目的 本研究设计并合成了一系列新型3-硫苄基取代的半胱氨酸衍生物,并对其抗肝细胞损伤活性进行了生物学评价。方法 以L-半胱氨酸为起始原料,经巯基上苄基取代、酰化、缩合等一系列反应,得到目标化合物。采用过氧化氢(H2O2)诱导的LO2肝细胞模型对目标化合物进行体外抗肝损伤活性评价,同时选取活性较优的化合物进行初步的药物代谢动力学性质研究。结果 合成得到15个目标化合物,其结构经核磁共振氢谱(1H-NMR)、核磁共振碳谱(13C-NMR)和电喷雾电离质谱(ESI-MS)表征。体外试验显示,有3个化合物能够明显提高H2O2诱导的损伤肝细胞的活力,与阳性对照N-乙酰半胱氨酸(N-acetylcysteine,NAC)的活性相当。同时,相比于阳性对照NAC,化合物9g能够更有效的降低损伤肝细胞的丙二醛(MDA)水平。进一步深入的研究显示,化合物9g显示出良好的Caco-2渗透性和药动学性质。在SD大鼠试验中,化合物9g单次口服半衰期可达到4.08 h,口服生物利用度可达45.3%。结论 化合物9g可作为抗肝细胞损伤药物的潜在先导分子,具有进一步开发的前景。
Abstract
OBJECTIVE To design and synthesize a series of novel 3-thioxenyl-substituted cysteine derivatives and biologically evaluate their anti-hepatocellular injury activities. METHODS Using L-cysteine as the starting material, the target compounds were obtained through a series of reactions such as benzyl substitution on the mercapto group, acylation and condensation. The LO2 hepatocyte model induced by hydrogen peroxide (H2O2) was used to evaluate the anti-hepatocellular injury activities of the target compounds in vitro, and the superior compound was selected for the preliminary pharmacokinetic properties study. RESULTS Fifteen novel compounds were obtained and their structures were characterized by 1H-NMR,13C-NMR and ESI-MS. In vitro experiments showed that three compounds could significantly increase the activity of H2O2-induced LO2 hepatocytes, which was comparable to the activity of the positive control N-acetylcysteine(NAC). Meanwhile, compared with NAC, compound 9g could more effectively reduce the level of malondialdehyde (MDA) in injured hepatocytes. Further in-depth studies have shown that compound 9g displayed excellent Caco-2 permeability and pharmacokinetic properties. In the SD rat trial, the half-life of compound 9g after single-dose oral administration reached 4.08 h and the bioavailability reached 45.3%. CONCLUSION All these results suggest that compound 9g can be used as a potential lead molecule for anti-hepatocyte injury drugs, and has a prospect for further structural optimization and investigation.
关键词
N-乙酰半胱氨酸 /
3-硫苄基 /
抗肝损伤 /
过氧化氢 /
药动学
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Key words
N-acetylcysteine(NAC) /
3-thioxenyl /
anti-hepatocellular injury /
hydrogen peroxide /
pharmacokinetics
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中图分类号：
R914
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参考文献
[1] PEDRE B, BARAYEU U, EZERINA D, et al. The mechanism of action of N-acetylcysteine (NAC): the emerging role of H2S and sulfane sulfur species[J]. Pharmacol Ther, 2021, 228:107916. Doi:10.1016/j.pharmthera.2021.107916.
[2] RAGHU G, BERK M, CAMPOCHIARO P A, et al. The multifaceted therapeutic role of N-acetylcysteine (NAC) in disorders characterized by oxidative stress[J]. Curr Neuropharmacol, 2021, 19(8):1202-1224.
[3] TENÓRIO M C D S, GRACILIANO N G, MOURA F A, et al. N-acetylcysteine (NAC): impacts on human health[J]. Antioxidants (Basel), 2021, 10(6):967. Doi: 10.3390/antiox10060967.
[4] SADOWSKA A M, MANUEL-Y-KEENOY B, de BACKER W A, et al. Antioxidant and anti-inflammatory efficacy of NAC in the treatment of COPD. discordant in vitro and in vivo dose-effects. a review[J]. Pulm Pharmacol Ther, 2007, 20(1):9-22.
[5] DU K, RAMACHANDRAN A, JAESCHKE H. Oxidative stress during acetaminophen hepatotoxicity. sources, pathophysiological role and therapeutic potential[J]. Redox Biol, 2016, 10:148-156.
[6] ELBINI DHOUIB I, JALLOULI M, ANNABI A, et al. A minireview on N-acetylcysteine. an old drug with new approaches[J]. Life Sci, 2016, 151.359-363.
[7] PEI Y, LIU H, YANG Y, et al. Biological activities and potential oral applications of N-acetylcysteine. progress and prospects[J]. Oxid Med Cell Longev, 2018, 2018:2835787. Doi. 10.1155/2018/2835787.
[8] RUSHWORTH G F, MEGSON I L. Existing and potential therapeutic uses for N-acetylcysteine. the need for conversion to intracellular glutathione for antioxidant benefits[J]. Pharmacol Ther, 2014, 141(2):150-159.
[9] WEI L L, DUAN Z P. Experimental research progress on the mechanism of action of N-acetylcysteine[J]. Chin Pharm J (中国药学杂志), 2008, 43 (12):887-889.
[10] LIU X, LI C L, YIN G Y, et al. Effect of N-acetylcysteine on ethanol metabolism and its mechanism[J]. Chin Pharm J (中国药学杂志), 2006, 41(14):1063-1065.
[11] SAMUNI Y, GOLDSTEIN S, DEAN O M, et al. The chemistry and biological activities of N-acetylcysteine[J]. Biochim Biophys Acta, 2013, 1830(8):4117-4129.
[12] DEAN O, GIROLANDO F, BERK M. N-acetylcysteine in psychiatry. current therapeutic evidence and potential mechanisms of action[J]. J Psychiatry Neurosci, 2011, 36(2):78-86.
[13] GIUSTARINI D, MILZANI A, DALLE-DONNE I, et al. N-acetylcysteine ethyl ester (NACET). a novel lipophilic cell-permeable cysteine derivative with an unusual pharmacokinetic feature and remarkable antioxidant potential[J]. Biochem Pharmacol, 2012, 84(11):1522-1533.
[14] MAHESHWARI A, MISRO M M, AGGARWAL A, et al. N-acetyl-L-cysteine counteracts oxidative stress and prevents H2O2 induced germ cell apoptosis through down-regulation of caspase-9 and JNK/c-Jun[J]. Mol Reprod Dev, 2011, 78(2):69-79.
[15] KHAN S R, ALJUHANI N, MORGAN A G, et al. Cytoprotective effect of isoniazid against H2O2 derived injury in HL-60 cells[J]. Chem Biol Interact, 2016, 244:37-48.
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脚注
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基金
浙江省医药卫生科技计划项目资助(2021KY262)
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