CN107814784A - 一种咖啡酸内酯及其制备方法、药物组合物与应用 - Google Patents
一种咖啡酸内酯及其制备方法、药物组合物与应用 Download PDFInfo
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- CN107814784A CN107814784A CN201710102040.0A CN201710102040A CN107814784A CN 107814784 A CN107814784 A CN 107814784A CN 201710102040 A CN201710102040 A CN 201710102040A CN 107814784 A CN107814784 A CN 107814784A
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- acid lactone
- preparation
- coffee
- coffee acid
- tyrosinase
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- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
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Abstract
本申请涉及咖啡酸衍生物,具体讲,涉及一种如式I所示的咖啡酸内酯,其制备方法、药物组合物和应用。
Description
技术领域
本申请涉及咖啡酸衍生物,具体讲,涉及一种咖啡酸内酯,其制备方法、药物组合物和应用。
背景技术
酪氨酸酶是生物体黑色素合成的关键酶。酪氨酸酶的活性与黑素合成量相关,可通过调控其活力而调控黑色素的生成。黑色素(Melanin)是决定人类皮肤、眼睛和头发颜色的重要因素。酪氨酸酶催化酪氨酸氧化成多巴,多巴氧化形成多巴醌反应,控制黑色素细胞的活性,是黑色素合成的关键酶。其异常的表达量或直接或间接地导致人类的某些疾病,如酪氨酸酶的过量表达会导致恶性黑色素瘤、皮肤色斑等;若表达量过低则会导致白癜风、白化病等疾病。因此针对目前常见的色素沉着疾病如雀斑、老年斑或者黄褐斑等,国内外已经多达几百篇的文献报道;而针对酪氨酸酶过低表达的相关研究却明显少得多。
在皮肤色素缺陷疾病中,以白癜风最为严重。白癜风是一种后天性色素脱失性皮肤病,是皮肤毛囊的内黑素细胞酪氨酸系统的功能减退或丧失引起的,好发于暴露部位而影响美观,症状为皮肤出现局限性或泛发性色素脱失斑,皮损处黑色素的生成减少或消失,是一种容易诊断而难于治疗的皮肤病。目前治疗白癜风的常见方法是药物疗法、物理疗法和外科疗法,而药物疗法中主要采用中药治疗,绝大部分都是分离提取物,而人工合成药物几乎没有。并且天然提取物成分复杂,造成提取和加工工艺困难。而化学合成的药物利于大批量生产,制作工艺简单,效果快速而显著,但容易存在安全性的问题。
鉴于此,特提出本申请。
发明内容
本申请的首要发明目的在于提出一种咖啡酸内酯。
本申请的第二发明目的在于提出该咖啡酸内酯的制备方法。
本申请的第三发明目的在于提出含有该咖啡酸内酯的药物组合物。
本申请的第四发明目的在于提出该咖啡酸内酯的应用。
为了完成本申请的目的,采用的技术方案为:
本申请涉及一种咖啡酸内酯,所述咖啡酸内酯的结构式如式I所示:
本申请还涉及该咖啡酸内酯的制备方法,至少包括以下步骤:
(1)将咖啡酸加入到二甲基亚砜溶液中溶解,得到咖啡酸二甲基亚砜溶液;
(2)在所述咖啡酸二甲基亚砜溶液中加入碱和有机溶剂,然后加热进行反应;
(3)反应结束后,经过滤和沉淀,得到所述咖啡酸内酯。
优选的,在步骤(1)中,所述咖啡酸的纯度为99.5%~99.99%,优选为99.75%~99.9%。
