异阿魏酸酰胺类衍生物的合成及其美白活性的研究

doi:10.3969/j.issn.1001-1803.2021.11.010

摘要/Abstract

摘要：

以异阿魏酸和氨基酸乙酯盐酸盐为原料,1-（3-二甲基氨基丙基）-3-乙基碳二亚胺盐酸盐（EDC·HCl）和1-羟基苯并三唑（HOBt）为催化剂,采用EDC缩合的方法合成异阿魏酰丙氨酸乙酯（a）、异阿魏酰苯丙氨酸乙酯（b）、异阿魏酰亮氨酸乙酯（c）、异阿魏酰异亮氨酸乙酯（d）、异阿魏酰缬氨酸乙酯（e）、异阿魏酰蛋氨酸乙酯（f）。利用核磁共振氢谱（¹H NMR）和高效液相色谱-质谱（HPLC-MS）对产物结构进行表征,并对比研究了异阿魏酸与异阿魏酰氨基酸乙酯对DPPH自由基清除率和酪氨酸酶活性抑制率的影响,发现6种异阿魏酰氨基酸乙酯均呈现良好的清除DPPH自由基和抑制酪氨酸酶活性的效果,其中异阿魏酰丙氨酸乙酯抑制效果较强,清除DPPH自由基IC₅₀值为1.13 mg/mL,酪氨酸酶活性抑制率为95.43%。B16黑素瘤细胞水平结果表明,2 mg/mL质量浓度下异阿魏酰丙氨酸乙酯、异阿魏酰苯丙氨酸乙酯和异阿魏酰蛋氨酸乙酯对黑色素抑制效果比异阿魏酸单体更强,且刺激性有所降低。

关键词: 异阿魏酸, 异阿魏酰氨基酸乙酯, DPPH自由基, 酪氨酸酶, B16黑色素瘤细胞

Abstract:

Using isoferulic acid and amino acid ethyl ester hydrochloride as raw materials, 1- （3-dimethylaminopropyl）-3-ethylcarbodiimide hydrochloride （EDC HCl） and 1-hydroxybenzotriazole （HOBt） as catalysts, isoferuloyl-alanine ethyl ester （a）, isoferuloyl-phenylalanine ethyl ester （b）, isoferuloyl-leucine ethyl ester （c）, isoferuloyl-isoleucine ethyl ester （d）, isoferuloyl-valine ethyl ester （e）, isoferuloyl-methionine ethyl ester （f） were synthesized by EDC condensation. The structure of the products was characterized by nuclear magnetic resonance （¹H NMR） and high performance liquid chromatography-mass spectrometry （HPLC-MS）. The whitening activity of ethyl isoferulyl-amino acid was detected by two in vitro non-cellular experiments of scavenging DPPH free radicals and inhibiting tyrosinase activity. It can be seen from the experimental results that the six isoferulyl amino acids have a good ability to scavenge DPPH free radicals, which are higher than that of isoferulic acid. Isoferulyl-alanine ethyl ester has the strongest ability to scavenge DPPH free radicals. Its IC₅₀ value reaches 1.13 mg/mL. It also has a certain inhibitory effect on tyrosinase activity, of which isoferulyl-alanine ethyl ester has the best effect, with the inhibition rate of 95.43%. The results of B16 melanoma cells show that isoferulyl-alanine ethyl ester, isoferulyl-phenylalanine ethyl ester and isoferulyl-methionine ethyl ester have better inhibitory effects on melanin than isoferulic acid at 2 mg/mL mass concentration and its irritation is reduced. The differences in the efficacy of the six products may be due to the different types of side chain amino acids on each substance. In the follow-up investigation, the biological activity of isoferulyl amino acid derivatives can be analyzed to clarify the relationship between the molecular structure of the substance and the physiological activity, and to increase the transdermal absorption effect and safety of the substance in animal experiments.

Key words: isoferulic acid, isoferulic acid ethyl ester, DPPH radical, tyrosinase, B16 melanoma cells

中图分类号:

TQ658

罗天骥,梅子坤,宋京九,祝钧. 异阿魏酸酰胺类衍生物的合成及其美白活性的研究[J]. 日用化学工业, 2021, 51(11): 1102-1108.

Luo Tianji,Mei Zikun,Song Jingjiu,Zhu Jun. Study on synthesis and whitening activity of isoferic acid amides[J]. China Surfactant Detergent & Cosmetics, 2021, 51(11): 1102-1108.

