CN113616646B - 咔啉生物碱在制备抗uvb辐射制剂中的应用 - Google Patents
咔啉生物碱在制备抗uvb辐射制剂中的应用 Download PDFInfo
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- CN113616646B CN113616646B CN202111126644.1A CN202111126644A CN113616646B CN 113616646 B CN113616646 B CN 113616646B CN 202111126644 A CN202111126644 A CN 202111126644A CN 113616646 B CN113616646 B CN 113616646B
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
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- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
- A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
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Abstract
提供1‑(β‑咔啉‑1‑基)‑3,4,5‑三羟基‑1‑戊酮和1‑羟甲基‑β‑咔啉在制备抗UVB辐射的药物制剂中的应用，以及在制备化妆品中的应用。本发明属于医药和化妆品技术领域。1‑(β‑咔啉‑1‑基)‑3,4,5‑三羟基‑1‑戊酮（PFH‑5，0.01~1μg/mL）和1‑羟甲基‑β‑咔啉（PFH‑7，1μg/mL）在非常低的浓度下，既能使UVB辐照后的人表皮角质细胞活性有显著提升，且能显著降低促炎因子IL‑1α的释放，可以用于治疗和预防UVB辐射引起的皮肤衰老、皮肤炎症和皮肤癌变，以及相关药物和化妆品的制备。
Description
技术领域：
本发明属于医药和化妆品技术领域，尤其涉及1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮和1-羟甲基-β-咔啉在制备抗UVB辐射的药物制剂中的应用，以及在制备化妆品中的应用。
背景技术：
人体皮肤接受的日光紫外线辐射主要为UVA(320～400nm)和UVB(280～320nm)，皮肤光老化为UVA和UVB共同作用的结果：一方面，UVA和UVB诱导表皮角质形成细胞和真皮成纤维细胞表达和分泌基质金属蛋白酶(MMPs)，对真皮的细胞外基质发挥降解作用；另一方面，UVA诱导真皮成纤维细胞合成和分泌出细胞因子IL-6，通过自分泌机制促进其自身表达MMPs；更为重要的是，UVB诱导表皮角质形成细胞合成和分泌出细胞因子IL-1、TNF-α、IL-6等，通过旁分泌机制促进真皮成纤维细胞表达MMPs[Nam EJ,Yoo G,Lee JY,Kim M,Jhin C,Son Y-J,Kim SY,Jung SH,Nho CW.Glycosyl flavones from HumulusjaponicussuppressMMP-1production via decreasing oxidative stress in UVB irradiated humandermal fibroblasts.BMB Reports.2020,53,379-384；任倩倩,孙旭,李楠,吴华,金建明.化妆品植物原料(I)——在防晒化妆品中的研究与开发.日用化学工业,2021,51,10-16；王小勇.UVB辐射表皮角质形成细胞和UVA辐射真皮成纤维细胞在皮肤光老化中的作用机理研究.南京医科大学,2006]。此外，UVB辐射还会导致皮肤的炎症和癌症[Takashima A,Bergstresser PR.Impact of UVB radiation on the epidermal cytokinenetwork.Photochemistry and Photobiology,1996,63,397-400]。
据2020版《中华人民共和国药典》记载，兰科植物铁皮石斛Dendrobiumofficinale Kimura et Migo的干燥茎，具有益胃生津、滋阴清热的功能；用于治疗热病津伤、口干烦渴、胃阴不足、食少干呕、病后虚热不退、阴虚火旺、骨蒸劳热、目暗不明、筋骨痿软等病症。铁皮石斛叶，则被作为地方特色食品在利用，如浙江省卫生健康委员会于2020年6月11日发布了浙江省食品安全地方标准《干制铁皮石斛叶》(DB33/3012-2020)(https:// mp.weixin.qq.com/s/-qzRMnAjPF4t1j6Nocuaxg)；贵州省卫生健康委员会于2020年7月17日发布了《铁皮石斛叶(干叶)》食品安全地方标准(http://www.gzhfpc.gov.cn/xwzx_ 500663/zwyw/202007/t20200724_61712723.html)。铁皮石斛叶主要含有多糖、黄酮、联苄、甾体等类型化学成分[Wang Y-H.Traditional uses,chemical constituents,pharmacological activities,and toxicological effects of Dendrobium leaves:Areview.Journal of Ethnopharmacology,2021,270,113851；张春花,徐巧林,曾雷,王颂,罗青文,陈颖乐.