Total Synthesis and Anti-inflammatory Activity of Asperjinone and Asperimide C.

IF 3.3 2区生物学 Q2 CHEMISTRY, MEDICINAL Journal of Natural Products Pub Date : 2024-08-23 Epub Date: 2024-08-07 DOI:10.1021/acs.jnatprod.4c00557

Kittisak Thongpat, Natthawat Milehman, Worarat Rojanaverawong, Pannita Holasut, Sunhapas Soodvilai, Chutima S Vaddhanaphuti, Kwanruthai Tadpetch

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Abstract

Total syntheses of two γ-butenolide natural products, asperjinone (1) and asperimide C (2) in both racemic and chiral forms have been accomplished utilizing Basavaiah's one-pot Friedel-Crafts/maleic anhydride formation protocol as a key strategy. Our syntheses verified the revised structure of 1 proposed by Williams et al. and the structure and absolute configuration of 2 reported by the Li group. This work also discloses the unprecedented anti-inflammatory activity of 1. Synthetic 1 exhibited significant anti-inflammatory activity in renal proximal tubular epithelial cells (RPTEC) by suppression of gene expression of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 under LPS-induced renal inflammation condition and was superior to (S)-1, rac-2, 2, and a positive drug control, indomethacin. Moreover, compound 1 inhibited downstream signaling of inflammation by significantly reducing iNOS and COX-2 gene expression and total NO production. The anti-inflammatory activity of asperjinone (1) renders it a potential and promising candidate for developing novel anti-inflammatory agents against inflammation worsening acute kidney injury.

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Asperjinone 和 Asperimide C 的全合成和抗炎活性。

我们采用 Basavaiah 的一锅弗里德尔-卡夫斯/马来酸酐形成协议作为关键策略，完成了两种γ-丁烯内酯天然产物外消旋和手性形式的全合成：asperjinone (1) 和 asperimide C (2)。我们的合成验证了 Williams 等人提出的 1 的修正结构，以及 Li 小组报告的 2 的结构和绝对构型。在 LPS 诱导的肾脏炎症条件下，合成的 1 通过抑制促炎细胞因子 TNF-α、IL-1β 和 IL-6 的基因表达，在肾近端肾小管上皮细胞（RPTEC）中表现出显著的抗炎活性，优于 (S)-1、rac-2、2 和阳性药物对照吲哚美辛。此外，化合物 1 通过显著降低 iNOS 和 COX-2 基因的表达以及 NO 的总生成量，抑制了炎症的下游信号传导。asperjinone（1）的抗炎活性使其成为开发新型抗炎药物以应对炎症恶化的急性肾损伤的潜在候选药物。

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来源期刊

Journal of Natural Products 生物-药学

CiteScore

9.10

自引率

5.90%

发文量

294

审稿时长

2.3 months

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.