优选的,在步骤(1)中,所述咖啡酸与二甲基亚砜的质量比为1:1.3~1.6,优选1:1.5。
优选的,在步骤(2)中,所述碱选自氢氧化钠、氢氧化钾中的至少一种;所述有机溶剂选自二氯甲烷、三氯甲烷、丙酮、石油醚、乙酸乙酯、乙腈、四氢呋喃、1,4-二氧六环、正己烷中的至少一种;所述咖啡酸与碱的质量比为1:0.09~0.12,优选1:0.11;在步骤(2)中,所述咖啡酸二甲基亚砜溶液与所述有机溶剂的体积比为1:8~10,优选1:9。
优选的,在步骤(2)中,所述加热为油浴加热,加热的温度为70~90℃,加热时间为5~6h;优选加热的温度为75~85℃。
优选的,在步骤(3)中,所述过滤为抽滤,采用蒸馏水或去离子水冲洗后进行沉淀,并优选重复2~3次。
本申请还涉及一种药物的组合物,含有权利要求1所述的化合物和制剂学可接受的载体。
本申请还涉及该咖啡酸内酯在制备治疗或预防白发症或色素紊乱症的药品、保健品或化妆品中应用。
优选的,所述白发症选自遗传性白发、后天性少白头或老年性白发,所述色素紊乱症选自白癜风、白化病。
本申请的技术方案至少具有以下有益的效果:
本申请提供了一种新型无毒的咖啡酸内酯化学物,对酪氨酸酶活性具有较好的激活作用,可应用于制备治疗或预防白发症或色素紊乱症的药品、保健品或化妆品。
本申请的咖啡酸内酯化合物制备工艺简单,收率高。
附图说明
图1为本申请实施例咖啡酸内酯的质谱图;
图2为本申请实施例咖啡酸内酯的核磁共振图谱;
图3为本申请实施例咖啡酸内酯的红外图谱;
图4为咖啡酸内酯对蘑菇酪氨酸酶二酚酶活性的激活作用曲线;
图5为咖啡酸内酯对蘑菇酪氨酸酶竞的争性激活曲线;
图6为未加咖啡酸内酯的情况下,酪氨酸酶催化氧化作用不同时间后的紫外可见光谱;
图7为咖啡酸内酯对酪氨酸酶催化氧化不同时间后的紫外可见光谱;
图8为咖啡酸内酯对酪氨酸酶荧光淬灭的影响曲线;
图9为咖啡酸内酯对酪氨酸酶最大荧光发射峰的影响曲线;
图10为咖啡酸内酯对酪氨酸酶的Stern-Volmer曲线方程;
图11为咖啡酸内酯对人M14黑色素瘤细胞中酪氨酸酶相关蛋白表达电泳图谱;
图12为咖啡酸内酯对人M14黑色素瘤细胞内酪氨酸活性的激活作用曲线;
图13为咖啡酸内酯对人正常肝细胞LO2增殖的影响的柱状图。
具体实施方式
下面实施例将结合附图对本申请作进一步的详细描述,以使本领域技术人员能够实践本发明。应当理解,可以采用其他实施方式,并且可以做出适当的改变而不偏离本申请的范围。为了避免对于使本领域技术人员能够实践本发明来说不必要的细节,说明书可能省略了对于本领域技术人员来说已知的某些信息。因此,以下详细描述不应以限制性的意义来理解,且本申请的范围仅由权利要求界定。
以下的实施例便于更好地理解本发明,但并不用来限制本发明的范围。
本申请涉及一种咖啡酸内酯,相对分子质量为162.16,结构式如式I所示:
本申请实施例还涉及该咖啡酸内酯的制备方法,至少包括以下步骤:(1)将咖啡酸加入到二甲基亚砜溶液中溶解,得到咖啡酸二甲基亚砜溶液;
(2)在所述咖啡酸二甲基亚砜溶液中加入碱和有机溶剂,然后加热进行反应;
(3)反应结束后,经过滤和沉淀,得到所述咖啡酸内酯。
作为本申请实施例制备方法的一种改进,咖啡酸的纯度为99.5%~99.99%,如果原料咖啡酸的纯度过低,则在反应过程中会产生其他的副产物,影响产物的提纯效率;且会降低产率,这就增加了生产成本。因此优选纯度为99.75%~99.9%的咖啡酸原料。
作为本申请实施例制备方法的一种改进,在步骤(1)中,咖啡酸与二甲基亚砜的质量比为1:1.3~1.6,优选1:1.5。如果咖啡酸比例过大,则溶解不完全;如果咖啡酸比例过小,则会影响产率。
作为本申请实施例制备方法的一种改进,在步骤(2)中,碱选自氢氧化钠、氢氧化钾;咖啡酸与碱的质量比为1:0.09~0.12,优选1:0.11。如果碱添加比例过大,反应体系内pH过高,影响咖啡酸的羟基与羧基的反应;如果碱添加比例过不足,反应体系内碱性不足,会导致反应不充分而影响产率。