铁皮石斛叶的化学成分研究.林业与环境科学,2020,36(3),30-34；唐靖雯,卢礼平,王欢,梁斌,潘梅.铁皮石斛叶的研究进展.中国民族民间医药,2020,29(7),63-67；任刚,陈优婷,叶金宝,钟国跃,肖川云,邓文赞,陈云龙.铁皮石斛叶的化学成分研究.中草药,2020,51(14),3637-3644；Ren G.,Deng W.-Z.,Xie Y.-F.,Wu C.-H.,Li W.-Y.,XiaoC.-Y.,Chen Y.-L.Bibenzyl derivatives from leaves of Dendrobiumofficinale.Natural Product Communications,2020,15(2),1-5]。
此前的专利申请公开了铁皮石斛叶中1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮和1-羟甲基-β-咔啉等生物碱的制备方法[王跃虎,张东东,罗吉凤.铁皮石斛叶生物碱的制备方法及其应用.2020.12.13,中国专利,202011453693.1]，但是，1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮和1-羟甲基-β-咔啉在抗UVB辐射方面的作用，尚未见到报道。
发明内容：
针对现有技术存在的1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮和1-羟甲基-β-咔啉研发中的空白，发明人对铁皮石斛叶中的生物碱抗UVB的活性进行了评价，1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮和1-羟甲基-β-咔啉表现出显著的活性，可以用于制备抗UVB的药物和化妆品。
为了实现本发明的上述目的，本发明提供了如下的技术方案：
1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮或/和1-羟甲基-β-咔啉在制备抗UVB辐射药物制剂中的应用。
1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮或/和1-羟甲基-β-咔啉在制备抗UVB辐射化妆品中的应用。
如所述的应用，其中1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮的用量为0.01～1μg/mL，1-羟甲基-β-咔啉的用量为1μg/mL。
如所述的应用，其中1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮或/和1-羟甲基-β-咔啉通过使UVB辐照后的人表皮角质细胞活性显著提升达到抗UVB辐照的活性作用。
如所述的应用，其中1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮或/和1-羟甲基-β-咔啉通过显著降低促炎因子IL-1α的释放达到抗UVB辐照的活性作用。
1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮和1-羟甲基-β-咔啉在制备治疗或预防UVB辐射引起的皮肤老化、皮肤炎症和皮肤癌的药物中的应用。
如所述的应用，其中1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮的用量为0.01～1μg/mL，1-羟甲基-β-咔啉的用量为1μg/mL。
如所述的应用，其中1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮或/和1-羟甲基-β-咔啉通过使UVB辐照后的人表皮角质细胞活性显著提升达到抗UVB辐照的活性作用。
如所述的应用，其中1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮或/和1-羟甲基-β-咔啉通过显著降低促炎因子IL-1α的释放达到治疗皮肤老化、皮肤炎症和皮肤癌的作用。
化妆品，其由1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮和1-羟甲基-β-咔啉其中之一或两者加合，以及化妆品常用辅料所组成。
与现有相关技术相比，本发明具备如下的优益性：
1. 1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮(0.01～1μg/mL)和1-羟甲基-β-咔啉(1μg/mL)在非常低的浓度即可发挥其对UVB辐射的保护作用。
2. 1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮和1-羟甲基-β-咔啉既能使UVB辐照后的人表皮角质细胞活性有显著提升，且能显著降低促炎因子IL-1α的释放。
3. 1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮和1-羟甲基-β-咔啉对人表皮角质细胞没有毒性。
4. 1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮和1-羟甲基-β-咔啉能用于治疗或预防皮肤病、炎症疾病、肿瘤疾病。
附图说明：
图1为本发明铁皮石斛叶生物碱成分的化学结构式。
图2为PFH-2的晶体结构。
图3为PFH-5的晶体结构。
