RESUMO
Salpratone A (1), a novel abietane diterpenoid containing a unique cis-fused A/B ring, was isolated from Salvia prattii. Bioactivity studies showed that 1 has potent activity in inhibiting platelet aggregation induced by multiple agonists as well as antithrombotic efficacy in the FeCl3-induced rat in vivo thrombosis model. Furthermore, a bioinspired synthesis of 1 from the abundant natural product ferruginol was achieved in 6 steps with a 22% overall yield. The key steps include a stereoselective allyl oxidation and a subsequent regioselective Meinwald rearrangement.
Assuntos
Abietanos , Salvia , Animais , Ratos , Salvia/química , Abietanos/síntese químicaRESUMO
Thirty-five diverse polyphenols, belonging to seven structure classes, were isolated from Garcinia gracilis, a medicinal and edible plant sampled from Laos. The structures of nine new compounds, gargarcilones A-I (1-3, 5-7, 10, 12, and 17), were established using spectroscopic, X-ray diffraction, and experimental and calculated ECD methods. Additionally, we revised the stereochemical assignment of cochinchinoxanthone and cochinchinoxanthone C. The compounds were evaluated for antiproliferative activity against five human tumor cell lines (HL-60, A549, SMMC-7721, MDA-MB-231, and SW480). Compounds 1-4, 7, and 8 exhibited cytotoxic activity with IC50 values of 0.5-8.9 µM. Compound 3 significantly induced apoptosis in SMMC-7721 cells.
Assuntos
Antineoplásicos , Garcinia , Humanos , Apoptose , Linhagem Celular Tumoral , Polifenóis/farmacologiaRESUMO
Eleven new abietane-type diterpene lactones, salpratlactones D-N (1-11), including five 11,12-seco-11-nor-abietane diterpenes (1-5), four 11,12-seco-abietane diterpenes (6-9), two 20(10 â 5)-abeo-4,5;11,12-bis-seco-abietane diterpenes (10-11), and two known analogues (12-13), were characterized from Salvia prattii. Notably, compounds 1-3 were characterized by a unique linear 6/6/6 tricyclic skeleton. The structures were established by spectroscopic data interpretation, calculated NMR-DP4+ and electronic circular dichroism analysis, as well as single-crystal X-ray diffraction. A bioactivity study showed that 1, 2, 5, 11, and 12 can potently inhibit platelet aggregation induced by arachidonic acid (AA), with IC50 values of 5.66-16.10 µg/ml, stronger than aspirin. In addition, the lactate dehydrogenase assay showed that they had no effect on platelet integrity. Structurally, the same 1,2-benzopyrone fragments of 1, 2, and 5 should be the important pharmacophore for antiplatelet activity.
Assuntos
Abietanos , Inibidores da Agregação Plaquetária , Salvia , Abietanos/farmacologia , Aspirina , Lactonas/farmacologia , Ensaios Enzimáticos , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologiaRESUMO
Ten new icetexane diterpenoids, salpratins E-N (1-10) and a known analogue (11) were characterized from Salvia prattii Hemsl. Structurally, 1 is the first 19(4 â 3)-abeo-icetexane diterpenoid featuring with a 6/7/6 ring system. The structures of isolated compounds were determined by comprehensive analyses of spectroscopic data, ECD calculation, and single-crystal X-ray diffraction. Biological studies initially revealed that 1, 7, 10, and 11 are notable Cav3.2 T-type Ca2+ channel (TTCC) inhibitors with IC50 values of 2.9, 5.1, 2.3, and 3.2 µM, respectively. Five icetexane related derivatives (13-17) were synthesized from an abietane type precursor, (+)-carnosic acid (12), for the purpose of overcoming the poor water solubility of aforementioned active compounds and further investigating diverse diterpenes with valuable activity. Among them, 13 and 14 showed potent inhibitions on Cav3.2, having IC50 values of 6.7 and 2.4 µM, respectively. Significantly, they exhibited dose-dependent (1, 3, and 10 mg/kg) and comparable analgesic effects as that of Z944, a TTCCs inhibitor under clinical trial for pain management, in the mouse acetic acid writhing test. These findings further enrich structural diversity and bioactivity of Salvia diterpenoids, as well as provide promising structural templates for the development of Cav3.2 analgesics.
