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1.
J Asian Nat Prod Res ; : 1-18, 2024 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-39067002

RESUMEN

A series of amino acid ester trifluoroacetate derivatives was synthesized from scaberol C. They were screened for their inhibitory activity against Non-Small Cell Lung Cancer (NSCLC) cells. Among them, compound 2 l showed significant cytotoxicity against A549 and H460 cells (IC50), and was more active than cisplatin (DDP). The epidermal growth factor receptor (EGFR) was overexpressed in NSCLC, which was the target of multiple cancer therapies and a strong prognostic indicator. Our previous studies reported that the target of scaberol C derivatives against NSCLC cells was EGFR. And then molecular docking analysis and molecular dynamics (MD) simulations indicated that 2 l can stably and covalently bind to the EGFR target protein.

2.
Fitoterapia ; 175: 105947, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38570097

RESUMEN

Employing an MS/MS-based molecular networking-guided strategy, three new eudesmane-type sesquiterpenes (1-3) and one undescribed pseudoguaianolide sesquiterpene (8), along with four known eudesmane-type sesquiterpene lactones (4-7) were extracted and purified from the herbs of Carpesium abrotanoides L. Structural elucidation encompassed comprehensive spectroscopic analysis, NMR calculations, DP4+ analysis, and ECD calculations. The cytotoxicity activity of all isolates was evaluated against two human hepatoma carcinoma cells (HepG2 and Hep3B) in vitro. It was demonstrated that compounds 2 and 4 showed moderate cytotoxic against HepG2 and Hep3B cells. Furthermore, all compounds were evaluated for their acetylcholinesterase (AChE) inhibitory activity. Particularly noteworthy is that, in comparison to the positive control, compound 1 demonstrated significant AChE inhibition with an inhibition rate of 77.86%. In addition, the inhibitory mechanism of compound 1 were investigated by in silico docking analyze and molecular dynamic simulation.


Asunto(s)
Antineoplásicos Fitogénicos , Asteraceae , Inhibidores de la Colinesterasa , Simulación del Acoplamiento Molecular , Sesquiterpenos , Humanos , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/aislamiento & purificación , Inhibidores de la Colinesterasa/química , Sesquiterpenos/farmacología , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/química , Estructura Molecular , Asteraceae/química , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Células Hep G2 , Espectrometría de Masas en Tándem , Línea Celular Tumoral , China , Acetilcolinesterasa/metabolismo
3.
Bioorg Chem ; 147: 107367, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38626492

RESUMEN

Lung cancer is the leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers. Euphorbia kansui yielded 13-oxyingenol-dodecanoate (13OD), an ingenane-type diterpenoid, which had a strong cytotoxic effect on NSCLC cells. The underlying mechanism and potential target, however, remained unknown. The study found that 13OD effectively inhibited the cell proliferation and colony formation of NSCLC cells (A549 and H460 cells), with less toxicity in normal human lung epithelial BEAS-2B cells. Moreover, 13OD can cause mitochondrial dysfunction, and apoptosis in NSCLC cells. Mechanistically, the transcriptomics results showed that differential genes were mainly enriched in the mTOR and AMPK signaling pathways, which are closely related to cellular autophagy, the related indicators were subsequently validated. Additionally, bafilomycin A1 (Baf A1), an autophagy inhibitor, reversed the mitochondrial damage caused by 13OD. Furthermore, the Omics and Text-based Target Enrichment and Ranking (OTTER) method predicted ULK1 as a potential target of 13OD against NSCLC cells. This hypothesis was further confirmed using molecular docking, the cellular thermal shift assay (CETSA), and Western blot analysis. Remarkably, ULK1 siRNA inhibited 13OD's toxic activity in NSCLC cells. In line with these findings, 13OD was potent and non-toxic in the tumor xenograft model. Our findings suggested a possible mechanism for 13OD's role as a tumor suppressor and laid the groundwork for identifying targets for ingenane-type diterpenoids.