具体实施方式：
下面结合附图，用本发明的实施例来进一步说明本发明的实质性内容，但并不以此来限定本发明。
实施例1：
铁皮石斛叶中生物碱成分(1S,3S)-1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸[(1S,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid,PFG-5]、(1R,3S)-1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸[(1R,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid,PFG-6a]、川芎哚(perlolyrine,PFH-1)、β-咔啉(β-carboline,PFH-2)、1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮[1-(β-carbolin-1-yl)-3,4,5-trihydroxy-1-pentanone,PFH-5]和1-羟甲基-β-咔啉(1-hydroxymethyl-β-carboline,PFH-7)的提取、分离：
铁皮石斛叶9.0kg，90～95％乙醇提取，回收溶剂，得到粗提物(浸膏)2.3kg。粗提物加入1L水制备成混悬液，加入3L石油醚萃取，重复8次；萃取后的水相用6M盐酸调节pH值为2～3，用3L乙酸乙酯萃取，重复5次；萃取后的水相用50％氢氧化钠水溶液调节pH值为9～10，用2L二氯甲烷萃取，重复5次；萃取后的水相用6M盐酸调节pH值至7左右，用2L正丁醇萃取，重复5次。回收溶剂后，分别得到石油醚萃取部位520.0g，乙酸乙酯萃取部位156.0g，二氯甲烷萃取部位(铁皮石斛叶的二氯甲烷萃取总生物碱部位)5.9g，以及正丁醇萃取部位85.6g。
二氯甲烷萃取部位经硅胶柱层析用石油醚-丙酮(5:1，3:1，1:1)，二氯甲烷-甲醇(1:1)，以及甲醇洗脱，得到Fr.A、Fr.B、Fr.C、Fr.D、Fr.E、Fr.F和Fr.G等七个部分。
(1)Fr.B(石油醚-丙酮5:1洗脱部分，815.5mg)经C18反相硅胶柱层析，甲醇-水(30:70→100:0)梯度洗脱，得到Fr.B1、Fr.B2、Fr.B3、Fr.B4和Fr.B5等五个部分。
(2)Fr.B2(30～50％甲醇洗脱部分)经LH-20凝胶柱层析用甲醇洗脱，用半制备高效液相色谱纯化得到PFH-1(23.4mg)和PFH-2(3.8mg)。
(3)Fr.C(石油醚-丙酮3:1洗脱部分，502.9mg)经C18反相硅胶柱层析，甲醇-水(10:90→100:0)梯度洗脱，得到Fr.C1、Fr.C2、Fr.C3、Fr.C4、Fr.C5和Fr.C6等六个部分。Fr.C3(20～30％甲醇洗脱部分)用半制备高效液相色谱纯化后得到PFH-7(1.9mg)。
(4)Fr.D(石油醚-丙酮1:1洗脱部分，223.3mg)经C18反相硅胶柱层析，甲醇-水(5:95→100:0)梯度洗脱，得到Fr.D1、Fr.D2、Fr.D3、Fr.D4、Fr.D5和Fr.D6等六个部分。Fr.D4(30～40％甲醇洗脱部分)用半制备高效液相色谱纯化得到PFH-5(15.4mg)。
正丁醇萃取部位经硅胶柱层析，用二氯甲烷-甲醇(20:1→1:1)，以及甲醇洗脱，得到Fr.H、Fr.I、Fr.J、Fr.K、Fr.L和Fr.M等六个部分。Fr.K(二氯甲烷-甲醇3:1洗脱部分，30.4g)经RP C18反相硅胶柱层析，甲醇-水(5:95→100:0)梯度洗脱，得到Fr.K1、Fr.K2、Fr.K3、Fr.K4、Fr.K5、Fr.K6和Fr.K7等七个部分。Fr.K4(10％甲醇洗脱部分，559.5mg)经LH-20凝胶柱层析用甲醇洗脱后，再用半制备高效液相色谱纯化得到PFG-5(3.5mg)和PFG-6a(2.5mg)。
上面所述的半制备高效液相色谱使用的仪器是安捷伦1260Infinity II液相色谱仪。
制备PFH-1和PFH-2所用色谱柱为Agilent Zorbax SB-C18柱，大小为9.4×250mm，洗脱剂为甲醇-水(比例60:40)，流速2mL/min，保留时间分别为25.600min和21.260min。
制备PFH-7所用色谱柱为Agilent Zorbax SB-C18柱，大小为9.4×250mm，洗脱剂为乙腈-水(30:70)，流速2mL/min，保留时间为17.070min。
制备PFH-5所用色谱柱为Agilent Zorbax SB-C18柱，色谱柱大小为9.4×250mm，洗脱剂为甲醇-水(55:45)，流速2mL/min，保留时间为14.513min。
制备PFG-5所用色谱柱为Agilent Zorbax SB-Aq柱，大小为4.6×250mm，洗脱剂为甲醇-水(比例5:95)，流速1mL/min，保留时间为16.800min。
制备PFG-6a所用色谱柱为Agilent Zorbax SB-Aq柱，大小为4.6×250mm，洗脱剂为甲醇-水(比例3:97)，流速1mL/min，保留时间为30.572min。
实施例2：
铁皮石斛叶生物碱成分的波谱数据：
