RESUMO
The tumor suppressor protein p53 is central to cancer biology, with its pathway reactivation emerging as a promising therapeutic strategy in oncology. This study introduced LZ22, a novel compound that selectively inhibits the growth, migration, and metastasis of tumor cells expressing wild-type p53, demonstrating ineffectiveness in cells devoid of p53 or those expressing mutant p53. LZ22's mechanism of action involves a high-affinity interaction with the histidine-96 pocket of the MDM2 protein. This interaction disrupted the MDM2-p53 binding, consequently stabilizing p53 by shielding it from proteasomal degradation. LZ22 impeded cell cycle progression and diminished cell proliferation by reinstating the p53-dependent suppression of the CDK2/Rb signaling pathway. Moreover, LZ22 alleviated the p53-dependent repression of Snail transcription factor expression and its consequent EMT, effectively reducing tumor cell migration and distal metastasis. Importantly, LZ22 administration in tumor-bearing mice did not manifest notable side effects. The findings position LZ22 as a structurally unique reactivator of p53, offering therapeutic promise for the management of human cancers with wild-type TP53.
Assuntos
Fatores de Transcrição , Proteína Supressora de Tumor p53 , Camundongos , Humanos , Animais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transdução de Sinais , Quinase 2 Dependente de Ciclina/metabolismoRESUMO
Two previously undescribed chain diarylheptanoid derivatives (2-3), five previously undescribed dimeric diarylheptanoids (4-8), together with one known cyclic diarylheptanoid (1) were isolated from Zingiber officinale. Their structures were elucidated by extensive spectroscopic analyses (HR-ESI-MS, IR, UV, 1D and 2D NMR) and ECD calculations. Biological evaluation of compounds 1-8 revealed that compounds 2, 3 and 4 could inhibit nitrite oxide and IL-6 production in lipopolysaccharide induced RAW264.7 cells in a dose-dependent manner.
Assuntos
Zingiber officinale , Diarileptanoides/farmacologia , Diarileptanoides/química , Espectroscopia de Ressonância Magnética , Anti-Inflamatórios/farmacologia , Estrutura MolecularRESUMO
As a widely consumed spice and traditional Chinese medicine, Zingiber officinale Roscoe (ginger) has been used in the treatment of nausea, coughs, and colds. In this article, 18 new glycosides (1-18) and six known analogues (19-24) were isolated from the peel of ginger. The planar structures of these compounds were determined by using HR-ESI-MS and extensive spectroscopic techniques (UV, IR, 1D-NMR, and 2D-NMR). Their relative and absolute configurations of the stereogenic centers in the new natural products were determined by analysis of NMR data, using a quantum mechanical NMR approach and time-dependent density functional theory based electronic circular dichroism calculations. The renal fibrosis activities of the isolated natural products together with those of 6-gingerol (6-Gi), 8-gingerol (8-Gi), and 10-gingerol (10-Gi) were evaluated in TGF-ß1 induced NRK-52E cells. Compounds 9, 10, 15, 22-24, 6-Gi, 8-Gi, and 10-Gi were found to be active toward extracellular matrix, indicating that they have potential renal fibrosis activities.
Assuntos
Zingiber officinale , Humanos , Zingiber officinale/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Glicosídeos , Álcoois Graxos/análise , Catecóis/química , FibroseRESUMO
As a widely consumed spice and Traditional Chinese Medicine, Alpinae oxyphylla has been used to treat conditions such as diarrhea, ulcers, dementia, and enuresis. Fruits of A. oxyphylla were phytochemically studied and the bioactive constituents against renal fibrosis were identified. Eight previously undescribed acetylated flavonol glucuronides named oxyphyllvonides A-H (1-7 and 10), two known acetylated flavonol glucuronides (8 and 9), together with seven known flavone glycosides (11-17) were isolated from the fruits of A. oxyphylla. Among them, flavonol glucuronides were discovered in Zingiberaceae for the first time. The planar structures of 1-7 and 10 were determined using HRESIMS and extensive spectroscopic techniques (UV, IR, 1D-NMR, and 2D-NMR). The absolute configurations of the sugar moiety in these compounds were determined by using LC-MS analysis of acid-hydrolyzed derivatized monosaccharides. Biological evaluation showed that 7-10, 13, 14, 16 and 17 inhibit renal fibrosis in TGF-ß1-induced kidney proximal tubular cells. In addition, 7, 8 and 14 were superior to nootkatone in inhibiting Fibronectin expression. The finding has significant relevance to our ongoing research on the anti-renal fibrosis activity of A. oxyphylla.
