Withanolides from Physalis angulata var. villosa and the Relative Configurational Revision of Some Known Analogs.

Physalis angulata var. villosa is a plant possessing abundant withanolides, but in-depth research is lacking. In our ongoing study of P. angulata var. villosa, 15 previously undescribed withanolides (1-15), along with 21 known analogs (16-36), were isolated from the whole plant. The structures of the withanolides (1-15) were elucidated based on analysis of their 1D and 2D NMR, HRESIMS, and ECD data. Additionally, the application of γ-gauche effects with the help of ROESY correlations led to the formulation of empirical rules for withanolides with 14-OH/15-OAc to rapidly determine the 14-OH orientations, making it possible to propose configurational revisions of 19 previously reported analogs (1'-19'). Withanolides 1, 4-6, and 10 showed potent cytotoxic activities against three human cancer cell lines (HCT-116, MDA-MB-231, and A549).

Discovery of piperine derivatives as inhibitors of human dihydroorotate dehydrogenase to induce ferroptosis in cancer cells.

Inhibition of human dihydroorotate dehydrogenase (hDHODH) represents a promising strategy for suppressing the proliferation of cancer cells. To identify novel and potent hDHODH inhibitors, a total of 28 piperine derivatives were designed and synthesized. Their cytotoxicities against three human cancer cell lines (NCI-H226, HCT-116, and MDA-MB-231) and hDHODH inhibitory activities were also evaluated. Among them, compound H19, exhibited the strongest inhibitory activities (NCI-H226 IC50 = 0.95 µM, hDHODH IC50 = 0.21 µM). Further pharmacological investigations revealed that H19 exerted anticancer effects by inducing ferroptosis in NCI-H226 cells, with its cytotoxicity being reversed by ferroptosis inhibitors. This was supported by the intracellular growth or decline of ferroptosis markers, including lipid peroxidation, Fe2+, GSH, and 4-HNE. Overall, H19 emerges as a promising hDHODH inhibitor with potential anticancer properties warranting development.

Withanolides from Physalin angulata and Their Inhibitory Effects on Nitric Oxide Production.

Six new withanolides, angulasteroidins A-F (1-6), along with twelve known analogs (7-18) were isolated from the whole plants of Physalis angulata. Their structures were elucidated by analysis of 1D and 2D NMR, ECD and IR spectra, HR-ESI-MS data, and ECD calculation. Compounds 1 and 6 were rare 1-10 seco withanolides. Compounds 2-4, 7-9, and 15 exhibited significant inhibitory activity on the production of nitric oxide in the LPS-activated RAW 264.7 mouse macrophage cell lines with IC50 values ranging from 0.23 to 9.06 µM.

Bioactive Dimeric Diterpenoids from Taiwania cryptomerioides (Hayata) and Their Biological Activities.

Taiwania cryptomerioides Hayata is an endangered relict plant belonging to Taxodiaceae, and it is also an endemic plant to China. The decay-resistant of Taiwania timber can provide highly quality wood for building and furniture. Plenty of regenerative of leaves of T. cryptomerioides also has been used as a resource for the discovery of new dimeric diterpenoids. In a search for structurally diverse dimeric diterpenoids and potent bioactive isolates, ten new heterodimeric diterpenoids, taiwaniadducts K-T (1-4, 6, 8-11, and 14), along with five known ones (5, 7, 12, 13, and 15), were isolated from the leaves of T. cryptomerioides. These new compounds were defined by comprehensive spectroscopic analyses, putative biosynthetic pathways, and the values of optical. Biologically, anti-multidrug resistance (MDR) activities of compounds were evaluated. Compounds 4 and 10 exerted a 9.18-fold potentiation effect on bortezmib (BTZ) susceptibility at a tested concentration (20 µM) better than the positive control verapamil. The research of the leaves of T. cryptomerioides not only added the new data to the structural diversity and activities of dimeric diterpenoids but also could provide support for the medical and industrial application of the leaves of this endangered relict plant.

Synthesis and biological evaluation of novel withangulatin A derivatives as potential anticancer agents.

Novel withangulatin A (WA) derivatives were synthesized and evaluated for antiproliferative activity against four human cancer cell lines (U2OS, MDA-MB-231, HepG2, and A549). Among these derivatives, 10 exhibited the most potent antiproliferative activity, with an IC50 value of 74.0 nM against the human breast cancer cell line MDA-MB-231 and potency that was 70-fold that of WA (IC50 = 5.22 µM). Moreover, 10 caused G2-phase cell cycle arrest in a concentration-dependent manner and induced the apoptosis of MDA-MB-231 cells by increasing intracellular reactive oxygen species (ROS). Compound 10 showed a high selectivity index (SI = 267.03) for breast cancer MDA-MB-231 cells. These results suggest that 10 is a promising anticancer agent.

