CN108484373B - 一个具有促胶原蛋白分泌功效的化合物及其应用 - Google Patents
一个具有促胶原蛋白分泌功效的化合物及其应用 Download PDFInfo
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Abstract
本发明提供一个来源于傣药紫色姜(Zingiber purpureum Rosc.)的天然产物化合物1:cis‑3‑(3,4‑Dimethoxyphenyl)‑4‑[(E)‑2,4,5‑trimehoxystyryl]cyclohex‑1‑ene,其在抗衰老护肤产品中的应用和其制备方法。通过对傣药紫色姜根茎的乙醇提取物进行化学成分分离,对得到的单体化合物进行了促进成人真皮纤维原细胞(human dermal fibroblasts‑adult,HDFa)分泌胶原蛋白的活性评价和分析,化合物1的半数有效浓度EC50(ug/mL)为13.906±1.562,对正常HDFa细胞未显示细胞毒性。因此,该化合物在护肤产品中具有应用价值。
Description
技术领域:
本发明属于化妆品和医药技术领域,具体涉及一种中国传统民族药用植物中分离得到的一个天然产物化合物1:cis-3-(3,4-Dimethoxyphenyl)-4-[(E)-2,4,5-trimehoxystyryl]cyclohex-1-ene,其具有促进HDFa细胞分泌胶原蛋白的活性,以及该化合物的制备方法和应用。
背景技术:
抗衰老自古以来就是人们所追求的,而随着人们生活水平的提高,如何抵抗容颜的衰老,越来越受到人们的关注,所以开发健康安全的抗衰老护肤品越来越受到人们的重视。根据全球消费情况来看,抗衰老护肤产品在护肤品的消费量中占有较高的比重。
皮肤由表皮、真皮和皮下组织构成,是人体最大的器官,可防止体内水分、电解质和其他物质的丢失,防止外界有害物质的侵入;是维护人体生命和健康的重要部分,是人体的第一道屏障。皮肤中75%由胶原蛋白组成,皮肤的生长、修复和营养都离不开胶原蛋白,皮肤健康的两大关键保湿和抗皱都与胶原蛋白有关。由于遗传因素等不可抗内因以及紫外线、辐射等外界刺激,皮肤逐渐发生老化,而胶原蛋白的流失是皮肤衰老的开始。随着年龄的增长,皮肤中的胶原蛋白的合成开始下降,胶原蛋白开始逐渐减少。所以补充皮肤中的胶原蛋白,恢复、重建皮肤中的胶原蛋白层,是保持皮肤年轻,恢复皮肤健康的关键。目前,补充皮肤胶原蛋白主要有以下几种方式:(1)口服富含胶原蛋白的食物,(2)皮下注射胶原蛋白,(3)使用富含胶原蛋白的护肤品,(4)在护肤品中添加能刺激皮肤合成胶原蛋白的活性成分。前三种存在作用有限、时间长、过敏、易感染、吸收有限等各种局限性,且治标不治本,而在护肤品中添加可刺激皮肤合成胶原蛋白的活性成分是通过刺激自身皮肤合成胶原蛋白来达到补充胶原蛋白的目的,可以从根本上解决胶原蛋白流失的问题,以重建皮肤的胶原蛋白骨架,保持肌肤年轻,富有弹性。
紫色姜(Zingiber purpureumRosc.)又名卡萨蒙纳姜(Zingiber cassumunarRoxb)为姜科(Zingiberaceae)姜属(Zingiber)植物,云南南部与东南部有栽培。印度、斯里兰卡及柬埔寨、南亚有分布或栽培。紫色姜性辛、微苦,温。入肝、胃、肾经。具有健胃消食,通气止痛,除风解毒,活血消肿,利胆退黄的功效。用于胃脘胁肋胀痛,食积不化,呕吐腹泻;胆汁病;肾虚腰腿痛,风湿痹痛;跌打损伤;疔疮痈疖,毒虫咬伤。其根茎提取物和根茎油被收录于化妆品原料目录中。近年来,关于紫色姜挥发油的报道主要为萜类,包括单萜、倍半萜及其含氧衍生物。其挥发油中的萜类化合物大致相同,但含量随样品的产地、采收时间、提取部位、提取方法等外界因素的不同而不同。其挥发油药理作用侧重于抗菌、抗真菌、抗炎、抗氧化和杀虫等作用,未见对其活性成分研究的报道。其非挥发性成分主要有三类:苯基丁烯类、姜黄素类、醌类,具有较多的生物活性。
发明内容:
本发明所要解决的技术问题是化合物1:cis-3-(3,4-Dimethoxyphenyl)-4-[(E)-2,4,5-trimehoxystyryl]cyclohex-1-ene在抗衰老护肤品中的应用,以及该化合物的制备方法。本发明通过对傣药紫色姜中分离到的化合物进行促进HDFa细胞分泌胶原蛋白的活性评价,首次发现从傣药紫色姜中分离到的所述的化合物1具有较好的促进HDFa细胞分泌胶原蛋白的活性。
本发明的上述目的是通过如下的技术得以实现的:
如下结构式所示的化合物1,cis-3-(3,4-Dimethoxyphenyl)-4-[(E)-2,4,5-trimehoxystyryl]cyclohex-1-ene,
所述的化合物1,其半数有效浓度EC50(ug/mL)为13.906±1.562,具有促进成人真皮纤维原细胞分泌胶原蛋白的作用,对正常HDFa细胞未显示细胞毒性。
抗衰老活性添加剂,其特征在于:其有效成分中包括权利要求1所述的化合物1。
抗衰老护肤品,其特征在于:其有效成分中包括权利要求1所述的化合物1。所述的抗衰老护肤品包括但不限于化妆水、爽肤水、乳液、霜膏、洁面霜等。
化合物1的制备方法,该方法包括下述步骤:将紫色姜根茎阴干,过20目筛,用95%的乙醇-水冷浸提取3次,每次24小时,合并提取液,提取液浓缩至仅剩水时用石油醚萃取,萃取3次,得到石油醚萃取物经反复的正相硅胶柱层析,最后经HPLC半制备得到该活性化合物1。
根据所述的化合物1的制备方法,该方法包括下述步骤:阴干的紫色姜块茎粉碎,经95%乙醇-水冷浸提取3次,每次24小时,合并提取液,提取液浓缩至仅剩水时用石油醚萃取,萃取3次,得石油醚提取物,石油醚提取物经正相硅胶柱层析,用石油醚/乙酸乙酯系统按以下梯度洗脱:石油醚洗脱3L,石油醚/乙酸乙酯20:1洗脱9L,石油醚/乙酸乙酯15:1洗脱3L,石油醚/乙酸乙酯9:1洗脱7L,石油醚/乙酸乙酯4:1洗脱3L,石油醚/乙酸乙酯3:1洗脱3L,石油醚/乙酸乙酯2:1洗脱6L,通过薄层色谱TLC分析后共合并为20个段,记为P1-P20;其中P18经Sephadex LH-20凝胶柱层析,丙酮洗脱,TLC检测分析后合并为P18a,P18b,P18c三部分;P18b部分经正相硅胶柱层析,用石油醚/氯仿系统按以下梯度洗脱:石油醚/氯仿1∶2洗脱0.8L,石油醚/氯仿1:3洗脱1L,石油醚/氯仿1∶4洗脱0.6L,石油醚/氯仿1∶5洗脱0.5L,石油醚/氯仿1∶8洗脱0.5L,氯仿洗脱0.2L,最后TLC检测分析后合并为P18b1,P18b2,P18b3,P18b4四部分,P18b2经正相硅胶柱层析,用石油醚/氯仿系统按以下梯度洗脱:石油醚/氯仿1∶4洗脱0.8L,石油醚/氯仿1∶5洗脱0.6L,石油醚/氯仿1∶7洗脱0.6L,石油醚/氯仿1∶9洗脱0.3L,最后TLC检测分析后合并为P18b2a,P18b2b两部分;P18b2b经HPLC,78%甲醇-水半制备柱分离得化合物1。
化合物1在制备抗衰老活性添加剂中的应用。
化合物1在制备抗衰老护肤品中的应用。
具体实施方式
以下对本发明的原理和特征进行描述,所举实例只用于解释本发明,并非用于限定本发明的范围。
实施例1:
1、化合物1的制备:
阴干的紫色姜块茎4kg粉碎,经95%乙醇-水冷浸提取3次,每次24小时,合并提取液,提取液浓缩至仅剩水时用石油醚萃取,萃取3次,得石油醚提取物55g。石油醚提取物(50g)经正相硅胶柱层析,用石油醚/乙酸乙酯系统按以下梯度洗脱:石油醚洗脱3L,石油醚/乙酸乙酯20:1洗脱9L,石油醚/乙酸乙酯15:1洗脱3L,石油醚/乙酸乙酯9:1洗脱7L,石油醚/乙酸乙酯4:1洗脱3L,石油醚/乙酸乙酯3:1洗脱3L,石油醚/乙酸乙酯2:1洗脱6L,通过薄层色谱(TLC)分析后共合并为20个段,记为P1-P20;其中P18(1.619g)经Sephadex LH-20凝胶柱层析,丙酮洗脱,TLC检测分析后合并为P18a,P18b,P18c三部分;P18b(1.06g)部分经正相硅胶柱层析,用石油醚/氯仿系统按以下梯度洗脱:石油醚/氯仿1:2洗脱0.8L,石油醚/氯仿1:3洗脱1L,石油醚/氯仿1:4洗脱0.6L,石油醚/氯仿1:5洗脱0.5L,石油醚/氯仿1:8洗脱0.5L,氯仿洗脱0.2L,最后TLC检测分析后合并为P18b1,P18b2,P18b3,P18b4四部分,P18b2(550mg)经正相硅胶柱层析,用石油醚/氯仿系统按以下梯度洗脱:石油醚/氯仿1:4洗脱0.8L,石油醚/氯仿1:5洗脱0.6L,石油醚/氯仿1:7洗脱0.6L,石油醚/氯仿1:9洗脱0.3L,最后TLC检测分析后合并为P18b2a,P18b2b两部分;P18b2b(90mg)经HPLC(78%甲醇-水)半制备柱分离得化合物1。
