Citation: Ji-Ping Liao, Ji-Chao Zhou, Ying-Li Fan, Jian-Shuang Jiang, Xu Zhang, Xiang Yuan, Pei-Cheng Zhang, Xiao-Wei Zhang, Ya-Nan Yang. Discovery and biomimetic synthesis of the first stilbenolignan-stilbene hybrids from Heterosmilax yunnanensis inhibiting myocardial fibroblast activation[J]. Chinese Chemical Letters, ;2026, 37(12): 112295. doi: 10.1016/j.cclet.2025.112295 shu

Discovery and biomimetic synthesis of the first stilbenolignan-stilbene hybrids from Heterosmilax yunnanensis inhibiting myocardial fibroblast activation

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

pczhang@imm.ac.cn

zhxw@imm.ac.cn

yyn@imm.ac.cn

Received Date: 26 September 2025
Revised Date: 16 December 2025
Accepted Date: 17 December 2025
Available Online: 17 December 2025

Figures(7)

Two racemic pairs of unprecedented stilbenolignan-stilbene hybrids, (±)–heterosmilphanols A and B [(+)/(–)–1 and (+)/(–)–2], with a rare 1,4-benzodioxane core and C(sp³)–C(sp²) bond, were isolated from the roots of Heterosmilax yunnanensis. Their structures were elucidated through comprehensive spectroscopic methods and quantum chemical calculations. Furthermore, our proposed biogenetic pathway led to their synthesis in seven concise steps by using a protecting-group-free strategy. The p-toluenesulfonic acid (p-TSA)-catalyzed Friedel-Crafts alkylation and Ag₂O-mediated oxidative cross-coupling reactions are essential steps for the constructions of C(sp³)–C(sp²) bond and the 1,4-benzodioxane core, proceeding with high regioselectivity and stereoselectivity. Interestingly, both 1 and 2 exerted potent anti-fibrotic effects in transforming growth factor-β1 (TGF-β1)-induced HL-1 cells through inhibiting cytoskeletal remodeling, cell migration and expression of fibrotic markers. A preliminary mechanism exploration demonstrated that (+)–2 could dose-dependently and significantly suppress the TGF-β1-induced upregulation of macrophage migration inhibitory factor (MIF) protein expression in HL-1 cells. Overall, this study not only enriches the library of stilbenolignan-derived molecules but also offers potential inhibitors for myocardial fibrosis therapy. Moreover, the established synthesis ensures a sufficient supply for subsequent druggability research.
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