(1S,3S)-1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸[(1S,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid，PFG-5]，浅黄色固体，分子式C13H14N2O2，CAS登记号40678-46-4。[α]24 D-100(c 0.13,MeOH)。1H NMR(methanol-d4,500MHz)δ:7.48(1H,brd,J＝7.9Hz,H-5),7.34(1H,br d,J＝8.1Hz,H-8),7.14(1H,m,H-7),7.05(1H,m,H-6),4.71(1H,q,J＝6.3Hz,H-1),3.97(1H,dd,J＝12.0,4.9Hz,H-3),3.45(1H,dd,J＝16.5,4.9Hz,H-4α),3.03(1H,m,H-4β),1.75(3H,d,J＝6.7Hz,1-Me)。13C NMR(methanol-d4,126MHz,)δ:173.7(C,3-COOH,detected by HMBC),138.6(C,C-8a),131.4(C,C-9a),127.5(C,C-4b),123.3(CH,C-7),120.6(CH,C-6),119.2(CH,C-5),112.3(CH,C-8),107.9(C,C-4a),59.8(CH,C-3),51.2(CH,C-1),24.3(CH2,C-4),17.2(CH3,1-Me)。ESI-MS m/z 253[M+Na]+。其核磁共振波谱数据跟文献[Alla A.Kicha,Natalia V.Ivanchina,Anatoly I.Kalinovsky,Pavel S.Dmitrenok,Valentin A.Stonik.Alkaloidosteroids from the starfish Lethasteriasnanimensischelifera.Tetrahedron Letters,2003,44(9),1935–1937]中的数据基本一致。
(1R,3S)-1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸[(1R,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid,PFG-6a]，浅黄色固体，分子式C12H14N2O，CAS登记号42438-72-2。[α]28 D-11(c 0.09,MeOH)。1H NMR(methanol-d4,500MHz)δ:7.46(1H,brd,J＝7.9Hz,H-5),7.31(1H,br d,J＝8.1Hz,H-8),7.12(1H,m,H-7),7.03(1H,m,H-6),4.83(1H,q,J＝6.7Hz,H-1),4.07(1H,dd,J＝8.7,5.6Hz,H-3),3.34(1H,dd,J＝16.2,5.6Hz,H-4α),3.13(1H,dd,J＝16.2,8.7Hz,H-4β),1.69(1H,d,J＝6.9Hz,1-Me)。13C NMR(methanol-d4,126MHz,)δ:138.4(C,C-8a),130.9(C,C-9a),127.6(C,C-4b),123.2(CH,C-7),120.4(CH,C-6),119.1(CH,C-5),112.1(CH,C-8),106.7(C,C-4a),54.8(CH,C-3),48.5(CH,C-1),24.1(CH2,C-4),18.8(CH3,1-Me)。ESI-MS m/z 231[M+H]+,253[M+Na]+,483[2M+Na]+。其核磁共振波谱数据跟文献[Wang X,Liu R,Yang Y,Zhang M.Isolation,purification andidentification of antioxidants in an aqueous aged garlic extract.FoodChemistry,2015,187,37-43]中的数据基本一致。
川芎哚(perlolyrine,PFH-1)，浅黄色针状晶体(甲醇)，分子式C16H12N2O2，CAS登记号29700-20-7。1H NMR(pyridine-d5,500MHz)δ:12.06(1H,s,NH),8.67(1H,d,J＝5.1Hz,H-3),8.26(1H,d,J＝8.0Hz,H-5),8.03(1H,d,J＝5.1Hz,H-4),7.57(1H,overlapped,H-8),7.51(1H,m,H-7),7.31(1H,m,H-6),7.19(1H,overlapped,H-2′),6.67(1H,br d,J＝3.3Hz,H-3′),4.70(2H,s,H-5′)。13C NMR(pyridine-d5,126MHz)δ:157.7(C,C-1′),154.2(C,C-4′),141.9(C,C-8a),138.9(CH,C-3),134.5(C,C-1),131.8(C,C-9a),130.4(C,C-4a),128.5(CH,C-7),121.8(CH,C-5),121.7(C,C-4b),120.0(CH,C-6),113.7(CH,C-4),112.6(CH,C-8),110.1(CH,C-2′),109.4(CH,C-3′),57.0(CH2,C-5′)。ESIMS m/z 287[M+Na]+,551[2M+Na]+。其核磁共振波谱数据跟文献[Dassonneville,B.；Witulski,B.；Detert,H.[2+2+2]Cycloadditions of alkynylynamides–A total synthesis of perlolyrine and thefirst total synthesis of“isoperlolyrine”.European Journal of OrganicChemistry,2011,2011(15),2836-2844]中的数据一致。
