Tokinolide A

Intricate polycyclic dimeric phthalides derived from Angelica sinensis with potential to attenuate renal fibrosis.[Pubmed:41447944]

Bioorg Chem. 2026 Feb;169:109424.

Chronic kidney disease (CKD), characterized by fibrosis, is primarily treated clinically by regulating excessive renin-angiotensin-aldosterone system (RAAS). Our previous research showed that dimeric phthalides from Angelica sinensis had the potential to alleviate CKD by suppressing renin expression and RAAS activation. To advance the search for anti-fibrotic and nephroprotective natural phthalides, a systematic investigation of phthalide polymers of A. sinensis was conducted. In this work, twenty-five dimeric phthalides, including seven new dimers, angesinenolides G-M (1, 13, 17, 18, 22-24), and eighteen known congeners were isolated from A. sinensis. The structures of new compounds were elucidated by spectroscopic and crystallographic data analyses. The anti-fibrosis activities of these phthalides were evaluated in TGF-beta1-stimulated HK-2 cells. The results revealed that phthalide dimers 5 (Tokinolide A, TA) and 13 significantly reduced the level of renin gene and down-regulated the fibrosis-related protein markers such as fibronectin (Fn), collagen I (Col I), E-cadherin and alpha-SMA. Mechanistically, treatment with phthalide dimers reduced the levels of renin and Ang II in the RAAS pathway and inhibited the activation of TGF-beta1/Smad signaling pathway in TGF-beta1-stimulated cells. In the 5/6 nephrectomy (Nx) model, the anti-renal fibrotic efficacy of TA was further substantiated, with in vivo mechanisms consistent with the cellular findings. Overall, these findings expanded the natural phthalide dimers of A. sinensis and supported TA as an attractive lead compound for renal fibrosis and renin-targeted CKD therapy.

Neuroprotective and Cytotoxic Phthalides from Angelicae Sinensis Radix.[Pubmed:27128890]

Molecules. 2016 Apr 26;21(5):549.

Seven phthalides, including a new dimeric one named tokinolide C (7), were isolated from Angelicae Sinensis Radix and characterized. The structures of these compounds were elucidated on the basis of comprehensive analysis of spectroscopic data and comparison with literature data. All of the compounds were evaluated for their cytotoxic activities against the A549, HCT-8, and HepG2 cancer cell lines. Riligustilide (4) showed cytotoxicity against three cancer cell lines, with IC50 values of 13.82, 6.79, and 7.92 muM, respectively. Tokinolide A (6) and tokinolide C (6) exerted low cytotoxicity in these cancer cell lines, while the remaining compounds were inactive. Flow cytometry analysis was employed to evaluate the possible mechanism of cytotoxic action of riligustilide (4). We observed that compound 4 was able to arrest the cell cycle in the G1, S phases and induce apoptosis in a time-dependent manner in HCT-8 cell lines. In addition, these compounds were evaluated for neuroprotective effect against SH-SY5Y cells injured by glutamate. The result showed that ligustilide (1), Z-butylidenephthalide (3) and Tokinolide A (6) exhibited significant neuroprotective effects.