2、化合物1的结构解析:
化合物1白色粉末,C25H30O5,其波谱数据如下:1H-NMR(CDCl3,500MHz)δ:5.94-6.02(1H,m,H-1),5.79(1H,ddt,J=10.0,4.5,2.1Hz,H-2),3.52(1H,s,H-3),2.68-2.81(1H,m,H-4),1.59-1.74(2H,m,H-5),2.13-2.29(2H,m,H-6),6.71(1H,d,J=2.0Hz,H-2'),6.80(1H,d,J=8.2Hz,H-5'),6.75(1H,dd,J=8.2,2.0Hz,H-6'),5.53(1H,dd,J=16.0,9.2Hz,H-1”),6.60(1H,dd,J=16.0,0.9Hz,H-2”),6.47(1H,s,H-3”'),6.71(1H,s,H-6”'),3.87(3H,s,OMe),3.85(3H,s,OMe),3.78(3H,s,OMe),3.77(6H,s,2×OMe);13CNMR(CDCl3,500MHz)δ:128.2(CH,C-1),129.3(CH,C-2),45.9(CH,C-3),43.0(CH,C-4),24.4(CH2,C-5),25.0(CH2,C-6),134.1(C,C-1'),113.7(CH,C-2'),148.9(C,C-3'),147.6(C,C-4'),110.3(CH,C-5'),122.1(CH,C-6'),133.0(CH,C-1”),122.8(CH,C-2”),118.9(C,C-1”'),150.8(C,C-2”'),97.9(CH,C-3”'),148.1(C,C-4”'),143.4(C,C-5”'),109.6(CH,C-6”'),55.9(OMe),56.2(OMe),56.8(OMe),56.0(OMe),56.5(OMe)。通过对化合物1的碳氢谱数据分析可看出其属于二聚苯丁烯类化合物,并且含5个甲氧基,通过与文献波谱数据对比,最终确定了化合物1为:cis-3-(3,4-Dimethoxyphenyl)-4-[(E)-2,4,5-trimehoxystyryl]cyclohex-1-ene。其结构式为:
实施例2:
1、化合物1促进HDFa细胞分泌胶原蛋白的活性评价及细胞毒性评价
成人真皮纤维原细胞(human dermal fibroblasts-adult,HDFa)购自CascadeBiologics。
HDFa细胞毒性实验:96孔细胞培养板上,分别将HDFa细胞与待测药物溶液混合,设定3个重复孔,同时设置不含药物的空白对照,37℃,5%CO2培养24h,采用MTS比色法检测细胞毒性,酶标仪测定OD值,测定波长490nm。计算得到细胞存活率。
细胞存活率(%)=实验孔OD490nm/空白孔OD490nm×100%
促HDFa胶原蛋白分泌实验:12孔细胞培养板上,将HDFa细胞与10g/mL的待测药物溶液混合,设置不含药物的空白对照和TGF-β阳性对照。37℃,5%CO2培养3天,收取细胞培养上清,存于-80℃;加入MTS,采用MTS比色法检测490nm的OD值;按胶原蛋白ELISA试剂盒中提供的方法检测胶原蛋白的分泌,上清以1:200倍稀释,酶标仪测定OD值,检测波长为450nm。计算得到胶原蛋白分泌增加率。
细胞存活率(%)=实验孔OD490nm/空白孔OD490nm×100%
胶原蛋白分泌增加率(%)=(实验孔OD450nm/细胞存活率/空白孔OD450nm-1)×100%
2、化合物1促进HDFa细胞分泌胶原蛋白的活性评价及细胞毒性评价结果。