PFH-1的晶体数据:C16H12N2O2·CH4O,M＝296.32, α＝90°,β＝90°,γ＝90°,/>T＝100.(2)K,space group Fdd2,Z＝16,μ(Cu Kα)＝0.783mm-1,22212reflections measured,2822independent reflections(Rint＝0.0306).The final R1 values were0.0273(I>2σ(I)).The final wR(F2)values were 0.0727(I>2σ(I)).The final R1 values were0.0274(all data).The final wR(F2)values were 0.0729(all data).The goodness offit on F2 was 1.082.Flack parameter＝-0.03(4).
β-咔啉(β-carboline,PFH-2)，白色固体，分子式C11H8N2，CAS登记号244-63-3。1HNMR(methanol-d4,600MHz)δ:8.80(1H,s,H-1),8.29(1H,d,J＝5.1Hz,H-3),8.19(1H,br d,J＝8.1Hz,H-5),8.10(1H,d,J＝5.1Hz,H-4),7.57(2H,m,H-7,H-8),7.27(1H,m,H-6)。13CNMR(methanol-d4,151MHz,)δ:142.8(C,C-8a),138.4(CH,C-3),137.8(C,C-9a),134.1(CH,C-1),130.5(C,C-4a),129.8(CH,C-7),122.7(CH,C-5),122.2(C,C-4b),120.9(CH,C-6),116.1(CH,C-4),112.8(CH,C-8)。ESIMS m/z 169[M+H]+。其核磁共振波谱数据跟文献[杨泊涛；刘录；张敉；刘亚平；李宝才；秦徐杰.景东山橙根中生物碱成分研究.天然产物研究与开发,2016,28(6),868-873,954]中的数据一致。
1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮[1-(β-carbolin-1-yl)-3,4,5-trihydroxy-1-pentanone,PFH-5]，浅黄色片状结晶(甲醇)，分子式C16H16N2O4，CAS登记号180995-40-8。[α]25 D–14(c 0.3,MeOH)。ECD(c0.024,MeOH)λmax(Δε)225(+1.59),201(-2.72)nm。1H NMR(methanol-d4,500MHz)δ:8.46(1H,d,J＝5.0Hz,H-3),8.29(1H,d,J＝5.0Hz,H-4),8.21(1H,brd,J＝7.9Hz,H-5),7.70(1H,brd,J＝8.2Hz,H-8),7.59(1H,m,H-7),7.31(1H,m,H-6),4.35(1H,m,H-3′),3.83(1H,m,H-5′a),3.60-3.69(4H,m,H2-2′,H-4′,H-5′b)。13C NMR(methanol-d4,126MHz)δ:203.6(C,C-1′),143.4(C,C-8a),138.5(CH,C-3),137.3(C,C-1),136.3(C,C-9a),133.3(C,C-4a),130.3(CH,C-7),122.7(CH,C-5),121.6(C,C-4b),121.6(CH,C-6),120.1(CH,C-4),113.4(CH,C-8),76.2(CH,C-4′),70.3(CH,C-3′),64.7(CH2,C-5′),43.1(CH2,C-2′)。ESIMS m/z 323[M+Na]+,623[2M+Na]+。其核磁共振波谱数据跟文献[Aimi,N.；Kitajima,M.；Oya,N.；Nitta,W.；Takayama,H.；Sakai,S.-i.；Kostenyuk,I.；Gleba,Y.；Endreb,S.；J.Isolation of alkaloids fromcultured hybrid cells ofRauwolfiaserpentina×Rhazyastricta.Chemical andPharmaceutical Bulletin,1996,44(8),1637-1639]中的数据一致。
PFH-5的晶体数据:C16H16N2O4,M＝300.31, α＝94.7500(10)°,β＝93.7600(10)°,γ＝99.7690(10)°,/> T＝100.(2)K,space group P1,Z＝1,μ(Cu Kα)＝0.874mm-1,8649reflections measured,2568independent reflections(Rint＝0.0311).The finalR1 values were 0.0299(I>2σ(I)).The final wR(F2)values were 0.0833(I>2σ(I)).Thefinal R1values were 0.0299(all data).The final wR(F2)values were 0.0833(alldata).The goodness of fit on F2 was 1.176.Flack parameter＝0.05(5).
