine A和Vitrofolal F，它们的化学结构如下：
上述化合物以牡荆属植物为原料制备得到，制备方法可参考文献ZhengCJ，Huang BK，Han T，Zhang QY，Zhang H，Rahman K，Qin LP.Nitric oxidescavenging lignans from Vitex negundo seeds.J.Nat.Prod.，2009，72(9)：1627-1630或文献Zheng CJ，Tang WZ，Huang BK，Han T，Zhang QY，Zhang H，Qin LP.Bioactivity-guided fractionation for analgesic properties and constituentsof Vitex negundo L.seeds.Phytomedicine.2009，16：560-567。
上述化合物的制备方法包括如下步骤：
(1)制备提取液：将牡荆属植物药材粉碎后，投入提取罐，用40～90％的乙醇热提2～3次，每次溶媒用量约为生药量的8～10倍，每次提取时间为1～2小时，合并提取液；
(2)精制浓缩干燥：将上述提取液进行浓缩，浓缩液经石油醚脱脂后，用乙酸乙酯萃取，浓缩得到乙酸乙酯部位；
(3)分离纯化：将上述乙酸乙酯部位溶于水后上样大孔吸附树脂，收集60～80％乙醇洗脱部分，并以Sephadex LH-20纯化，甲醇-水为洗脱系统，得到高纯度(90％以上)的苯代萘型木脂素类化合物。
制备方法中，步骤“(1)制备提取液”中：所述的牡荆属植物包括黄荆、蔓荆、单叶蔓荆、牡荆、穗花牡荆、灰毛牡荆、山牡荆或莺哥木中的一种。
步骤“(2)精制浓缩干燥”中：所述的浓缩是减压回收溶剂。
步骤“(3)分离纯化”中：所述的的大孔树脂是选自AB-8、D-101、ZTC-1、HPD-100或DA201中的一种。
所述牡荆属植物可用其根、茎、叶、枝条或果实中的一种。
上述化合物经人淋巴母细胞(AHH-1)体外试验和动物试验，发现上述4个苯代萘型木脂素类化合物均可显著提高辐射损伤的AHH-1细胞活力，增加辐射损伤小鼠存活率和存活时间，具有良好的抗辐射活性，因此可用于制备抗辐射药物或食品。
具体实施方式
现结合实施例对本发明作详细描述，但本发明的实施不仅限于此。
实施例1：苯代萘型木脂素类化合物的制备
(1)制备提取液：将牡荆属植物药材粉碎后，投入提取罐，用40～90％的乙醇热提2～3次，每次溶媒用量约为生药量的8～10倍，每次提取时间为1～2小时，合并提取液；
(2)精制浓缩干燥：将上述提取液进行浓缩，浓缩液经石油醚脱脂后，用乙酸乙酯萃取，浓缩得到乙酸乙酯部位；
(3)分离纯化：将上述乙酸乙酯部位溶于水后上样大孔吸附树脂AB-8，上样吸附后，用5倍量柱床体积的水洗除杂，再依次用体积分数为20、40、60、80、95％的乙醇洗脱，每次用量为6倍量柱床体积，收集合并60～80％乙醇洗脱部分，减压浓缩，浓缩液上样凝胶柱色谱Sephadex LH-20，以80％甲醇-水为洗脱系统进行分离纯化，分段收集洗脱液，分别得到4个苯代萘型木脂素类化合物VNL、Vitedoin A、Vitedoamine A和Vitrofolal F。
结合1H-NMR、13C-NMR、DEPT、1H-1H COSY、HSQC、HMBC以及NOESY等波谱数据(Zheng CJ，Huang BK，Han T，Zhang QY，Zhang H，RahmanK，Qin LP.Nitric oxide scavenging lignans from Vitex negundo seeds.J.Nat.Prod.，2009，72(9)：1627-1630)，鉴定它们的化学结构如下：
实施例2：苯代萘型木脂素类化合物对辐照损伤人淋巴母细胞(AHH-1)活力的影响
(一)AHH-1细胞培养
人淋巴母细胞AHH-1细胞培养体系为DMEM培养基(Gibco)，含10％胎牛血清(hyclone)、100U/ml青霉素、100U/ml链霉素于37℃、5％CO2饱和湿度条件下培养。
(二)γ射线照射
采用60Co放射治疗机(上海医用核子仪器厂Fyc-50H)照射细胞，设定受照射细胞的照射剂量率为1Gy/min，照射剂量为4Gy。
(三)细胞分组
将对数生长期AHH-1细胞分为对照组、单纯照射组、单纯用药组和照射+药物高、中、低剂量组。对照组细胞不予照射和药物处理，单纯用药组仅给予不同浓度药物处理；单纯照射组和照射+药物组给予4Gy的γ射线照射，照射+药物组细胞照射前1h给予10和100mg/L药物共孵育。经不同处理后的细胞继续孵育48h，进行存活率检测。