化合物1对促进HDFa细胞胶原蛋白分泌的促进作用和细胞毒作用结果如下表1所示。
表1.化合物1对HDFa细胞胶原蛋白分泌的促进作用细胞毒作用
综合以上结果,活性化合物1对HDFa细胞胶原蛋白分泌具有较好的促进作用,其半数有效浓度EC50(ug/mL)为13.906±1.562,此外化合物1对正常HDFa细胞也未显示细胞毒性。因此,活性化合物1在抗衰老护肤品中具有应用价值。该活性化合物可刺激自身皮肤合成胶原蛋白来达到补充胶原蛋白的目的,从根本上解决胶原蛋白流失的问题,保持肌肤年轻,富有弹性。
实施例3:
含有化合物1的美白霜配方(wt%):
按常规制作化妆品的方法制得本发明上述配方的化妆品。
实施例4:
含有化合物1的乳剂配方(wt%):
按常规制作化妆品的方法制得本发明上述配方的化妆品。
Claims (6)
2.根据权利要求1所述的化合物1在制备抗衰老活性添加剂或抗衰老护肤品中的应用,其特征在于,其半数有效浓度EC50(ug/mL)为13.906±1.562,具有促进成人真皮纤维原细胞分泌胶原蛋白的作用,对正常HDFa细胞未显示细胞毒性。
3.抗衰老活性添加剂,其特征在于,其有效成分中包括权利要求1所述的化合物1。
4.抗衰老护肤品,其特征在于,其有效成分中包括权利要求1所述的化合物1。
5.根据权利要求4所述的抗衰老护肤品,其特征在于,所述的抗衰老护肤品为化妆水、爽肤水、乳液、霜膏、洁面霜。
6.权利要求1所述的化合物1的制备方法,该方法包括下述步骤:
阴干的紫色姜块茎粉碎,经95%乙醇-水冷浸提取3次,每次24小时,合并提取液,提取液浓缩至仅剩水时用石油醚萃取,萃取3次,得石油醚提取物,石油醚提取物经正相硅胶柱层析,用石油醚/乙酸乙酯系统按以下梯度洗脱:石油醚洗脱3L,石油醚/乙酸乙酯20:1洗脱9L,石油醚/乙酸乙酯15:1洗脱3L,石油醚/乙酸乙酯9:1洗脱7L,石油醚/乙酸乙酯4:1洗脱3L,石油醚/乙酸乙酯3:1洗脱3L,石油醚/乙酸乙酯2:1洗脱6L,通过薄层色谱TLC分析后共合并为20个段,记为P1-P20;其中P18经Sephadex LH-20凝胶柱层析,丙酮洗脱,TLC检测分析后合并为P18a,P18b,P18c三部分;P18b部分经正相硅胶柱层析,用石油醚/氯仿系统按以下梯度洗脱:石油醚/氯仿1∶2洗脱0.8L,石油醚/氯仿1:3洗脱1L,石油醚/氯仿1∶4洗脱0.6L,石油醚/氯仿1∶5洗脱0.5L,石油醚/氯仿1∶8洗脱0.5L,氯仿洗脱0.2L,最后TLC检测分析后合并为P18b1,P18b2,P18b3,P18b4四部分,P18b2经正相硅胶柱层析,用石油醚/氯仿系统按以下梯度洗脱:石油醚/氯仿1∶4洗脱0.8L,石油醚/氯仿1∶5洗脱0.6L,石油醚/氯仿1∶7洗脱0.6L,石油醚/氯仿1∶9洗脱0.3L,最后TLC检测分析后合并为P18b2a,P18b2b两部分;P18b2b经HPLC,78%甲醇-水半制备柱分离得化合物1。
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Address after: 650201 No. 132 Lanhei Road, Kunming City, Yunnan Province Patentee after: KUNMING INSTITUTE OF BOTANY, CHINESE ACADEMY OF SCIENCES Patentee after: Beijing plant doctor Biotechnology Co.,Ltd. Address before: 650201 No. 132 Lanhei Road, Kunming City, Yunnan Province Patentee before: KUNMING INSTITUTE OF BOTANY, CHINESE ACADEMY OF SCIENCES Patentee before: BEIJING MINGHONG SCIENCE AND TRADE CO.,LTD. |