作为本申请实施例制备方法的一种改进,在步骤(2)中,有机溶剂选自但不限于:二氯甲烷、三氯甲烷、丙酮、石油醚、乙酸乙酯、乙腈、四氢呋喃、1,4-二氧六环、正己烷等中的至少一种;本申请中通过添加有机溶剂,使咖啡酸以最大溶解度在溶液体系中充分断键并重新连接,形成产物。
作为本申请实施例制备方法的一种改进,在步骤(2)中,咖啡酸二甲基亚砜溶液与有机溶剂的体积比为1:8~10,优选1:9。
作为本申请实施例制备方法的一种改进,在步骤(2)中,加热方式采用油浴加热,油浴加热的优势为受热均匀且稳定,便于控制。加热的温度为70~90℃,加热时间为5~6h;优选加热的温度为75~85℃。
作为本申请实施例制备方法的一种改进,步骤(3)中,过滤采用抽滤,采用蒸馏水或去离子水冲洗后进行沉淀以进一步提高纯度,并优选重复2~3次。
将制备得到的咖啡酸内酯采用质谱、红外和核磁共振进行结构鉴定。其中,使用Esquire 3000plus低分辨率电喷雾质谱质谱仪测试得到的质谱图如图1所示;如图1中所示,咖啡内酯分子量为162.16,加一个电子显示质量为163.24。应用核磁共仪Bruker 600M对咖啡酸内酯的结构进行鉴定,核磁共振图谱如图2所示,具体鉴定结果为:1H NMR(600MHz,DMSO)δ7.08(d,J=15.7Hz,1H),6.89(d,J=1.8Hz,1H),6.75(dd,J=8.1,1.8Hz,1H),6.68(d,J=8.1Hz,1H),6.12(d,J=10.5Hz,1H),6.11(s,1H)。采用GXH-3051型CO2红外线测定仪对物质结构的鉴定的红外图谱如图3所示。
采用申请的上述制备体系制备咖啡酸内酯的产率为56.9~59.7%。
本申请实施例还涉及一种药物组合物,含有本申请的咖啡酸内酯和制剂学可接受的载体。该药物组合物可根据本领域公知的方法制备。可通过将咖啡酸内酯与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合,制成适于人或动物使用的任何剂型。咖啡酸内酯在其药物组合物中的含量通常为0.1~95重量%。
本申请实施例咖啡酸内酯的或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、皮肤等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本申请实施例咖啡酸内酯可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将申请实施例咖啡酸内酯制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;湿润剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将给药单元制成胶囊剂,可以将有效成分本申请实施例咖啡酸内酯与稀释剂、助流剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本申请实施例咖啡酸内酯先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本申请实施例咖啡酸内酯片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本申请实施例咖啡酸内酯的胶囊剂。
为将本申请实施例咖啡酸内酯制成注射剂,可以用异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。
