Punam Thapa, Shristi Khanal, Kibria Gulam, Trung Huy Ngo, Zhiying Chen, Young Jun Ok, Kyu Joon Lee, Hyukjae Choi, Joo-Won Nam, Dong-Young Choi
{"title":"蝉的n -乙酰多巴胺二聚体通过抗氧化作用对神经具有选择性保护作用。","authors":"Punam Thapa, Shristi Khanal, Kibria Gulam, Trung Huy Ngo, Zhiying Chen, Young Jun Ok, Kyu Joon Lee, Hyukjae Choi, Joo-Won Nam, Dong-Young Choi","doi":"10.4062/biomolther.2025.140","DOIUrl":null,"url":null,"abstract":"<p><p>N-Acetyldopamine oligomers are typically biosynthesized as racemic mixtures, yet enantiomers can differ markedly in pharmacological efficacy and safety. In this study, we isolated a pair of enantiomers of an N-acetyldopamine dimer (compound <b>1</b>) from Cicadidae Periostracum, a traditional medicinal substance, and characterized their structures using mass spectrometry and 1D/2D NMR spectroscopy. The absolute configurations of the enantiomers-<b>1a</b> (2S,3R,1''R) and <b>1b</b> (2R,3S,1''S)-were determined for the first time through a combination of electronic circular dichroism and Mosher's esterification analysis. Biological evaluation revealed striking differences in activity between the two enantiomers. Specifically, <b>1a</b> exhibited significant neuroprotective effects against rotenone-induced cytotoxicity in SH-SY5Y neuroblastoma cells, while <b>1b</b> was inactive. Compound <b>1a</b> attenuated oxidative stress by reducing intracellular and mitochondrial reactive oxygen species and elevating glutathione levels. Mechanistically, only <b>1a</b> activated nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant defenses. Molecular docking studies further indicated a stronger interaction of <b>1a</b> with Keap1, the repressor of Nrf2, suggesting a structural basis for the enantioselective activation of the pathway. To our knowledge, this is the first report to assign the absolute configuration at C-1'' of this class of compounds and to demonstrate enantioselective neuroprotective activity mediated by the Nrf2 pathway. These findings underscore the therapeutic potential of insect-derived chiral natural products and provide a rationale for developing stereochemically defined neuroprotective agents for the treatment of neurodegenerative diseases such as Parkinson's disease.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":""},"PeriodicalIF":3.2000,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"N-Acetyldopamine Dimer from Cicadidae Periostracum Is Enantioselectively Neuroprotective via Antioxidant Property.\",\"authors\":\"Punam Thapa, Shristi Khanal, Kibria Gulam, Trung Huy Ngo, Zhiying Chen, Young Jun Ok, Kyu Joon Lee, Hyukjae Choi, Joo-Won Nam, Dong-Young Choi\",\"doi\":\"10.4062/biomolther.2025.140\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>N-Acetyldopamine oligomers are typically biosynthesized as racemic mixtures, yet enantiomers can differ markedly in pharmacological efficacy and safety. In this study, we isolated a pair of enantiomers of an N-acetyldopamine dimer (compound <b>1</b>) from Cicadidae Periostracum, a traditional medicinal substance, and characterized their structures using mass spectrometry and 1D/2D NMR spectroscopy. The absolute configurations of the enantiomers-<b>1a</b> (2S,3R,1''R) and <b>1b</b> (2R,3S,1''S)-were determined for the first time through a combination of electronic circular dichroism and Mosher's esterification analysis. Biological evaluation revealed striking differences in activity between the two enantiomers. Specifically, <b>1a</b> exhibited significant neuroprotective effects against rotenone-induced cytotoxicity in SH-SY5Y neuroblastoma cells, while <b>1b</b> was inactive. Compound <b>1a</b> attenuated oxidative stress by reducing intracellular and mitochondrial reactive oxygen species and elevating glutathione levels. Mechanistically, only <b>1a</b> activated nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant defenses. Molecular docking studies further indicated a stronger interaction of <b>1a</b> with Keap1, the repressor of Nrf2, suggesting a structural basis for the enantioselective activation of the pathway. To our knowledge, this is the first report to assign the absolute configuration at C-1'' of this class of compounds and to demonstrate enantioselective neuroprotective activity mediated by the Nrf2 pathway. These findings underscore the therapeutic potential of insect-derived chiral natural products and provide a rationale for developing stereochemically defined neuroprotective agents for the treatment of neurodegenerative diseases such as Parkinson's disease.