1-羟甲基-β-咔啉(1-hydroxymethyl-β-carboline,PFH-7)，浅黄色固体，分子式C12H10N2O，CAS登记号17337-22-3。1H NMR(pyridine-d5,600MHz)δ:12.43(1H,s,NH),8.60(1H,d,J＝5.2Hz,H-3),8.29(1H,d,J＝8.0Hz,H-5),8.06(1H,d,J＝5.2Hz,H-4),7.72(1H,d,J＝8.0Hz,H-8),7.58(1H,m,H-7),7.33(1H,m,H-6),5.54(2H,s,H2-1′)。13C NMR(pyridine-d5,151MHz)δ:146.6(C,C-1),142.2(C,C-8a),138.4(CH,C-3),135.3(C-9a),129.7(C,C-4a),128.9(CH,C-7),122.5(CH,C-5),122.4(C,C-4b),120.2(CH,C-6),114.5(CH,C-4),112.9(CH,C-8),65.6(CH2,C-1′)。ESIMS m/z 199[M+H]+,221[M+Na]+,419[2M+Na]+。该化合物的结构得到二维核磁共振波谱和单晶X射线衍射的确认。其核磁共振波谱数据跟文献[Szabó,T.；Hazai,V.；Volk,B.；Simig,G.；Milen,M.First total synthesis oftheβ-carboline alkaloids trigonostemine A,trigonostemine B and a newsynthesis of pityriacitrin and hyrtiosulawesine.Tetrahedron Letters,2019,60(22),1471-1475]中用DMSO-d6测试的数据接近。
实施例3：
咔啉类化合物对人原代表皮角质细胞活力实验。
人原代表皮角质细胞在37℃、5％CO2、饱和湿度的培养条件下，利用专用的角质细胞培养基正常培养。细胞生长达到80％汇合时进行消化，细胞悬液密度调整至1×105个/mL，以每孔200μL细胞悬液接种于96孔板中，贴壁48h后，加入5个浓度梯度(10μg/mL、1μg/mL、0.5μg/mL、0.1μg/mL、0.01μg/mL)的样品处理角质细胞，同时设置溶剂对照组(Vehicle)，即含有0.1％DMSO的角质细胞培养基。
处理角质细胞24h后测试其活性，按照说明书加入CCK-8试剂孵育1h，在450nm处测量吸光度，计算相对细胞活性。
相对细胞活性％＝(样品组OD值/溶剂对照组OD值)×100％。
实验结果见表1。从表1可以看出，除化合物PFH-1在浓度10μg/mL时，对表皮角质细胞有弱的抑制作用外，其余化合物在10μg/mL、1μg/mL、0.5μg/mL、0.1μg/mL、0.01μg/mL五个浓度下，均对表皮角质细胞没有抑制作用。说明咔啉类化合物PFG-5、PFG-6a、PFH-1、PFH-2、PFH-5和PFH-7在本实验所设置的浓度下，对表皮角质细胞几乎没有毒性。
表1.咔啉类化合物的表皮角质细胞活性测试数据
实施例3：
咔啉类化合物对UVB辐射人原代表皮角质细胞的活力影响和IL-1α生成量测定：
在含5％CO2、37℃、饱和湿度的培养条件下，利用Promocell完全培养基正常培养人原代表皮角质细胞。选取处于最佳生长状态的细胞，将其按照1×105个/mL、每孔200μL的密度接种于96孔板中，贴壁生长48h后，先用UVB10mJ/cm2辐照细胞，随后用安全浓度下的样品处理细胞，同时设置溶剂对照组(0.1％DMSO)和抗炎阳性对照组，即1μM蓝萼甲素(Glaucocalyxin A，GLA)[周鲁先,李宁,王惠琇.蓝萼甲素在制备消炎和抗光老化产品中的应用.2021.05.11,中国专利,ZL201910119443.5.]。继续培养24h后，收集细胞上清液用IL-1αELISA试剂盒进行炎症因子检测。同步平行用CCK法检测本实验中各组细胞的活性，IL-1α定量检测结果用CCK所测得的细胞活性进行归一化处理。
