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澳大利亚木犀桉成分的α

花匠小妙招
2024-11-28 16:25

澳大利亚木犀桉成分的α-突触核蛋白聚集抑制和抗疟原虫活性

IF 3.3 2区生物学 Q2 CHEMISTRY, MEDICINAL

Dale W. Prebble, Darren C. Holland, Francesca Ferretti, Joshua B. Hayton, Vicky M. Avery, George D. Mellick and Anthony R. Carroll*,

摘要

淀粉样蛋白聚集体与神经退行性疾病的进展有关，可能在恶性疟原虫的生命阶段发挥作用，恶性疟原虫是导致疟疾的寄生虫。我们假设淀粉样蛋白聚集抑制剂可能表现出抗疟原虫活性，反之亦然。为了验证这一假设，我们使用结合亲和质谱分析法筛选了25株澳大利亚桉树花的抗疟原虫活性提取物，以鉴定与帕金森病相关蛋白α-syn结合的分子。结果表明，紫桉花提取物中的Myrtucmmulone P（1）具有α-syn亲和力和抗疟原虫活性，并能抑制α-syn聚集。1以四种相互转化的旋转异构体的混合物的形式存在。对所有四种旋转异构体的NMR共振的分配使我们能够定义溶液中旋转异构物的相对构型、构象和比率。此外，还从E.cloeziana中分离出另外四种新化合物，cloeziones A–C（2–4）和cloeproxide（5），以及三种已知化合物。使用HRMS和NMR分析阐明了所有化合物的结构，并通过比较TDDFT计算和实验ECD数据确定了2-4的绝对构型。化合物1-3在IC50 6.6和16μM之间表现出抗疟原虫活性。桃金娘内酯P（1）的α-syn抑制和抗疟原虫活性支持了抗糜蛋白酶活性和抗疟原虫作用之间的假设联系。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

α-Synuclein Aggregation Inhibitory and Antiplasmodial Activity of Constituents from the Australian Tree Eucalyptus cloeziana

Amyloid protein aggregates are linked to the progression of neurodegenerative conditions and may play a role in life stages of Plasmodium falciparum, the parasite responsible for malaria. We hypothesize that amyloid protein aggregation inhibitors may show antiplasmodial activity and vice versa. To test this hypothesis, we screened antiplasmodial active extracts from 25 Australian eucalypt flowers using a binding affinity mass spectrometry assay to identify molecules that bind to the Parkinson’s disease-implicated protein α-syn. Myrtucommulone P (1) from a flower extract of Eucalyptus cloeziana was shown to have α-syn affinity and antiplasmodial activity and to inhibit α-syn aggregation. 1 exists as a mixture of four interconverting rotamers. Assignment of the NMR resonances of all four rotamers allowed us to define the relative configuration, conformations, and ratios of rotamers in solution. Four additional new compounds, cloeziones A–C (2–4) and cloeperoxide (5), along with three known compounds were also isolated from E. cloeziana. The structures of all compounds were elucidated using HRMS and NMR analysis, and the absolute configurations for 2–4 were determined by comparison of TDDFT-calculated and experimental ECD data. Compounds 1–3 displayed antiplasmodial activities between IC50 6.6 and 16 μM. The α-syn inhibitory and antiplasmodial activity of myrtucommulone P (1) supports the hypothesized link between antiamyloidogenic and antiplasmodial activity.

来源期刊

Journal of Natural Products

期刊介绍： The Journal of Natural Products invites and publishes papers that make substantial and scholarly contributions to the area of natural products research. Contributions may relate to the chemistry and/or biochemistry of naturally occurring compounds or the biology of living systems from which they are obtained. Specifically, there may be articles that describe secondary metabolites of microorganisms, including antibiotics and mycotoxins; physiologically active compounds from terrestrial and marine plants and animals; biochemical studies, including biosynthesis and microbiological transformations; fermentation and plant tissue culture; the isolation, structure elucidation, and chemical synthesis of novel compounds from nature; and the pharmacology of compounds of natural origin. When new compounds are reported, manuscripts describing their biological activity are much preferred. Specifically, there may be articles that describe secondary metabolites of microorganisms, including antibiotics and mycotoxins; physiologically active compounds from terrestrial and marine plants and animals; biochemical studies, including biosynthesis and microbiological transformations; fermentation and plant tissue culture; the isolation, structure elucidation, and chemical synthesis of novel compounds from nature; and the pharmacology of compounds of natural origin.