Assuntos
Canais de Cálcio Tipo T , Diterpenos , Salvia , Analgésicos/química , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Cristalografia por Raios X , Diterpenos/química , Diterpenos/farmacologia , Camundongos , Estrutura Molecular , Salvia/químicaRESUMO
The isolation and structure elucidation of six new prenylated acylphloroglucinols, faberiones A-F, from the whole plant of Hypericum faberi is reported. Faberiones A-D (1-4) share a rare styrene substituent and may be biosynthetically generated via further acylation of the acylphloroglucinols. By analyzing the MS and NMR data, the structures of the new isolates were established. Faberiones B (2) and C (3) showed moderate cytotoxicity against the pancreatic cell line (PANC-1) with IC50 values of 6.2 and 9.0 µM, respectively.
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Hypericum/química , Floroglucinol/química , Floroglucinol/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Neoplasias Pancreáticas/tratamento farmacológico , PrenilaçãoRESUMO
Hypseudohenones A-C (1-3), the first rearranged homoadamantane-type polycyclic polyprenylated acylphloroglucinols, were isolated from Hypericum pseudohenryi. Their structures with an unprecedented tricyclo[4.3.1.13,8]undecane-2,4,10-trione core were determined by spectroscopic analysis, quantum-chemical calculations, and X-ray crystallography. A method for determining the relative configuration at C-3 was established by the peak shape of H-28 or J-value of H-3/H-28. Moreover, 2-3 exhibited significant AChE inhibitory activity, and the interactions of 2-3 with AChE were evaluated by molecular docking.
Assuntos
Hypericum , Estrutura Molecular , Hypericum/química , Simulação de Acoplamento Molecular , Floroglucinol/química , Cristalografia por Raios XRESUMO
Five caged polycyclic polyprenylated acylphloroglucinols including an unprecedented octahydro-2,5-methanoindene skeleton (1) were discovered from Hypericum curvisepalum. Biologically, 1 and 2 are potent Cav3.2 T-type Ca2+ channel inhibitors with negligible effect on the cardiovascular antitarget, the human ether-à-go-go-related gene potassium channel. Additionally, 2 indicates strong antinociception in the mouse acetic acid writhing test.
Assuntos
Hypericum , Humanos , Camundongos , Animais , Floroglucinol/farmacologia , Estrutura MolecularRESUMO
Diabetes is an urgent health issue characterized by ethnic and regional variations, and is inseparable from the different dietary habits. It is worthy to note that the incidence of diabetes in Bai nationality has been reported to be much lower than Han in China. As a daily vegetable of Bai, the phytochemical and antidiabetic study of Ottelia acuminata var. acuminata had not been carried out. In this study, 41 metabolites with diverse diarylheptanoid (six new ones, Otteacumienes A-F), flavone, sesquiterpenoid, coumarin, lignan, polyacetylene, and alkaloid skeletons were characterized from O. acuminata var. acuminata. Among them, the racemic nature of 3 was characterized by chiral resolution and calculated ECD methods. The biological study revealed diarylheptanoids showed significant α-glucosidase inhibitory activities with 5 as the most effective one (60-fold stronger than acarbose). Molecular docking studies indicated that these structures have different binding cavities with acarbose. This study demonstrated that O. acuminata var. acuminata might correlated with the low incidence diabetes of Bai and the diarylheptanoids may have potential therapeutic value for diabetes mellitus.