为将本申请实施例的咖啡酸内酯制成外用制剂或化妆品,可将咖啡酸内酯与甘油混合,形成乳浊液,然后加入约100℃的热水,室温搅拌1~2h,咖啡酸内酯逐渐溶解,从而可制备各种外用制剂或添加于化妆品中。例如,可采用本申请实施例的咖啡酸内酯制备用于使白发变黑的化妆品,例如染发剂等产品。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本申请实施例咖啡酸内酯药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度,患者或动物的个体情况,给药途径和剂型等可以有大范围的变化。一般来讲,本申请实施例咖啡酸内酯的每天的合适剂量范围0.001~150mg/Kg体重,优选为0.01~100mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药,这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本申请实施例咖啡酸内酯或组合物可单独使用,或与其他治疗药物或对症药物合并使用。当申请实施例咖啡酸内酯与其它治疗药物存在协同作用时,应根据实际情况调整它的剂量。
本申请实施例还涉及咖啡酸内酯在制备治疗或预防白发或色素紊乱症的药品、保健品或化妆品中应用。
本申请实施例对所制备得到的咖啡酸内酯的生理活性进行了研究,经研究发现,本申请实施例的咖啡酸内酯能在试管中有效激活蘑菇酪氨酸酶、人酪氨酸酶的活力,能在人体黑色素瘤M14细胞中有效上调酪氨酸酶及多种相关蛋白的表达量,例如:酪氨酸酶相关蛋白(TRP-1)、酪氨酸酶相关蛋白(TRP-2)、小眼畸形相关转录因(MITF)、促黑细胞激素抗体(α-MSH)、GAPDH等。并且经实验证实,本申请的咖啡酸内酯对酪氨酸酶的激活属于竞争性激活。本申请的咖啡酸内酯羟基上的自由氢可以与酪氨酸酶的活性中心的Met280残基形成氢键,羧基供氧可以与酪氨酸酶活性中心的His61、His94形成氢键,这些氢键可以改变蛋白质的构象;除此之外,咖啡酸内酯还与活性中心的Phe90、Phe264、Asn260、His259、His85、Phe292、Ser282、Ala286和Glu256残基相互作用。因此,其可对酪氨酸酶表达失调所引起的色素紊乱症和白发症起到治疗的效果。例如酪氨酸酶表达不足引起的白癜风、白化病。白发症包括遗传性白发、后天性少白头或老年性白发。
本申请实施例对所制备得到的咖啡酸内酯进行了毒性试验,经实验证实,对人体正常肝细胞LO2和小鼠无毒性。
下述实施例中所使用的各原料,除特别指出的以外,均可由市售获得。
实施例:咖啡酸内酯的制备
纯度为99.9%的咖啡酸7.2g先加入10mL的二甲基亚砜(DMSO,约11.014g)搅拌使咖啡酸充分溶解,再加入0.8g的氢氧化钠,90mL的二氯甲烷,搅拌,油浴加热至80℃。5h后反应停止,冷却至室温后,直接抽滤,用去离子水或蒸馏水对沉淀进行冲洗3次,干燥后得到黄色固体产物4.24g。该产物的结构验证图谱与图1~图3相同。
实验例1:咖啡酸内酯对蘑菇酪氨酸酶活性的影响
首先配制1mg/mL的L-多巴溶液,轻轻摇晃使其充分溶解;再配制0.2mmol/L磷酸缓冲液和0.2mg/mL蘑菇酪氨酸酶溶液。将双蒸水和磷酸缓冲液置于30℃的水浴锅中保温,在比色杯中加入1.8mL双蒸水、0.75mL磷酸缓冲液、0.3mL多巴溶液以及不同浓度的咖啡酸内酯溶液后,再加入0.05mL酪氨酸酶溶液,立即充分混匀后,于475nm处测定吸光值。其中,蘑菇酪氨酸酶的浓度为3.33μg/mL,比活力为6680U/mg。最终反应体系为3.0mL,咖啡酸内酯的终浓度为0~0.45mmol/L,以双蒸水作为实验对照。
30℃恒温条件下测定波长为475nm的光密度值(OD475nm)随时间的增长直线,从直线的斜率求得酪氨酸酶的活力,产物的消光系数按3700L/(mol·cm)来计算。绘制得到的曲线如图4所示。