</p>\",\"PeriodicalId\":8949,\"journal\":{\"name\":\"Biomolecules & Therapeutics\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.2000,\"publicationDate\":\"2025-10-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biomolecules & Therapeutics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.4062/biomolther.2025.140\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biomolecules & Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.4062/biomolther.2025.140","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
摘要
n -乙酰多巴胺低聚物通常是作为外消旋混合物生物合成的,但对映体在药理功效和安全性方面可能有显着差异。本研究从传统药材Cicadidae Periostracum中分离到一对n -乙酰基多巴胺二聚体(化合物1),并利用质谱和1D/2D NMR对其结构进行了表征。对映体1a (2S,3R,1”R)和1b (2R,3S,1”S)的绝对构型首次通过电子圆二色性和Mosher酯化分析相结合的方法确定。生物学评价显示两种对映体的活性存在显著差异。具体来说,1a对鱼藤酮诱导的SH-SY5Y神经母细胞瘤细胞毒性表现出显著的神经保护作用,而1b则无活性。化合物1a通过减少细胞内和线粒体活性氧和提高谷胱甘肽水平来减轻氧化应激。在机制上,只有1a激活了核因子红细胞2相关因子2 (Nrf2),这是抗氧化防御的关键调节因子。分子对接研究进一步表明,1a与Nrf2的抑制因子Keap1的相互作用更强,提示该通路的对映选择性激活具有结构基础。据我们所知,这是第一次报道这类化合物在C-1位点的绝对构型,并证明Nrf2通路介导的对映选择性神经保护活性。这些发现强调了昆虫衍生的手性天然产物的治疗潜力,并为开发用于治疗神经退行性疾病(如帕金森病)的立体化学定义的神经保护剂提供了理论依据。
N-Acetyldopamine Dimer from Cicadidae Periostracum Is Enantioselectively Neuroprotective via Antioxidant Property.
N-Acetyldopamine oligomers are typically biosynthesized as racemic mixtures, yet enantiomers can differ markedly in pharmacological efficacy and safety. In this study, we isolated a pair of enantiomers of an N-acetyldopamine dimer (compound 1) from Cicadidae Periostracum, a traditional medicinal substance, and characterized their structures using mass spectrometry and 1D/2D NMR spectroscopy. The absolute configurations of the enantiomers-1a (2S,3R,1''R) and 1b (2R,3S,1''S)-were determined for the first time through a combination of electronic circular dichroism and Mosher's esterification analysis. Biological evaluation revealed striking differences in activity between the two enantiomers. Specifically, 1a exhibited significant neuroprotective effects against rotenone-induced cytotoxicity in SH-SY5Y neuroblastoma cells, while 1b was inactive. Compound 1a attenuated oxidative stress by reducing intracellular and mitochondrial reactive oxygen species and elevating glutathione levels. Mechanistically, only 1a activated nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant defenses. Molecular docking studies further indicated a stronger interaction of 1a with Keap1, the repressor of Nrf2, suggesting a structural basis for the enantioselective activation of the pathway. To our knowledge, this is the first report to assign the absolute configuration at C-1'' of this class of compounds and to demonstrate enantioselective neuroprotective activity mediated by the Nrf2 pathway. These findings underscore the therapeutic potential of insect-derived chiral natural products and provide a rationale for developing stereochemically defined neuroprotective agents for the treatment of neurodegenerative diseases such as Parkinson's disease.
期刊介绍:
Biomolecules & Therapeutics (Biomolecules & Therapeutics) (Print ISSN 1976-9148, Online ISSN 2005-4483) is an international, peer-reviewed, open access journal that covers pharmacological and toxicological fields related to bioactive molecules and therapeutics. It was launched in 1993 as "The Journal of Applied Pharmacology (ISSN 1225-6110)", and renamed "Biomolecules & Therapeutics" (Biomol Ther: abbreviated form) in 2008 (Volume 16, No. 1). It is published bimonthly in January, March, May, July, September and November. All manuscripts should be creative, informative, and contribute to the development of new drugs. Articles in the following categories are published: review articles and research articles.