(四)细胞活力测试
采用Cell Counting Kit-8试剂盒(CCK-8，日本同仁化学研究所)，取一定数量指数生长期的AHH-1细胞接种于96孔板，每组设7个复孔。按上述处理细胞后，分别培养至规定时间后，加CCK-810μl，继续孵育2h，酶标仪检测450nm处光密度(OD)值(630nm为参照波长)，重复实验3次。按公式计算细胞存活率(％)：细胞存活率＝(处理组OD值-空白组OD值)/(阴性对照组OD值-空白组OD值)×100％。结果见表1。
由表1可见4种苯代萘型木脂素化合物各组剂量组与辐射对照组比较细胞活力均有差异，且呈明显的剂量依赖关系。特别中、高剂量组对AHH-1细胞增殖作用非常明显，与辐射对照组比较有显著性差异。说明4种苯代萘型木脂素化合物均可对抗AHH-1细胞的辐射损伤，显著提高细胞活力，其中以化合物VNL效果最佳。
表1苯代萘型木脂素对辐照损伤AHH-1细胞存活率的影响
*p＜0.05；**p＜0.01vs辐射对照组
实施例3：苯代萘型木脂素类化合物对辐照损伤小鼠的影响
30天存活率实验：ICR雄性小鼠，6～8周龄，体重20±2g，中国人民解放军第二军医大学实验动物中心提供。饲养室温度18-22℃，相对湿度60％-75％，人工混合饲料喂养。随机分组：正常对照组、辐射对照组、给药组(80mg/kg·d)，每组10只小鼠，连续给药7天，6Gy照射，每天灌胃给药0.4ml，对照组灌胃等量生理盐水0.4ml。观察小鼠状态，记录死亡情况。结果见表2。
由表2可见，4个苯代萘型木脂素的均能提高辐射损伤小鼠的存活率和显著延长平均存活时间，与辐射对照组比较均有统计学差异。
表2苯代萘型木脂素对辐照损伤小鼠30天存活率和存活时间的影响(n＝10)
*p＜0.05vs辐射对照组
上述实验结果表明，苯代萘型木脂素类化合物VNL、Vitedoin A、Vitedoamine A和Vitrofolal F均可显著提高辐射损伤人淋巴母细胞的活力，增加辐射损伤小鼠存活率和存活时间，具有良好的抗辐射活性，因此可用于制备抗辐射药物或食品。
Claims (5)
1.苯代萘型木脂素类化合物在制备抗辐射药物或食品中的应用，其特征在于苯代萘型木脂素类化合物是指6-羟基-4β-(4-羟基-3-甲氧基苯基)-3α-羟甲基-7-甲氧基-3，4-二氢-2-萘醛、Vitedoin A、Vitedoamine A或Vitrofolal F。
2.根据权利要求1所述的苯代萘型木脂素类化合物在制备抗辐射药物或食品中的应用，其特征在于苯代萘型木脂素类化合物是用以下方法制得的：
(A)制备提取液：将牡荆属植物药材粉碎后，投入提取罐，用40～90％的乙醇热提2～3次，每次溶媒用量为生药量的8～10倍，每次提取时间为1～2小时，合并提取液；
(B)精制浓缩干燥：将上述提取液进行浓缩，浓缩液经石油醚脱脂后，用乙酸乙酯萃取，浓缩得到乙酸乙酯部位；
(C)分离纯化：将上述乙酸乙酯部位溶于水后上样大孔吸附树脂，收集合并60～80％乙醇洗脱部分，并以Sephadex LH-20凝胶柱色谱进行纯化，甲醇-水为洗脱系统，得到苯代萘型木脂素类化合物。
3.根据权利要求2所述的苯代萘型木脂素类化合物在制备抗辐射药物或食品中的应用，其特征在于步骤(A)中：所述的牡荆属植物是黄荆、蔓荆、单叶蔓荆、牡荆、穗花牡荆、灰毛牡荆、山牡荆或莺哥木。
4.根据权利要求2所述的苯代萘型木脂素类化合物在制备抗辐射药物或食品中的应用，其特征在于步骤(B)中：所述的浓缩是指减压回收溶剂。
5.根据权利要求2所述的苯代萘型木脂素类化合物在制备抗辐射药物或食品中的应用，其特征在于步骤(C)中：所述的的大孔树脂是AB-8、D-101、ZTC-1、HPD-100或DA201。
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| CN105796764B (zh) * | 2016-04-28 | 2019-12-10 | 中国人民解放军第二军医大学 | 黄荆子总木脂素制备方法及其用途 |
| CN105832898A (zh) * | 2016-05-26 | 2016-08-10 | 佛山科学技术学院 | 一种黄荆籽中黄酮的提取方法 |
| CN113018281B (zh) * | 2021-02-23 | 2023-02-03 | 中国人民解放军海军军医大学 | 一种Pellino1天然小分子抑制剂及其应用 |
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