Dimeric guaianes from leaves of Xylopia vielana as snail inhibitors identified by high content screening.

The transcriptional repressor Snail trriggers epithelial-mesenchymal transition (EMT), the process allowing cancer cells with invasive and metastasis properties. In this study, we screened medicinal plants for the Snail inhibitory active components by high content screen (HCS) and found that the crude extract of Xylopia vielana leaves showed potential activity. Subsequently, bioassay-guided isolation of the extract of Xylopia vielana was performed to obtain twenty-four dimeric guaianes (1-24), including 16 new analogues (1-5, 8-11, 13-15, 17, 18, 21, and 22). Their structures were elucidated by the comprehensive application of multiple spectroscopic methods. Compounds 1, 11, 12, and 16 were initially identified as the active compounds. Wound healing assay, transwell migration assay and western blot experiments verified that compounds 1 and 12 inhibited the expression of Snail in a concentration-dependent manner, and compound 12 was verified as a potent tumor migration inhibitory agent. This work showed a practical strategy for the discovery of new Snail inhibitors from natural products and provided potential insights for dimeric guaianes as anticancer lead compounds specifically targeting Snail protein.

Patulignans A-C, three structurally unique lignans from the leaves of Melicope patulinervia.

(±)-Patulignans A-C (1-3), three unique pairs of lignan enantiomers were isolated from the leaves of Melicope patulinervia. Patulignan A (1) possesses an unprecedented dimethyloxonane moiety in nature, meanwhile patulignans B (2) and C (3) are epimers carrying a novel dimethyl-1,6-dioxaspiro[4.5]decane skeleton. Their structures were established by spectroscopy methods and electronic circular dichroism (ECD) calculations. Compounds 1-3 showed significant inhibitory activity against α-glucosidase.

Cytotoxic Germacranolides from the Whole Plant of Carpesium minus.

Eight new germacranolides, minusolides A-H (1-8), along with two known analogues, 9 and 10, were isolated from the whole plant of Carpesium minus. Their structures were elucidated by spectroscopic analysis. Compounds 1 and 2, and 6 and 9 are two pairs of rare epimers with opposite configurations at C-2 of the 2-methylbutyryloxy group. The absolute configurations were determined by X-ray diffraction studies. Compound 7 exhibited cytotoxic activities against MDA-MB-231, A549, and HCT-116 cells with IC50 values of 6.1 ± 0.2, 8.4 ± 0.6, and 3.7 ± 0.6 µM, respectively. Compound 7 induced the apoptosis of HCT-116 cells via suppression of PARP and promoting cleavage of PARP.

Taxumarienes A-G, seven new α-glucosidase inhibitory taxane-diterpenoids from the leaves of Taxus mairei.

Seven new taxane diterpenoids taxumarienes A-G (1-7) were isolated from the leaves of Taxus mairei, along with seven known analogous (8-14). The structures of the new compounds were elucidated based on the analysis of NMR and MS spectroscopy. All isolates were evaluated for their α-glucosidase inhibitory activities. Among them, taxumarienes A (1) and F (6) showed potent effect with IC50 values of 5.9 ±â€¯1.30 µM and 3.7 ±â€¯0.75 µM, respectively.

New obovatol trimeric neolignans with NO inhibitory activity from the leaves of Magnolia officinalis var. biloba.

Six new obovatol trimeric neolignans, houpulignans A-F (1-6) were isolated from the leaves of Magnolia officinalis var. biloba. Their structures were determined on the basis of the interpretation of HRESIMS, NMR data, and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 are the first examples of neolignans derived from three units of obovatol bearing a rare 1,4-benzodioxepane moiety. Compound 3 possesses a benzodihydropyran ring, meanwhile three units of obovatol in 4-6 are connected by an alkyl chain. Compounds 1-3 inhibited NO production in LPS-stimulated RAW264.7 cells with IC50 values of 8.01, 20.21, and 4.05 µM, respectively.

Isolation, Chiral-Phase Resolution, and Determination of the Absolute Configurations of a Complete Series of Stereoisomers of a Rearranged Acetophenone with Three Stereocenters.

