Spirohypertones A and B as potent antipsoriatics: Tumor necrosis factor-α inhibitors with unprecedented chemical architectures

作者：Yulin Duan, Weiguang Sun, Yongqi Li, Zhengyi Shi, Lanqin Li, Yeting Zhang, Yeting Zhang, Kun Huang, Zhiping Zhang, Changxing Qi, Yonghui Zhang, Yonghui Zhang · 发表于：Acta Pharmaceutica Sinica B · 年份：2024 · DOI：10.1016/j.apsb.2024.02.002 · 被引用次数：24 · 研究领域：Natural Compound Pharmacology Studies、Bioactive Compounds and Antitumor Agents、Sphingolipid Metabolism and Signaling

Tumor necrosis factor-α (TNF-α) is a promising target for inflammatory and autoimmune diseases. Spirohypertones A (1) and B (2), two unprecedented polycyclic polyprenylated acylphloroglucinols with highly rearranged skeletons, were isolated from Hypericum patulum. The structures of 1 and 2 were confirmed through comprehensive spectroscopic analysis, single-crystal X-ray diffraction and electronic circular dichroism calculations. Importantly, 2 showed remarkable TNF-α inhibitory activity, which could protect L929 cells from death induced by co-incubation with TNF-α and actinomycin D. It also demonstrated the ability to suppress the inflammatory response in HaCaT cells stimulated with TNF-α. Notably, in an imiquimod-induced psoriasis murine model, 2 restrained symptoms of epidermal hyperplasia associated with psoriasis, presenting anti-inflammatory and antiproliferative effects. This discovery positions 2 as a potent TNF-α inhibitor, providing a promising lead compound for developing an antipsoriatic agent.