ABSTRACT
In this research, five new indolequinazoline alkaloids (1-5), along with six known indolequinazoline alkaloids (6-11) were obtained from the fruits of Tetradium ruticarpum. Their structures were elucidated through comprehensive spectroscopic data of 1D and 2D NMR, HRESIMS and ECD spectra. Additionally, all isolates were assayed for their SIRT1 inhibitory activities in vitro and compounds 2, 7, 10 and 11 exhibited activities with IC50 values ranged from 43.16 to 118.35 µM.
Subject(s)
Alkaloids , Evodia , Evodia/chemistry , Fruit/chemistry , Molecular Structure , Alkaloids/analysis , Magnetic Resonance SpectroscopyABSTRACT
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).
Subject(s)
Antineoplastic Agents, Phytogenic , Physalis , Withanolides , Humans , Withanolides/pharmacology , Withanolides/chemistry , Physalis/chemistry , Plant Extracts/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Cell Line , Molecular StructureABSTRACT
Distiller's grains, byproducts of the brewing process, represent a valuable resource for extracting natural phenolic compounds due to their significant global production. This study presents the first evidence of the protective effects of Moutai distiller's grain polyphenol extract (MDGP) on dextran sulfate sodium (DSS)-induced colitis in mice. These protective effects manifest predominantly through the amelioration of general colitis indices and histopathological improvements. Utilizing liquid chromatography-high-resolution electrospray ionization mass spectrometry (LC-HR-ESI-MS), the main components of MDGP were identified as rutin, quercetin, naringenin, and dihydroquercetin. Moreover, a novel mechanism was elucidated by which rutin, the primary active component of MDGP, alleviates DSS-induced colitis. Assessment of intestinal barrier function, microbial sequencing, fecal transplantation, and antibiotic depletion experiments revealed that rutin suppresses the abundance of pathogenic bacteria (Helicobacter, Klebsiella, and Veillonella) while promoting the proliferation of beneficial bacteria (Ruminococcus_torques_group, Lachnoclostridium, and norank_f__Muribaculaceae). This modulation culminates in elevated butyric acid concentrations within short-chain fatty acids (SCFAs), amplified integrity of tight (ZO-1, occludin) and adherent (E-cadherin, ß-catenin) junctional complexes, fortified intestinal barrier function, and diminished intestinal inflammation.This investigation accentuates the innovative therapeutic potential of MDGP and its main active component, rutin, in assuaging DSS-induced intestinal inflammation and fortifying the intestinal barrier through a mechanism predominantly mediated by the intestinal microbiota. Such insights potentially elevate the prominence of distiller's grains in the realm of functional food development.
ABSTRACT
Glutathione peroxidase 4 (GPX4) is an essential antioxidant enzyme that negatively regulates ferroptosis. To exploit novel GPX4 inhibitors, we designed and synthesized 32 indirubin derivatives. Compound 31 exhibited the strongest antitumor activity against HCT-116 cells (IC50 = 0.49 ± 0.02 µM). Further studies suggested that 31 could induce ferroptosis in colon cancer cells and its cytotoxic activity could be reversed by ferroptosis inhibitors. Mechanism research showed that 31 promoted the degradation of GPX4, causing the accumulation of lipid ROS to induce ferroptosis. Animal experiments also proved that 31 could inhibit the growth of colon cancer cells in vivo and reduce the expression of GPX4 in tumor tissues. These results indicated that compound 31 had potential as a novel ferroptosis inducer agent for colon cancer.
Subject(s)
Colonic Neoplasms , Ferroptosis , Animals , Glutathione Peroxidase/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Colonic Neoplasms/drug therapyABSTRACT
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 9.06â µM.
Subject(s)
Physalis , Withanolides , Animals , Mice , Structure-Activity Relationship , Withanolides/pharmacology , Withanolides/chemistry , Nitric Oxide , RAW 264.7 Cells , Plant Extracts/pharmacology , Plant Extracts/chemistry , Physalis/chemistry , Physalis/metabolism , Molecular StructureABSTRACT
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.â 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.â 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 (20â µM) better than the positive control verapamil. The research of the leaves of T.â 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.
Subject(s)
Cupressaceae , Diterpenes , Diterpenes/chemistry , Plant Extracts/chemistry , Wood , Spectrum Analysis , Cupressaceae/chemistry , Molecular StructureABSTRACT
(±)-Patulinervones A (1) and B (2), two diastereomers of spiro-lignans sharing an unprecedented dimethyl-spiro[furan-2,2'-furo[2,3-b]furan] 5/5/5 tricyclic moiety were isolated from the leaves of Melicope patulinervia (Merr. & Chun) C.C. Huang. Their structures were established by extensive spectroscopic data and electronic circular dichroism (ECD) analyses. The racemates (±)-1 and 2 and their enantiomers exhibited α-glucosidase inhibitory effect with IC50 values range of 10.08 ± 1.24 - 25.58 ± 1.97 µM.