A synthesis-inspired chemical investigation of the leaves of Melicope ptelefolia led to the isolation of evodialones A-D (1-4), four rearranged acetophenone stereoisomers possessing a prenylated acylcyclopentenone skeleton with three stereogenic carbons. Evodialones C and D (3 and 4) are new minor constituents. The chiral-phase HPLC resolution gave (+)-1-4 and (-)-1-4, eight enantiomers forming a complete stereoisomer library. Their absolute configurations were elucidated via extensive spectroscopic data and a modified Mosher's method. The relationship between the chiral structures and their NMR and ECD data is discussed. Compounds (±)-1, -2, and -4 have significant protective effects on high-glucose-induced oxidative stress in human vein endothelial cells.

Taicrypnacids A and B, a Pair of C37 Heterodimeric Diterpenoid Stereoisomers from Taiwania cryptomerioides.

Two uncommon C37 heterodimeric diterpenoids, taicrypnacids A (1) and B (2), and a known labdane-type diterpenoid (3) were isolated from the leaves of Taiwania cryptomerioides. Several techniques, such as comprehensive spectroscopic analysis, chemical conversion, X-ray crystallography, and ECD data, were employed to define the structures. The two new compounds displayed cytotoxicity against human breast cancer (MCF-7), osteosarcoma (U-2 OS), and human colon carcinoma (HCT-116) cell lines, while the methyl ester 1a showed no activity. Compound 1 induced Ca2+-ROS pathway-mediated endoplasmic reticulum stress, and excessive stress led to cell death by activating apoptosis and autophagy.

Artemisianins A-D, new stereoisomers of seco-guaianolide involved heterodimeric [4+2] adducts from Artemisia argyi induce apoptosis via enhancement of endoplasmic reticulum stress.

Artemisianins A-D (1-4), four stereoisomers of sesquiterpenoid dimers, forming via [4+2] cycloaddition from a 1, 10-seco-guaianolide dienophile and a guaianolide diene, along with two biosynthetically related precurors 5 and 6, were isolated from the famous traditional Chinese medicine Artemisia argyi. The structures of 1-4, including their absolute configurations, were elucidated by extensive spectroscopic data and ECD/TDDFT calculation analysis. Compounds 1-4 exhibited cytotoxicity with IC50 values ranging from 7.2 to 23.3 µM. The accumulation of Ca2+ in cytoplasm and enlarged endoplasmic reticulum (ER) indicated that 1 mediated HT-29 cancer cell apoptosis through improvement of ER-stress, which was further proved by unfolded protein response (UPR) pathway on basis of the upregulation of IRE1α, p-PERK, ATF6, and CHOP.

Hyperpatulols A-I, spirocyclic acylphloroglucinol derivatives with anti-migration activities from the flowers of Hypericum patulum.

Nine new spirocyclic acylphloroglucinol derivatives, hyperpatulols A-I (1-9), were characterized from the flowers of Hypericum patulum. Their structures were elucidated by the basic analysis of the obtained spectroscopic data, and their absolute configurations were assigned by both the electronic circular dichroism (ECD) exciton chirality method and ECD calculation. The evaluation of their anti-migration effects on U2-OS human osteosarcoma cells showed that compound 4 exhibited moderate inhibitory activity in a dose-dependent manner. Further pharmacological studies revealed that 4 could regulate the expression of the proteins Vimentin and E-cadherin.

Cytotoxic and neuroprotective activities of constituents from Alternaria alternate, a fungal endophyte of Psidium littorale.

Chemical investigation of the EtOAc extract of the plant-associated fungus Alternaria alternate in rice culture led to the isolation of a novel liphatic polyketone, alternin A (1), a new indole alkaloid (8), and a new sesquiterpene (11), together with 12 known compounds. Their structures were elucidated by the interpretation of extensive spectroscopic data, and the absolute configurations of 1-3 were established using calculations of ECD spectra, NMR data, and optical rotation values. Compound 1 possesses an unprecedented C25 liphatic polyketone skeleton. Compounds 5 and 10 exhibited potential cytotoxic activities against MCF-7 and HepG cells, and compounds 2, 7, and 9 exhibited potential neuroprotective activities in glutamate induced-PC12 injured cells.

Red-Emitting Fluorescent Probe for Detection of γ-Glutamyltranspeptidase and Its Application of Real-Time Imaging under Oxidative Stress in Cells and in Vivo.