Assuntos
Alpinia , Frutas , Alpinia/química , Glucuronídeos , FlavonóisRESUMO
The Ganoderma lucidum mushroom, which has been used as a traditional medicine in China for more than 2000 years, is a source of many interesting natural product. In this study, the five undescribed minor meroterpenoids baoslingzhines F-J (1-5), containing a dihydropyran moiety, were isolated as racemic mixtures from the fruiting bodies of G. lucidum. These substances were structurally and stereochemically characterized by using spectroscopic and computational methods. Chiral HPLC was employed to separate the (+)- and (-)-antipodes. A survey of the activities against kidney fibrosis showed that both enantiomers of baoslingzhines F-J inhibit expression of renal fibrosis-related proteins, including fibronectin, collagen I and É-SMA in TGF-ß1-induced rat kidney proximal tubular cells.
Assuntos
Ganoderma , Reishi , Ratos , Animais , Terpenos/química , Ganoderma/química , Estrutura Molecular , Fibrose , Carpóforos/químicaRESUMO
Eight previously unknown 2-(2-phenylethyl)chromone derivatives, called aquichromones A - E (1-3, 5 and 6) and 8-epi-aquichromone C (4), including two pairs of enantiomers [(±)-1 and (±)-2] were isolated from the agarwood of Aquilaria sinensis. The structures and absolute stereochemistry of these natural products were elucidated by using spectroscopic and computational methods. The result of biological assay showed that two members of this group, 4 and 5, have significant dose-dependent anti-inflammatory activity.
Assuntos
Cromonas , Thymelaeaceae , Cromonas/farmacologia , Estrutura Molecular , Flavonoides/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Thymelaeaceae/química , Madeira/químicaRESUMO
Six new diterpenoids, identified as two abietane derivatives, euphraticanoids J and K (1 and 2), two pimarane derivatives, euphraticanoids L and M (3 and 4), and two 9,10-seco-abietane derivatives, euphraticanoids N and O (5 and 6) were isolated from Populus euphratica resins. Their structures including absolute configurations were characterized using spectroscopic, quantum chemical NMR, and ECD calculation methods. The anti-inflammatory activity of the compounds was tested and the results revealed that compounds 4 and 6 inhibited the production of iNOS and COX-2 in a dose-dependent manner in lipopolysaccharide (LPS)-induced RAW 264.7 cells.
Assuntos
Diterpenos , Populus , Abietanos/farmacologia , Estrutura Molecular , Diterpenos/farmacologia , Diterpenos/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Resinas VegetaisRESUMO
Ganoderpetchoids A-E and (-)-dayaolingzhiol H, six undescribed meroterpenoids, were isolated from Ganoderma petchii. Their structures including the relative configurations were identified by means of spectroscopic methods and 13C NMR calculations. Chiral separation of the new racemics was performed to afford their respective enantiomers. The absolute configurations of the new isolates were clarified by computational approaches, CD comparisons and X-ray diffraction analysis. Biological studies toward triple negative breast cancer indicated that (+)-6 and (-)-6 significantly inhibit the migration of MDA-MB-231 cell line.