ABSTRACT
Six new alkaloids (1-6) and six known alkaloids (7-12) were obtained from the stems of Sinomenium acutum. Among them, compounds 1-3 and 6 were four N-oxide alkaloids. The structures and absolute configurations of these new alkaloids were elucidated through comprehensive data of 1D and 2D NMR, HRESIMS and ECD spectra. All isolated compounds were evaluated in vitro for their inhibitory activities against nitric oxide (NO) production and inhibitory effects on AChE. Among them, the sinomenine N-oxide (9) was the most potent NO production inhibitor, with an IC50 value of 23.04 µM.
Subject(s)
Alkaloids , Drugs, Chinese Herbal , Sinomenium/chemistry , Oxides , Molecular Structure , Alkaloids/pharmacology , Alkaloids/chemistry , Drugs, Chinese Herbal/pharmacologyABSTRACT
Harringtonolide (HO, 1) is a bioactive diterpenoid tropone isolated from Cephalotaxus harringtonia with antiproliferation activity. Until now there have been no reports to elucidate its anticancer mechanism. Herein we report the synthesis of HO-derived probes (10, 11, and 12) to identify the possible target of HO. As a result, the application of a novel photoaffinity alkyne-tagged probe from HO (compound 12) showed direct engagement between HO and receptor for activated C kinase 1 (RACK1). Furthermore, HO could suppress the epithelial-mesenchymal transition (EMT) process and inhibit activation of the FAK/Src/STAT3 signaling pathway in A375 cells. This study provides a groundwork for HO as an effective antitumor agent that targets RACK1 to suppress cancer cell migration.
ABSTRACT
Five new spirocyclic polycyclic polyprenylated acylphloroglucinols, Hyperpatulones C-G (1-5), were obtained from the leaves of Hypericum patulum. Their structures were characterized by the comprehensive analysis of their IR, NMR, CD spectra and HRESIMS data. All the new compounds were evaluated for the α-glycosidase inhibitory activities. Among them, compounds 3-5 showed α-glucosidase inhibitory activities, with IC50 values of 14.06-37.69 µM.
Subject(s)
Glycoside Hydrolase Inhibitors/pharmacology , Hypericum/chemistry , Phloroglucinol/pharmacology , China , Glycoside Hydrolase Inhibitors/isolation & purification , Molecular Structure , Phloroglucinol/isolation & purification , Phytochemicals/isolation & purification , Phytochemicals/pharmacology , Plant Leaves/chemistry , alpha-GlucosidasesABSTRACT
Six new Cephalotaxus alkaloids, including five cephalotaxine-type alkaloids, and one homoerythrina-type alkaloid, along with six known analogues, were isolated from the seeds of Cephalotaxus fortunei. Their structures were elucidated by combination of spectroscopic data analyses, time-dependent density functional theory (TDDFT) ECD calculation, and single-crystal X-ray diffraction. Cephalofortine B represents the first example of C-5 epi-cephalotaxine-type alkaloid. All isolated compounds were tested for cytotoxicities against HCT-116, A375, and SK-Mel-28 cell lines. Cephalofortine E showed moderate activity against HCT-116 cell line, with an IC50 value of 7.46 ± 0.77 µM.
Subject(s)
Alkaloids , Antineoplastic Agents, Phytogenic , Cephalotaxus , Harringtonines , Alkaloids/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Harringtonines/pharmacology , Homoharringtonine , Humans , Molecular Structure , SeedsABSTRACT
Six new oligomeric neolignans including two trimeric neolignans (1 and 2) and four dimeric neolignans (3-6) were isolated from the leaves of Magnolia officinalis var. biloba. Their structures were determined based on HR-ESIMS and NMR data, as well as electronic circular dichroism (ECD) calculations. Compound 1 is formed from two obovatol moieties directly linked to an aromatic ring of the remaining obovatol moiety, which is an unprecedented type of linkage between monomers. All isolates were assessed for their inhibitory effects on NO production in LPS-stimulated RAW 264.7 macrophage cells. Compounds 1 and 3 showed significantly inhibitory activities with IC50 values of 6.04 and 3.26 µmol·L-1, respectively.