由图4可以看出,咖啡酸内酯对蘑菇酪氨酸酶的活力具有明显的激活作用,在咖啡酸内酯浓度为0.45mmol/L,酪氨酸酶活力达到半激活率。随着咖啡酸内酯浓度的增加,酪氨酸酶的活力显著提高。
实验例2:咖啡酸内酯在试管中对蘑菇酪氨酸酶的激活类型
首先配制1mg/mL的L-多巴溶液,轻轻摇晃使其充分溶解;再配制0.2mmol/L磷酸缓冲液和0.2mg/mL蘑菇酪氨酸酶溶液。将双蒸水和磷酸缓冲液置于30℃的水浴锅中保温,在比色杯中加入1.8mL双蒸水、0.75mL磷酸缓冲液、0.3mL多巴溶液以及不同浓度的咖啡酸内酯溶液后,再加入0.05mL酪氨酸酶溶液,立即充分混匀后,于475nm处测定吸光值。其中,蘑菇酪氨酸酶的浓度为3.33μg/mL,咖啡酸内酯的不同浓度0、1、2、3、4分别代表0、0.125mmol/L、0.25mmol/L、0.375mmol/L、0.5mmol/L;最终反应体系为3.0mL,以双蒸水作为实验对照。
30℃恒温条件下测定波长为475nm的光密度值(OD475nm)随时间的增长直线,从直线的斜率求得酪氨酸酶的活力,产物的消光系数按3700L/(mol·cm)来计算。用Lineweaver-Burk双倒数作图,以判定激活剂作用于底物和酪氨酸酶的方式。
由图5可知,Lineweaver-Burk双倒数作图为相交于Y轴的一组直线。随着咖啡酸浓度的增大,直线横轴截距和直线斜率减小,符合竞争性激活的特征,因此可认为咖啡酸内酯对酪氨酸酶的激活属于竞争性激活。
实验例3:咖啡酸内酯对蘑菇酪氨酸酶的紫外可见光谱学研究
通过紫外可见光谱研究该类化合物对酪氨酸酶的抑制机理。
在石英比色杯中加入1.8mL双蒸水、0.75mL磷酸缓冲液、0.3mL多巴溶液以及不同浓度的咖啡酸内酯溶液后,再加入0.05mL酪氨酸酶溶液,立即充分混匀后,于240~800nm波长范围内每隔1min扫描一条线。其中,咖啡酸内酯的浓度分别为0和0.25mmol/L;且在咖啡酸内酯加入后,先对溶液进行扫描,标记为0号线,目的在于排除咖啡酸内酯在特征峰处的影响。
在图6中,曲线1~10是L-DOPA在未加效应物的情况下,酪氨酸酶催化氧化作用不同时间后的紫外可见光谱,由图可知L-DOPA被酪氨酸酶催化氧化后紫外光谱产生了特征峰(最大吸收峰)。475nm是测定酪氨酸酶活性时所采用,吸收值随着催化反应时间的延长不断增大,是产物在可见区的特征峰。
在图7中,曲线0是咖啡酸内酯本身在紫外可见光谱中的吸收峰,可以发现其在475nm处是没有特征峰的;而曲线1~10是L-DOPA在加咖啡酸内酯的情况下,酪氨酸酶催化氧化作用不同时间后的紫外可见光谱,由图可知L-DOPA被酪氨酸酶催化氧化后紫外光谱同样在475nm处产生了特征峰(最大吸收峰),并且吸收值随着催化反应时间的延长和咖啡酸内酯浓度的增大而不断增大,该结果进一步验证咖啡酸内酯在试管中能够激活蘑菇酪氨酸酶活性的结果。
实验例4:对蘑菇酪氨酸酶的作用机理
采用Cary Eclipse荧光光度计测试酪氨酸酶内源荧光强度的变化。首先是对相关参数进行设定:激发光波长设定为290nm,发射光夹缝宽度为10nm,波长范围为300~450nm。在石英比色杯中加入双蒸水,放入荧光光度计进行调零后,再加入咖啡酸内酯进行扫描。发现咖啡酸内酯在酪氨酸酶的最强发射荧光337nm附近无吸收峰,因此可进行该实验。对石英比色杯进行清洗后,重新加入1.9mL蘑菇酪氨酸酶,再加入0.1mL不同浓度的咖啡酸内酯,在酶与样品混匀1min后测定发射荧光强度。其中,咖啡酸内酯的浓度为0~0.25mmol/L。色氨酸作为酶本身的芳环发色基团,经常被用于研究酪氨酸酶的构象变化。通过测定在蘑菇酪氨酸酶中有无加入咖啡酸内酯两种情况下的发射荧光强度来衡量咖啡酸内酯对蘑菇酪氨酸酶的作用以及酪氨酸酶构象的变化。
由图8、图9可以看出,固定酪氨酸酶摩尔质量不变时,随着作用的咖啡酸内酯浓度不断增加,酪氨酸酶的荧光强度均呈现有规律的降低,且荧光发射波长出现了略微红移。