图/表 5

表 1

表 2

表 3

表 4

表 5

参考文献 15

[1]	Jia Xiushan. Determination of ferulic acid and isoferulic acid in Rhizoma Nanchuan by RP-HPLC[D]. Chongqing: Southwest University, 2010.
[2]	Meeprom A, Sompong W, Chan C, et al. Isoferulic acid, a new anti-glycation agent, inhibits fructose- and glucose-mediated protein glycation in vitro[J]. Molecules, 2013, 18(6): 6439-6454. doi: 10.3390/molecules18066439
[3]	Liu Hongmei. Study on synthesis and hypoglycemic activity of isoferulic acid derivatives[D]. Guangzhou: Guangdong Institute of Pharmacy, 2007.
[4]	Liu I M, Hsu F L, Chen C F, et al. Antihyperglycemic action of isoferulic acid in streptozotocin-induced diabetic rats[J]. British Journal of Pharmacology, 2000, 129(4): 631-636. pmid: 10683186
[5]	Sakai S, Ochiai H, Mantani N, et al. Administration of isoferulic acid improved the survival rate of lethal influenza virus pneumonia in mice[J]. Mediators of Inflammation, 2001, 10(2): 93-96. pmid: 11405556
[6]	Aramsri, Meeprom, Weerachat, et al. Isoferulic acid prevents methylglyoxal-induced protein glycation and DNA damage by free radical scavenging activity[J]. BMC Complementary and Alternative Medicine, 2015, 15(1): 1-8. doi: 10.1186/s12906-015-0520-z
[7]	Yu Qijian. Synergistic effects of calycosin and isoferulic acid on antioxidant and inhibiting proliferation of HepG2 cells[D]. Taian: Shandong Agricultural University, 2016.
[8]	Sadaf A, Ahmed S G, Aabgeena N, et al. Inhibition of advanced glycation end products by isoferulic acid and its free radical scavenging capacity: An in vitro and molecular docking study[J]. International Journal of Biological Macromolecules, 2018, 118(PB):1479-1487. doi: 10.1016/j.ijbiomac.2018.06.182
[9]	Gong S, Yin M, Yun Z. Kinetics of inhibitory effect of isoferulic acid on mushroom tyrosinase[J]. Journal of Cosmetic Science, 2013, 64(4): 235-241.
[10]	Lu W, Wang F, Zhang T, et al. Search for novel histone deacetylase inhibitors. Part II: Design and synjournal of novel isoferulic acid derivatives[J]. Bioorg Med Chem, 2014, 22(9): 2707-2713. doi: 10.1016/j.bmc.2014.03.019
[11]	Takahashi T, Miyazawa M. Tyrosinase inhibitory activities of cinnamic acid analogues[J]. Die Pharmazie, 2010, 65(12): 913-918.
[12]	Chochkova M, Stoykova B, Ivanova G, et al. N-Hydroxycinnamoyl amides of fluorinated amino acids: Synjournal, anti-tyrosinase and DPPH scavenging activities[J]. Journal of Fluorine Chemistry, 2013, 156:203-208. doi: 10.1016/j.jfluchem.2013.09.013
[13]	Wei Q Y, Jiang H, Zhang J X, et al. Synjournal of N -hydroxycinnamoyl amino acid ester analogues and their free radical scavenging and antioxidative activities[J]. Medicinal Chemistry Research, 2012, 21(8): 1905-1911. doi: 10.1007/s00044-011-9713-2
[14]	Qin R L, Lv C N, Zhao Y, et al. Assessment of phenolics contents and antioxidant properties in Cimicifuga dahurica (Turcz.) Maxim during drying process[J]. Industrial Crops and Products, 2017, 107:288-296. doi: 10.1016/j.indcrop.2017.06.004
[15]	Niu Chao, Li Gen, Medina. Synjournal and tyrosinase activity of new chalcone derivatives[J]. Journal of Chemistry of Colleges and Universities, 2014, 35(6): 1204-1211.

物质	IC₅₀/（mg·mL^-1）
a	1.13±0.14^*
b	1.41±0.03^**
c	1.36±0.13^**
d	1.25±0.09^**
e	1.18±0.07^**
f	1.41±0.12^**
IFA	2.71±0.35^**
V_C	0.018 5±0.005

物质	抑制率/%
a	95.43±0.37^*
b	28.35±1.84^*
c	60.35±2.85^*
d	75.60±0.42^*
e	93.65±2.67^*
f	86.12±3.15^*
IFA	94.49±0.54^*
熊果苷	89.51±0.47

物质	细胞存活率/%
a	96.92±2.68^*
b	96.26±3.51^*
c	93.95±4.51^*
d	87.96±2.41^**
e	88.66±3.37^*
f	92.76±5.01^*
IFA	88.76±1.67^*
熊果苷	99.31±0.34

物质	黑素含量/%
a	81.10±2.33^*
b	83.18±4.07^**
c	85.52±2.14^*
d	90.83±1.07^**
e	94.67±1.86^*
f	84.05±4.60^*
IFA	84.56±2.67^**
熊果苷	82.91±8.08