Assuntos
Ganoderma , Neoplasias de Mama Triplo Negativas , Humanos , Terpenos/farmacologia , Terpenos/química , Estrutura Molecular , Ganoderma/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Linhagem CelularRESUMO
Daedracoflavan A-E (1-5), five new flavonoids were isolated from the resin of Daemonorops draco. Their structures including absolute configurations were established by using spectroscopic and computational methods. All the compounds are new chalcones with the same retro-dihydrochalcone skeleton. Compound 1 features the presence of a cyclohexadienone unit originating from a benzene ring, and the ketone group of C-9 reduced to a hydroxyl group. The bioactivity of all isolated compounds was evaluated in kidney fibrosis and found that compound 2 could dose-dependently inhibit the expression of fibronectin, collagen I, and α-SMA in TGF-ß1-induced rat kidney proximal tubular cells (NRK-52E). Interestingly, the replacement of a proton by a hydroxyl group at C-4' seems to play a crucial role in anti-renal fibrosis activity.
Assuntos
Chalconas , Ratos , Animais , Estrutura Molecular , Chalconas/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , FibroseRESUMO
Phytochemical investigation of the 95% ethanol extract from Pinus yunnanensis Franch resin induced the isolation of six previously unreported diterpenoids pinuyunnanacids K - N, P - Q, a nor-diterpenoid with a novel skeleton pinuyunnanacid O and six known analogues. Their structures were elucidated by spectroscopic analysis and computational methods, including nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, calculated NMR chemical shifts method and electronic circular dichroic (ECD) spectra. All the compounds were analyzed for anti-inflammatory activity through western blotting and cell viability, compounds 2, 10 and 12 significantly downregulated the protein expression of iNOS at the concentration of 40 µM. At the same time, compounds 10 and 12 decreased the expression of COX-2 in LPS-treated RAW264.7 (leukemia cells in mouse macrophage) cells at the concentration of 40 µM.
Assuntos
Diterpenos , Pinus , Camundongos , Animais , Estrutura Molecular , Diterpenos/farmacologia , Diterpenos/química , Espectroscopia de Ressonância Magnética , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Resinas VegetaisRESUMO
Five new norneolignans sinkianlignans G-K (1-5), one phenolic compound ferulagenol A (6) and seven known compounds (7-13) were isolated from Ferula sinkiangensis. All the norneolignans were racemic mixtures, and chiral HPLC was used to further separate them. Their structures were assigned, including absolute configurations, using spectroscopic and computational methods. Biological evaluation showed that compounds 1-9 had significant COX-2 inhibitory activity with IC50 values ranging from 3.00 µM to 23.19 µM.
Assuntos
Inibidores de Ciclo-Oxigenase 2 , Ferula , Estrutura Molecular , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ferula/química , Ciclo-Oxigenase 2RESUMO
Four novel epimeric meroterpenoids, ganadone A (1), 3',10'-di-epi-ganadone A (2), 10'-epi-ganadone A (3), and 3'-epi-ganadone A (4) as well as another pairs of epimers, ganadone B (5) and 10'-epi-ganadone B (6), with a same basic skeleton compound ganadone C (7), together with two lactonized meroterpenoids, ganadones D and E (8 and 9) were isolated from the fruiting bodies of Ganoderma cochlear. Compounds 1-7 were constructed with fascinating adjacent 6',7'-bifuran ring system. Fortunately, we have revised our previously reported structure cochlearol Q, which was proposed pyrano[6',7'-b]pyran ring system into 6',7'-bifuran motif. All the isolates were characterized by analysis of HRESIMS, NMR spectroscopy and 1 was supported by X-ray crystallography analysis. The absolute stereochemistry of 1-9 were assigned by quantum chemical calculations. Biological evaluation of 1-9 showed that 5, 6, and 9 have significant anti-inflammatory potentials.
