Abstract:From the whole plant of Daphne pedunculata, 12 macrocyclic daphnane diterpenoids, including six new compounds, daphnepedunins A−F (1−4, 9, and 10), were isolated. Their structures were elucidated by physiochemical and spectroscopic data analysis, the modified Mosher's method, and X-ray crystallography. The isolated compounds were evaluated for anti-HIV activity against HIV-1 infection in MT4 cells and showed significant anti-HIV activity with IC 50 values of 36.3−994 nM. A consideration of the anti-HIV activit… Show more
“…A recent study reported the isolation of daphnepedunin A ( DA ). [ 52 ] In their study, DA displayed a therapeutic activity against HIV, but this activity was much weaker than the positive control gnidimacrin, and its underlying pharmacological mechanism remained untested. For inhibiting the fibrotic protein expression in activated renal fibroblasts and kidney fibrosis mouse models, DA exerted a beneficial effect, superior to that of PFD, a small molecule compound that has been approved to treat human idiopathic pulmonary fibrosis, and extensively explored in clinical trials for the treatment of kidney fibrosis.…”
Kidney fibrosis is a common fate of chronic kidney diseases (CKDs), eventually leading to renal dysfunction. Yet, no effective treatment for this pathological process has been achieved. During the bioassay‐guided chemical investigation of the medicinal plant Wikstroemia chamaedaphne, a daphne diterpenoid, daphnepedunin A (DA), is characterized as a promising anti‐renal fibrotic lead. DA shows significant anti‐kidney fibrosis effects in cultured renal fibroblasts and unilateral ureteral obstructed mice, being more potent than the clinical trial drug pirfenidone. Leveraging the thermal proteome profiling strategy, cell division cycle 42 (Cdc42) is identified as the direct target of DA. Mechanistically, DA targets to reduce Cdc42 activity and down‐regulates its downstream phospho‐protein kinase Cζ(p‐PKCζ)/phospho‐glycogen synthase kinase‐3β (p‐GSK‐3β), thereby promoting β‐catenin Ser33/37/Thr41 phosphorylation and ubiquitin‐dependent proteolysis to block classical pro‐fibrotic β‐catenin signaling. These findings suggest that Cdc42 is a promising therapeutic target for kidney fibrosis, and highlight DA as a potent Cdc42 inhibitor for combating CKDs.
“…A recent study reported the isolation of daphnepedunin A ( DA ). [ 52 ] In their study, DA displayed a therapeutic activity against HIV, but this activity was much weaker than the positive control gnidimacrin, and its underlying pharmacological mechanism remained untested. For inhibiting the fibrotic protein expression in activated renal fibroblasts and kidney fibrosis mouse models, DA exerted a beneficial effect, superior to that of PFD, a small molecule compound that has been approved to treat human idiopathic pulmonary fibrosis, and extensively explored in clinical trials for the treatment of kidney fibrosis.…”
Kidney fibrosis is a common fate of chronic kidney diseases (CKDs), eventually leading to renal dysfunction. Yet, no effective treatment for this pathological process has been achieved. During the bioassay‐guided chemical investigation of the medicinal plant Wikstroemia chamaedaphne, a daphne diterpenoid, daphnepedunin A (DA), is characterized as a promising anti‐renal fibrotic lead. DA shows significant anti‐kidney fibrosis effects in cultured renal fibroblasts and unilateral ureteral obstructed mice, being more potent than the clinical trial drug pirfenidone. Leveraging the thermal proteome profiling strategy, cell division cycle 42 (Cdc42) is identified as the direct target of DA. Mechanistically, DA targets to reduce Cdc42 activity and down‐regulates its downstream phospho‐protein kinase Cζ(p‐PKCζ)/phospho‐glycogen synthase kinase‐3β (p‐GSK‐3β), thereby promoting β‐catenin Ser33/37/Thr41 phosphorylation and ubiquitin‐dependent proteolysis to block classical pro‐fibrotic β‐catenin signaling. These findings suggest that Cdc42 is a promising therapeutic target for kidney fibrosis, and highlight DA as a potent Cdc42 inhibitor for combating CKDs.
“…δ C 172–174 are observed in the 13 C-NMR spectra (Fig. 10 ) [ 18 , 19 , 35 – 38 ]. In the B-ring, most daphnanes ( 7 , 9 , 11 , and 12 ) have an α-oriented 6,7-epoxy group, with the oxymethine carbon resonance of C-7 observed at ca.…”
Section: Structure Determinationmentioning
confidence: 99%
“…Determination of the relative configuration of alkyl groups branching on the macrocyclic ring part is a key point in the structural elucidation of MDOs, requiring careful analysis of NOE (or ROE). Recently, we reported a facile way to assign the relative configuration of the methyl group at C-9′ in the C 10 aliphatic chain-type MDO by observing the chemical shift of C-10 or C-10′ [ 35 ]. Fig.…”
Tigliane and daphnane diterpenoids are characteristically distributed in plants of the Thymelaeaceae family as well as the Euphorbiaceae family and are structurally diverse due to the presence of polyoxygenated functionalities in the polycyclic skeleton. These diterpenoids are known as toxic components, while they have been shown to exhibit a wide variety of biological activities, such as anti-cancer, anti-HIV, and analgesic activity, and are attracting attention in the field of natural product drug discovery. This review focuses on naturally occurring tigliane and daphnane diterpenoids from plants of the Thymelaeaceae family and provides an overview of their chemical structure, distribution, isolation, structure determination, chemical synthesis, and biological activities, with a prime focus on the recent findings.
Section: Detection Of Daphnane Diterpenoids In W Indica By Lc-ms/msunclassified
“…During our ongoing research aimed at discovering biological diterpenoids from plants of the Thymelaeaceae family [5,20,29,30], this study comprehensively examined and identified daphnane diterpenoids in the stems of W. indica using LC-MS/MS analysis.…”
Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) has emerged as a powerful tool for the rapid identification of compounds within natural resources. Daphnane diterpenoids, a class of natural compounds predominantly found in plants belonging to the Thymelaeaceae and Euphorbiaceae families, have attracted much attention due to their remarkable anticancer and anti-HIV activities. In the present study, the presence of daphnane diterpenoids in Wikstroemia indica, a plant belonging to the Thymelaeaceae family, was investigated by LC-MS/MS analysis. As a result, 21 daphnane diterpenoids (1–21) in the stems of W. indica were detected. Among these, six major compounds (12, 15, 17, 18, 20, and 21) were isolated and their structures were unequivocally identified through a comprehensive analysis of the MS and NMR data. For the minor compounds (1–11, 13, 14, 16, and 19), their structures were elucidated by in-depth MS/MS fragmentation analysis. This study represents the first disclosure of structurally diverse daphnane diterpenoids in W. indica, significantly contributing to our understanding of bioactive diterpenoids in plants within the Thymelaeaceae family.
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