引起蛋白荧光淬灭的原因有动态和(或静态)淬灭,无论是静态淬灭还是动态淬灭,荧光光子与淬灭剂之间的淬灭速率都遵循Stern-Volmer曲线方程:
F0/F=1+Kqτ0[c]=1+Ksv[c]
根据Stern-Volmer曲线方程,将F0/F对所加入的咖啡酸内酯的终浓度[c]作图,得到咖啡酸内酯对酪氨酸酶荧光的Stern-Volmer曲线,结果如图10所示。
由图10可以看出,F0/F随着酪氨酸酶浓度的增加逐渐增大,F0/F与[c]线性关系良好。通过计算可以知道,在本实验设定的条件下,荧光淬灭过程的速率常数Ksv=1.94×10-6(mol/L)-1,其动态淬灭速率常数Kq=1.94×102(mol·s/L)-1,小于各类淬灭剂对生物大分子的Kq最大值2.0×1010(mol·s/L)-1,说明咖啡酸内酯对酪氨酸酶的荧光淬灭属于动态淬灭机制。
实验例5:对人黑色素瘤M14细胞中酪氨酸酶的蛋白表达量
用DMEM HighGlucose培养基(含有10%胎生小牛血清、青霉素100U/mL、链霉素100μg/mL),在CO2孵箱中37℃、CO2=5%和饱和湿度的条件下培养细胞。待细胞生长至近融合状态,吸去培养基,加入用含血清培养基配置而成的0μg/mL、10μg/mL、20μg/mL、30μg/mL、40μg/mL的咖啡酸内酯作为培养基加入细胞培养皿,培养24h后,经0.25%胰蛋白酶消化后,收集细胞,5000rpm离心取出上清,加入200μL的RIPA裂解液(含有50mmol/L pH 7.4 Tris,150mmol/L NaCl,1%NP-40,0.5%sodium deoxycholate,0.1%SDS,以及sodiumorthovanadate,sodium fluoride,EDTA,leupeptin),冰上裂解1h后,10000rpm离心后取上清液,测定蛋白浓度,分装,按照10×20μg浓度配置加入4×loading缓冲液,100℃热变性30min。将所得样品SDS-PAGE电泳后转膜,孵育一抗二抗,显影,如图11所示,咖啡酸内酯在处理人黑色素瘤M14细胞伴随时间增长,能有效上调酪氨酸酶(TYR)、酪氨酸酶相关蛋白(TRP-1)、酪氨酸酶相关蛋白(TRP-2)、小眼畸形相关转录因(MITF)、促黑细胞激素抗体(α-MSH)、GAPDH等相关蛋白的表达量。
实验例6:对人M14黑色素瘤细胞内酪氨酸活性的影响
细胞培养方法同上。待细胞生长至近融合状态,经0.25%胰蛋白酶消化,再用培养基收集于4mL离心管中,1500rpm离心5min后弃上清,保留细胞沉淀。在细胞沉淀中加入0.01mol/L含有1%吐温-100的PBS缓冲液,悬浮细胞后,于-80℃中冷冻。冷冻完全后取出,于室温缓慢溶解,反复2次。再将细胞悬液于4℃下12000rpm离心15min后取上清,即为酶液。取干净的96孔板,在200μL的测定体系中180μL加入溶于pH 6.8的PBS中的L-DOPA,再加入10μL不同浓度的咖啡酸内酯和10μL细胞酪氨酸酶液。将反应体系置于30℃的恒温水浴锅中反应30min,酶标仪中测定475nm处的吸光值。每一浓度处理设3个重复,取平均值。每次实验均取同一传代细胞。
由图12可知:在浓度范围为0、0.1、0.2、0.3、0.4和0.5mmol/L的咖啡酸内酯的作用下,人M14黑色素瘤细胞内的酪氨酸活性受到激活,并且激活作用呈现出浓度依赖性。
实验例7:对人正常肝脏细胞L02增殖的影响