Assuntos
Ganoderma , Terpenos , Terpenos/química , Estrutura Molecular , Ciclo-Oxigenase 2 , Carpóforos/química , Ganoderma/químicaRESUMO
Pinuskesiols A-F (1-6), six new structurally diverse abietane diterpenoids were isolated from Pinus yunnanensis resins. Their structures including absolute configurations were characterized by using spectroscopic and computational methods. All the compounds bear a carbonyl functionality at C-4 with 1 and 2 behaving as a lactone thereof. The isopropyl group is attached to C-13 via O-atom in 3. In addition, the presence of a Δ5(6) double bond and a ketone at C-7 makes 2 a large conjugated system. Biological evaluation revealed that 1, 2, and 4 could concentration-dependently inhibit iNOS and COX-2 expression in lipopolysaccharide-induced RAW 264.7 cells with 2 to be the most active toward COX-2 inhibition.
Assuntos
Diterpenos , Pinus , Animais , Camundongos , Abietanos/farmacologia , Abietanos/química , Ciclo-Oxigenase 2 , Diterpenos/farmacologia , Diterpenos/química , Estrutura Molecular , Pinus/química , Células RAW 264.7 , Óxido Nítrico Sintase Tipo II/antagonistas & inibidoresRESUMO
Baoslingzhines A-E (1-5), five new meroterpenoids were isolated from the fruiting bodies of Ganoderma lucidum. The structures including their absolute configurations were characterized by using spectroscopic and computational methods. Compound 1 is a novel trinormeroterpenoid featuring the presence of an unusual dihydronaphthalene representing an unprecedented meroterpenoid skeleton. Compounds 2-4 are mononormeroterpenoids characteristic of a large conjugated system. Among them, racemic 3 and 4 were separated by HPLC on chiral phase. Biological evaluation toward kidney fibrosis found that compounds 2 and (+)-3 could inhibit the expression of fibronectin and collagen I dose dependently in TGF-ß1-induced rat kidney proximal tubular cells (NRK-52e). Additionally, (+)-3 could also down regulate É-SMA in a concentration dependent manner. Further investigation showed that 2 could inhibit Smad2 phosphorylation.
Assuntos
Ganoderma , Reishi , Animais , Fibrose , Ganoderma/química , Estrutura Molecular , Ratos , Terpenos/química , Terpenos/farmacologia , Fator de Crescimento Transformador beta1/farmacologiaRESUMO
Ganoderma mushrooms are a renowned Chinese medicine and functional food used worldwide. Seven undescribed spiro Ganoderma meroterpenoids spiroganodermaines A-G were isolated from Ganoderma species. Their structures were characterized by using spectroscopic, computational and X-ray diffraction methods. Biological studies showed that (+)-spiroganodermaine G significantly activates glucose uptake and IRS1 phosphorylation in insulin resistance C2C12 cells. Furthermore, (-)-spiroganodermaine G inhibits the expressions of fibronectin and α-SMA in TGF-ß1 induced NRK-52E cells. These findings demonstrate the potential of Ganoderma meroterpenoids as medicines and dietary supplements.
Assuntos
Ganoderma , Resistência à Insulina , Fibrose , Ganoderma/químicaRESUMO
Sinkianlignans A - D (1-4), four new sesquilignans with an unusual architectures was characterized with a rarely α-γ', ß-γ', and γ-γ' linkage pattern, and sinkianlignans E - F (5 and 6), two lignans, were isolated from the Ferula sinkiangensis. Hypothetic biosynthetic pathway of compound 3 contain a newly formed six-membered C-ring by Diels-Alder cycloaddition. The structures of isolates were established by spectroscopic techniques and computational methods. Biological evaluation of all the isolated compounds revealed that compounds 2a and 2b could inhibit IL-6 and TNF-α production in lipopolysaccharide (LPS) induced RAW264.7 cells in a dose-dependent manner.