Subject(s)
Lignans , Magnolia , Animals , Lignans/pharmacology , Magnolia/chemistry , Mice , Molecular Structure , Phytochemicals/pharmacology , Plant Extracts/pharmacology , Plant Leaves/chemistry , RAW 264.7 CellsABSTRACT
Fortuneicyclidins A (1) and B (2), a pair of epimeric pyrrolizidine alkaloids containing an unprecedented 7-azatetracyclo[5.4.3.0.02,8]tridecane core, were isolated from the seeds of Cephalotaxus fortunei, along with two biogenetically relative known analogues, 3 and 4. The structures were determined by multiple spectral techniques and chemical derivatization methods. Compound 1 showed inhibitory activity against α-glucosidase.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Cephalotaxus/chemistry , Glycoside Hydrolase Inhibitors/pharmacology , Plant Leaves/chemistry , Pyrrolizidine Alkaloids/pharmacology , Alkanes/chemistry , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/isolation & purification , Molecular Structure , Pyrrolizidine Alkaloids/chemistry , Pyrrolizidine Alkaloids/isolation & purificationABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemical synthesis , Pregnenes/chemical synthesis , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , Inhibitory Concentration 50 , Membrane Potential, Mitochondrial , Pregnenes/pharmacology , Reactive Oxygen Species/metabolism , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Plants, Medicinal/chemistry , Sesquiterpenes, Guaiane/pharmacology , Snail Family Transcription Factors/antagonists & inhibitors , Xylopia/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Plant Leaves/chemistry , Sesquiterpenes, Guaiane/chemistry , Sesquiterpenes, Guaiane/isolation & purification , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Two new phthalide dimers (1 and 2) were obtained from the rhizomes of Ligusticum sinense Oliv., along with three known dimeric phthalides (3-5). Their structures were determined with the aid of the spectroscopic data, and their absolute configurations were elucidated based on the comparison of calculated and experimental electronic circular dichroism (ECD) spectra. All the compounds were evaluated in vitro for their inhibitory activities against NO production in LPS-treated RAW264.7 macrophages. Among them, compounds 1 and 3 showed potent NO prohibitive activity with IC50 values at 4.86 ± 0.29 µM and 4.87 ± 0.32 µM, respectively.
Subject(s)
Benzofurans/pharmacology , Ligusticum/chemistry , Rhizome/chemistry , Animals , Benzofurans/isolation & purification , China , Mice , Molecular Structure , Nitric Oxide , Phytochemicals/isolation & purification , Phytochemicals/pharmacology , Plants, Medicinal/chemistry , RAW 264.7 CellsABSTRACT
Nonalcoholic steatohepatitis (NASH) is a common clinical condition that can lead to advanced liver diseases. The mechanism of the diaease progression, which is lacking effective therapy, remains obsure. Therefore, there is a need to understand the pathogenic mechanisms responsible for disease development and progression in order to develop innovative therapies. To accomplish this goal, experimental animal models that recapitulate the human disease are necessary. Currently, an increasing number of studies have focused on natural constituents from medicinal plants which have been emerged as a new hope for NASH. This review summarized the pathogenesis of NASH, animal models commonly used, and the promising targets for therapeutics. We also reviewed the natural constituents as potential NASH therapeutic agents.
Subject(s)
Biological Products , Non-alcoholic Fatty Liver Disease , Animals , Disease Models, Animal , Humans , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/pathologyABSTRACT
Four new lignans, patulinones A-D (1-4) and three new acetophenone derivatives, patulinones E-G (5-7) were isolated from the leaves of Melicope patulinervia. Their structures were elucidated on the basis of the interpretation of HR-ESIMS, NMR, CD data. All the isolated compounds were evaluated for α-glucosidase inhibitory activity. Of the isolates, compound 4 was found to exhibit the strongest inhibition against α-glucosidase with IC50 value of 6.02 ± 0.46 µM.
Subject(s)
Acetophenones/pharmacology , Glycoside Hydrolase Inhibitors/pharmacology , Lignans/pharmacology , Rutaceae/chemistry , Acetophenones/isolation & purification , China , Glycoside Hydrolase Inhibitors/isolation & purification , Lignans/isolation & purification , Molecular Structure , Phytochemicals/isolation & purification , Phytochemicals/pharmacology , Plant Leaves/chemistryABSTRACT
To develop novel GLS1 inhibitors as effective therapeutic agents for triple-negative breast cancer (TNBC), 25 derivatives were synthesized from the natural inhibitor withangulatin A (IC50 = 18.2 µM). Bioassay optimization identified a novel and selective GLS1 inhibitor 7 (IC50 = 1.08 µM). In MDA-MB-231 cells, 7 diminished cellular glutamate levels by blocking glutaminolysis pathway, further triggering the generation of reactive oxygen species to induce caspase-dependent apoptosis. Molecular docking indicated that 7 interacted with a new reacting site of allosteric binding pocket by forming various interactions in GLS1. The intraperitoneal administration of 7 at a dose of 50 mg/kg exhibited remarkable therapeutic effects and no apparent toxicity in the MDA-MB-231 xenograft model, indicating its potential as a novel GLS1 inhibitor for treatment of TNBC.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Enzyme Inhibitors/pharmacology , Glutaminase/antagonists & inhibitors , Pregnenes/pharmacology , Triple Negative Breast Neoplasms/drug therapy , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Glutaminase/metabolism , Humans , Molecular Structure , Pregnenes/chemical synthesis , Pregnenes/chemistry , Structure-Activity Relationship , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathologyABSTRACT
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.