γ-Glutamyltranspeptidase (GGT) plays critical roles in regulating various physiological/pathophysiological processes including the intracellular redox homeostasis. However, an effective fluorescent probe for dissecting the relationships between GGT and oxidative stress in vivo remains largely unexplored. Herein, we present a light-up fluorescent probe (DCDHF-Glu) with long wavelength emission (613 nm) for the highly sensitive and selective detection of GGT using dicyanomethylenedihydrofuran derivative as the fluorescent reporter and γ-glutamyl group as the enzyme-active trigger. DCDHF-Glu is competent to real-time image endogenous GGT in live cells and mice. In particular, DCDHF-Glu enables the direct real-time visualization of the upregulation of GGT under drug-induced oxidative stress in the HepG2 cells and the LO2 cells, as well as in vivo, vividly implying its excellent capacity in elucidation of GGT function in GGT-related biological events.

Taiwanoids A-D, four dimeric diterpenoids featuring tetracyclic [7. 75, 9. 4. 05, 10. 08, 9] octodecane from Taiwania cryptomerioidesim.

Biogenesis-inspired chemical research of the leaves of Taiwania cryptomerioides afforded four unprecedented dimeric diterpenes, featuring a tetracyclic [7. 75, 9. 4. 05, 10. 08, 9] octodecane core: taiwanoids A-D (1-4). The structures of these compounds were determined on the basis of comprehensive spectral analysis, chemical conversions and X-ray crystallography. A possible biosynthetic pathway for compounds 1-4 was proposed. Compounds 2 and 3 exerted a 5.37 and 6.26-fold potentiation effect on bortezmib (BTZ) susceptibility at a tested concentration of 20 µM, respectively.

Hypoxia-Protective Azaphilone Adducts from Peyronellaea glomerata.

Peyronellones A and B (1 and 2), a pair of rare tetracyclic caged adducts of azaphilone with pyruvic acid, along with four new analogues (3-6), were isolated from solid cultures of the endophytic fungus Peyronellaea glomerata. Their structures were elucidated through spectroscopic analysis, and their absolute configurations were unambiguously determined by a combination of single-crystal X-ray crystallography, Rh2(OCOCF3)4-induced ECD experiments, ECD calculations, and modified Mosher methods. Compound 2 (5 µM) was found to have a significant hypoxia-protective effect that improved the survival rate of hypoxia/reoxygenation-treated human umbilical vein endothelial cells from 35% to 70%, which was equal to the potency of the positive control, verapamil. Flow cytometry analysis suggested 2 could inhibit H/R-induced late-stage apoptosis of this cell line.

Highly Oxidized Guaianolide Sesquiterpenoids with Potential Anti-inflammatory Activity from Chrysanthemum indicum.

Ten new highly oxidized monomeric (1-8) and dimeric guaianolides (9 and 10), along with two known guaianolide derivatives (11 and 12), were isolated from the aerial parts of Chrysanthemum indicum using a bioassay-guided fractionation procedure. The new compounds were characterized by the basic analysis of the spectroscopic data obtained, and the absolute configurations were determined by both empirical approaches and ECD calculations. Inhibitory effects of 1-12 on nitric oxide production were investigated in lipopolysaccaride (LPS)-mediated RAW 264.7 cells, and most of them (1-8 and 11) displayed IC50 values in the range 1.4-9.7 µM. Moreover, a mechanistic study revealed that the potential anti-inflammatory activity of compound 1 appears to be mediated via suppression of an LPS-induced NF-κB pathway and down-regulation of MAPK activation.

Sesquiterpenoids from Chloranthus anhuiensis with Neuroprotective Effects in PC12 Cells.

Glutamate-induced excitotoxicity plays a vital role in neurodegenerative diseases. Neuroprotection against excitotoxicity has been considered as an effective experimental approach for preventing and/or treating excitotoxicity-mediated diseases. In the present study, six new sesquiterpenoids (1-6) and 26 known compounds of this type (7-32) were isolated and characterized from the whole plants of Chloranthus anhuiensis. Chlorantolide A (1) is the first example of a 5,6- seco-germacrane-type sesquiterpenoid, while phacadinane E (2) is a rare 4,5- seco-cadinane-type sesquiterpenoid. The structures of the new compounds were determined by spectroscopic analysis and by calculations of electronic circular dichroism (ECD) spectra. Their neuroprotective effects in mediating glutamate-induced PC12 cell apoptosis were evaluated. Compound 26 exhibited potent neuroprotective activity with an EC50 value of 3.3 ± 0.9 µM. Using Hoechst 33258 staining, a caspase-3 activity assay, and Western blot analysis it was demonstrated that this compound reduces the apoptosis of PC12 cells through inhibition of caspase-3 activity, while activating the Akt signaling pathway.