细胞培养方法同上。待细胞生长至近融合状态,经0.25%胰蛋白酶消化后,收集并调整细胞浓度为104/mL到96孔细胞培养板中。每孔加入200μL的人正常肝脏细胞L02单细胞悬液,过夜。待细胞贴壁后弃去原培养基,分别加入含0、5、10、20、40、60、80、100和120μg/mL的咖啡酸内酯的DMEM HighGlucose培养基200μL。继续培养24h、48h后弃培养液。于结束前4h,用pH 7.4的PBS缓冲液(137mmol/L NaCl、2.7mmol/L KCl、10mmol/L Na2HPO4、2mmol/LKH2PO4)洗涤2次,每孔加入20μL的0.5mg/mL MTT和180μL新鲜的DMEM HighGlucose培养液,在CO2孵箱中在37℃、CO2=5%和饱和湿度的条件下培养细胞4h后,弃上清液。每孔加入200μL DMSO,在37℃条件下,震荡10min,使蓝紫色结晶甲臜完全溶解,立即用酶标仪测定570nm光吸收值。每一浓度处理设3个重复,取平均值。每次实验均取同一传代细胞。
由图13可以看出,不同浓度的咖啡酸内酯对人正常肝脏细胞LO2的增殖没有明显影响,说明无细胞毒性。
实验例8:KM小鼠急性毒理学的影响
根据GB 15193.3-2014的检测依据,对实验小鼠进行灌胃给予咖啡酸内酯,给药体积为0.008mL/g,对照组灌胃给予同等体积玉米油,给药后观察小鼠毒性反应情况,连续观察14天。小鼠灌胃给予不同浓度咖啡酸内酯后,部分小鼠出现活动减少,反应迟钝。12h后开始有小鼠死亡,48h后不再出现死亡。死亡小鼠解剖发现胃肠道粘连。存活小鼠14天后外观,精神状态,行为活动,摄食,大小便,毛色和呼吸灯均未见异常,鼻、眼、口腔无异常分泌物,体重增加,解剖观察内脏器官未见异常病变。按Bliss法计算,咖啡酸内酯对小鼠的经口急性毒性LD50值为12246.3mg/kg,急性毒性分级为2级,实际无毒。
综上所述,咖啡酸内酯对于小鼠基本没有毒性。因此,本发明的咖啡酸内酯具有很好的皮肤渗透性,安全无毒。
本申请虽然以较佳实施例公开如上,但并不是用来限定权利要求,任何本领域技术人员在不脱离本申请构思的前提下,都可以做出若干可能的变动和修改,因此本申请的保护范围应当以本申请权利要求所界定的范围为准。
Claims (10)
1.一种咖啡酸内酯,其特征在于,所述咖啡酸内酯的结构式如式I所示:
2.一种如权利要求1所述的咖啡酸内酯的制备方法,其特征在于,至少包括以下步骤:
(1)将咖啡酸加入到二甲基亚砜溶液中溶解,得到咖啡酸二甲基亚砜溶液;
(2)在所述咖啡酸二甲基亚砜溶液中加入碱和有机溶剂,然后加热进行反应;
(3)反应结束后,经过滤和沉淀,得到所述咖啡酸内酯。
3.根据权利要求2所述的制备方法,其特征在于,在步骤(1)中,所述咖啡酸的纯度为99.5%~99.99%,优选为99.75%~99.9%。
4.根据权利要求2所述的制备方法,其特征在于,在步骤(1)中,所述咖啡酸与二甲基亚砜的质量比为1:1.3~1.6,优选1:1.5。
5.根据权利要求2所述的制备方法,其特征在于,在步骤(2)中,所述碱选自氢氧化钠、氢氧化钾中的至少一种;所述有机溶剂选自二氯甲烷、三氯甲烷、丙酮、石油醚、乙酸乙酯、乙腈、四氢呋喃、1,4-二氧六环、正己烷中的至少一种;所述咖啡酸与碱的质量比为1:0.09~0.12,优选1:0.11;所述咖啡酸二甲基亚砜溶液与所述有机溶剂的体积比为1:8~10,优选1:9。
6.根据权利要求2所述的制备方法,其特征在于,在步骤(2)中,所述加热为油浴加热,加热的温度为70~90℃,加热时间为5~6h;优选加热的温度为75~85℃。
7.根据权利要求2所述的制备方法,其特征在于,在步骤(3)中,所述过滤为抽滤,采用蒸馏水或去离子水冲洗后进行沉淀,并优选重复2~3次。
8.一种药物的组合物,其特征在于,含有权利要求1所述的化合物和制剂学可接受的载体。
9.如权利要求1所述的咖啡酸内酯在制备治疗或预防白发症或色素紊乱症的药品、保健品或化妆品中应用。
10.根据权利要求9所述的应用,其特征在于,所述白发症选自遗传性白发、后天性少白头或老年性白发,所述色素紊乱症选自白癜风、白化病。
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