实验结果见表2。化合物PFH-5和PFH-7对UVB辐照后的人表皮角质细胞活性有显著提升，且能显著降低炎症因子IL-1α的释放。化合物PFG-5、PFH-1和PFH-2对UVB辐照后的人表皮角质细胞活性有显著提升作用。
表2.UVB辐照的人原代表皮角质细胞活性和IL-1α测试数据
实施例4
β-咔啉(β-carboline,PFH-2)、1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮[1-(β-carbolin-1-yl)-3,4,5-trihydroxy-1-pentanone,PFH-5]的药物制剂：
1.片剂：将PFH-2或/和PFH-5 10mg，加入乳糖180mg，淀粉55mg等辅料混合均匀，并用水将其润湿后制成颗粒并干燥，再加入硬脂酸镁5mg混匀后压片，每片约重250mg。
2.安瓿剂：将PFH-2或/和PFH-52mg，氯化钠10mg，溶解于适量的注射用水中，过滤所得溶液，在无菌条件下装入安瓿瓶中。
3.注射用冻干剂：将PFH-2或/和PFH-5 10mg，碳酸氢钠2mg，甘露醇252mg。
制备方法：将碳酸氢钠、甘露醇，加注射用水溶解，加活性碳吸附30min除热原，过滤除去活性碳，在滤液中加入化合物或其盐，超声处理使溶解，用1N盐酸调节PH为5.0-7.0，微孔滤膜滤过，加注射用水，分装，冷冻干燥，上塞，轧盖，即得。
4.胶囊剂：将PFH-2或/和PFH-5 10mg，乳糖187mg，硬脂酸镁3mg；制备方法：将化合物或其盐与助溶剂混和，过筛，均匀混合，把得到的混合物装入硬明胶胶囊，每个胶囊重200mg，活性成分含量为10mg。
实施例5
β-咔啉(β-carboline,PFH-2)、1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮[1-(β-carbolin-1-yl)-3,4,5-trihydroxy-1-pentanone,PFH-5]的化妆品制剂：
1.含有PFH-2或/和PFH-5的美白霜配方(W％)：
按常规制作化妆品的方法制得本发明上述配方的化妆品。
2.含有PFH-2或/和PFH-5的乳剂配方(W％)：
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 (4)
1.1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮或/和1-羟甲基-β-咔啉在制备抗UVB辐射药物制剂中的应用，其中1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮的用量为0.01~1 μg/mL，1-羟甲基-β-咔啉的用量为1 μg/mL。
2.1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮或/和1-羟甲基-β-咔啉在制备抗UVB辐射化妆品中的应用，其中1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮的用量为0.01~1 μg/mL，1-羟甲基-β-咔啉的用量为1 μg/mL。
3.如权利要求1或2所述的应用，其中1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮或/和1-羟甲基-β-咔啉通过使UVB辐照后的人表皮角质细胞活性显著提升达到抗UVB辐照的活性作用。
4.如权利要求1或2所述的应用，其中1-(β-咔啉-1-基)-3,4,5-三羟基-1-戊酮或/和1-羟甲基-β-咔啉通过显著降低促炎因子IL-1α的释放达到抗UVB辐照的活性作用。
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