Asunto(s)
Homólogo de la Proteína 1 Relacionada con la Autofagia , Carcinoma de Pulmón de Células no Pequeñas , Proliferación Celular , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proliferación Celular/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Relación Estructura-Actividad , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Homólogo de la Proteína 1 Relacionada con la Autofagia/antagonistas & inhibidores , Estructura Molecular , Diterpenos/farmacología , Diterpenos/química , Apoptosis/efectos de los fármacos , Animales , Ratones , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química
4.
Bioorg Chem ; 145: 107208, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38354501

RESUMEN

Hepatocellular carcinoma (HCC) is a major challenge for human healthy. Daphnane-type diterpenes have attracted increasingly attention due to remarkable pharmaceutical potential including anti-HCC activity. To further develop this class of compounds as inhibitors of HCC, the daphnane diterpenoids 12-O-debenzoyl-Yuanhuacine (YHC) and 12-hydroxydaphnetoxin (YHE) were prepared by a standard chemical transformation from dried flower buds of the Daphne genkwa plant. Subsequently, 22 daphnane diterpenoidal 1,3,4-oxdiazole derivatives were rationally designed and synthesized based on YHC and YHE. The assessment of the target compound's anti-hepatocellular carcinoma activity revealed that YHC1 exhibited comparable activity to sorafenib in the Hep3B cell line, while demonstrating higher selectivity. The mechanistic investigation demonstrates that compound YHC1 induces cell cycle arrest at the G0/G1 phase, cellular senescence, apoptosis, and elevates cellular reactive oxygen species levels. Moreover, molecular docking and CETSA results confirm the interaction between YHC1 and YAP1 as well as TEAD1. Co-IP experiments further validated that YHC1 can effectively inhibit the binding of YAP1 and TEAD1. In conclusion, YHC1 selectively targets YAP1 and TEAD1, exhibiting its anti-hepatocellular carcinoma effects through the inhibition of their interaction.


Asunto(s)
Carcinoma Hepatocelular , Daphne , Diterpenos , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular , Daphne/química , Diterpenos/farmacología , Diterpenos/química , Neoplasias Hepáticas/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Oxadiazoles/química , Oxadiazoles/farmacología
5.
Phytochemistry ; 220: 113992, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38301947

RESUMEN

Seven undescribed neovibsane-type diterpenoids (1-7) were isolated from the leaves of Viburnum odoratissimum. Their planar structures and relative configurations were elucidated based on a combination of 1D and 2D NMR analysis. The absolute configurations were confirmed by Rh2(OCOCF3)4-induced ECD analysis and comparison of experimental and TDDFT-calculated ECD spectrum. Based on the empirical results of the ECD of in situ formed Rh-complexes, rapid determination of the absolute configuration of C-14 within vibsane-type diterpenoids was proposed. In addition, 3 exhibited a high neuroblastoma cell protective effect of 81.8 % at 50 µM (the control group showed a neuroblastoma cell protective effect of 56.2 % at 50 µM).


Asunto(s)
Diterpenos , Neuroblastoma , Viburnum , Viburnum/química , Estructura Molecular , Diterpenos/química , Hojas de la Planta/química
6.
J Asian Nat Prod Res ; : 1-13, 2024 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-38347741

RESUMEN

Gastric cancer is one of the common malignant tumors. It is reported that daphne-type diterpenes have inhibitory effects on gastric cancer cells, but the mechanism is still unknown. To explore the detailed mechanism of the anticancer effect of daphne-type diterpenes, we carried out an integrated network pharmacology prediction study and selected an effective component (yuanhuacine, YHC) for the following validation in silico and in vitro. The result showed that daphne-type diterpenes exerted an anti-tumor effect by targeting proto-oncogene tyrosine-protein kinase SRC as well as regulating the Ras/MAPK signaling pathway, which caused the apoptosis and mitochondrial damage in gastric cancer cells.

7.
Phytochemistry ; 218: 113950, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38101591

RESUMEN

Eight structurally diverse rearranged sesquiterpenoids, including seven undescribed sesquiterpenoids (1a/1b and 3-8) were obtained from the aerial parts of Daphne penicillata. 1a/1b, 3, 5 and 6 possess rare rearranged guaiane skeletons and 4 represents the first example of rearranged carotene sesquiterpenoids. Their structures and absolute configurations were determined by extensive spectroscopic analyses, NMR and ECD calculations. Interestingly, 1a and 1b were a pair of magical interconverting epimers that may interconvert by retro-aldol condensation. The mechanism of interconversion has been demonstrated indirectly by 9-OH derivatization of 1a/1b and a hypothetical biogenetic pathway was proposed. All compounds were evaluated for anti-inflammatory and cytotoxic activities. Among them, 1a/1b and 2 exhibited potential inhibitory activities on the production of NO against LPS-induced BV2 microglial cells.


Asunto(s)
Daphne , Sesquiterpenos , Daphne/química , Estructura Molecular , Isomerismo , Sesquiterpenos/farmacología , Sesquiterpenos/química , Componentes Aéreos de las Plantas
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