Assuntos
Ferula , Sesquiterpenos , Anti-Inflamatórios/farmacologia , Ferula/química , Estrutura Molecular , Resinas Vegetais , Sesquiterpenos/químicaRESUMO
Ferulasinkins A-D (1-4), four new norlignans, were isolated from the resins of Ferula sinkiangensis, a medicinal plant of the Apiaceae family. All of them were obtained as racemic mixtures, chiral HPLC was used to produce their (+)- and (-)-antipodes. The structures of these new compounds, including their absolute configurations, were elucidated by spectroscopic and computational methods. This isolation provides new insight into the chemical profiling of F. sinkiangensis resins beyond the well-investigated structure types such as sesquiterpene coumarins and disulfides. Compounds 2a and 3a were found to significantly inhibit the invasion and migration of triple-negative breast cancer (TNBC) cell lines via CCK-8 assay. On the other hand, the wound-healing assay also demonstrated that compounds 4a and 4b could promote the proliferation of human umbilical vein endothelial cells (HUVECs). Notably, the promoting effects of 4a and 4b were observed as more significant versus a positive control using basic fibroblast growth factor (bFGF).
Assuntos
Ferula , Sesquiterpenos , Cumarínicos/química , Cumarínicos/farmacologia , Células Endoteliais , Ferula/química , Humanos , Estrutura Molecular , Resinas Vegetais , Sesquiterpenos/química , Sesquiterpenos/farmacologiaRESUMO
Meyeniines A-C (1-3), three new lignans, two known neolignans (4-5), and three known lignans (6-8) were isolated from the rhizomes of Lepidium meyenii. Their structures were identified by comprehensive spectroscopic analyses and computational methods. Compound 1 represents a unique lignan featuring an aromatic ring migration. Compoundsâ 2 and 4-6 were analyzed by chiral HPLC column as enantiomers. Biological evaluation revealed that compoundâ 8 could inhibit IL-6 production in lipopolysaccharide (LPS) induced RAW264.7 cells in a dose-dependent manner.
Assuntos
Anti-Inflamatórios/química , Lepidium/metabolismo , Lignanas/química , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Interleucina-6/metabolismo , Lignanas/isolamento & purificação , Lignanas/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Conformação Molecular , Extratos Vegetais/química , Células RAW 264.7RESUMO
Belamcandaoids A-N (1-14), fourteen new triterpenoids were isolated from the seeds of Belamcanda chinensis. Their structures including absolute configurations were assigned by using spectroscopic, computational, and crystallographic methods. All the compounds except 1 and 2 are 3,4-seco-triterpenoids belonging to fernane type. Biological evaluation results indicated that 3 and 13 could reduce fibronectin and collagen I expression respectively in TGF-ß1 induced kidney proximal tubular cells.
Assuntos
Células Epiteliais/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Iridaceae/química , Extratos Vegetais/farmacologia , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Triterpenos/farmacologia , Animais , Linhagem Celular , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Células Epiteliais/metabolismo , Matriz Extracelular/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Ratos , Sementes/química , Relação Estrutura-Atividade , Fator de Crescimento Transformador beta1/metabolismo , Triterpenos/química , Triterpenos/isolamento & purificaçãoRESUMO
Five new compounds (xuejieins A-E), including three new phenolic glycosides (1, 2, and 5) and two new flavonoids (10 and 11), together with six known compounds were isolated from the resins of Dracaena cochinchinensis (Chinese dragon's blood). The structures of the new compounds were confirmed by extensive spectroscopic methods and electronic circular dichroism (ECD) data analysis. Especially, the absolute configurations of the sugar moieties in compounds 1, 2, and 5 were clarified by GC analysis after acid hydrolysis. All isolated compounds have been tested for antifungal and wound healing promoting activities, The results showed that compound 9 shows significant antifungal activities against Botrytis cinerea, Magnaporthe grisea, Penicillium digitatum, and Sclerotinia sclerotiorum. In addition, compound 4 could significantly stimulate human keratinocytes (HaCAT) proliferation, mobility, and human umbilical vein vascular endothelial cells (HUVECs) tube formation at 40 µM.