RESUMO
Dearomatized isoprenylated acylphloroglucinols (DIAPs) are specific natural products mainly distributed in the plants of genus Hypericum. In this study, guided by HPLC-UV screening, 46 DIAPs (approximately 70% of all DIAPs) including 20 new ones and an unprecedented architecture, were discovered from the roots of Hypericum henryi, which were elucidated by comprehensive spectroscopic, X-ray crystallography, and ECD methods. Compounds 1-7, 39, and 41-42 exhibited remarkable cytotoxicities (IC50 = 0.84-5.63 µM) in human colon cancer HCT116 cells, in which 2 and 6 possessed selective cytotoxicities towards colon cancer cells. The preliminary structure-activity relationships of these tested compounds were discussed. In addition, mechanistic investigations demonstrated that 2 and 6 could significantly suppress the expressions of NFκB, FAT1, and promoted novel tumor suppressor gene PDCD4 in HCT116 cells. Furthermore, in HCT116 colon xenograft-bearing mouse model, treatments with 2 and 6 reduced the growth of xenograft tumors in dose-dependent manner. Expressions of FAT1 in tumors were also decreased in mice treated with 2 and 6, suggesting their anti-tumor effects were via FAT1 signaling pathway. In conclusion, this is the first report on the mechanistic and in vivo studies of DIAP, indicating that these metabolites can be considered as a new type of anti-colon cancer lead agents for further drug development.
Assuntos
Antineoplásicos , Neoplasias do Colo , Hypericum , Animais , Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Humanos , Hypericum/química , Hypericum/metabolismo , Camundongos , Floroglucinol/química , Floroglucinol/farmacologia , Proteínas de Ligação a RNA/metabolismo , Transdução de SinaisRESUMO
The abnormal proliferation and hypertrophy of adipocytes mediate the expansion of adipose tissue and then cause obesity-related diseases. Theoretically, an approach for preventing and curing obesity is to inhibit cell proliferation during the mitotic clonal expansion (MCE) progression of adipocyte differentiation. Polycyclic polyprenylated acylphloroglucinols (PPAPs) are mainly found from Hypericum and Garcinia genus, which have been reported to have various biological activities such as anti-depressant, anti-oxidant, and anti-tumor. Previously, our group has reported that adamantane-type PPAPs exhibited blunting activity in adipogenesis. In this study, another six adamantane PPAPs were screened to investigate their anti-adipogenesis activities and then discussed the structure-activity relationship. Particularly, sampsonione F, one of the PPAPs dramatically suppressed adipogenesis dose-dependently in vitro, along with decreased expressions of C/EBPß, C/EBPα, PPARγ, FABP4, and FAS. Moreover, sampsonione F upregulated the expression of p27 by activating p53 pathway and then downregulated the expressions of key regulators during G1/S phase arrest. Our data support that sampsonione F suppressed adipogenesis by activating p53 pathway, regulating cyclins, and resulting in G1/S phase arrest during the MCE progression of adipogenesis. This work provides a new adamantane-type PPAPs in the regulation of adipogenesis and extends our knowledges on the mechanism of the type PPAPs in regulation of adipogenesis.
Assuntos
Adamantano , Adipócitos , Adipogenia , Diferenciação Celular , Proteína Supressora de Tumor p53 , Células 3T3-L1 , Adamantano/análogos & derivados , Adamantano/farmacologia , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Animais , Camundongos , Mitose , Obesidade , Compostos Fitoquímicos/farmacologia , Proteína Supressora de Tumor p53/metabolismoRESUMO
Hypulatones A and B (1 and 2), two racemic meroterpenoids possessing an unprecedented spiro[benzofuran-2,1'-cycloundecan]-4'-ene-4,6(5H)-dione core, were characterized from Hypericum patulum. Compound 2 was found to significantly inhibit the late current of Nav1.5 (late INa, IC50 = 0.2 µM). Importantly, 2 exhibited remarkable separation (>100-fold) of late INa relative to peak INa and notable selectivity over Cav3.1, Kv1.5, and hERG. 1 showed comparable inhibition on late INa compared to that of 2 with poorer selectivity.
Assuntos
Hypericum/química , Miócitos Cardíacos/fisiologia , Sódio/química , Humanos , Estrutura Molecular , Miócitos Cardíacos/químicaRESUMO
A hybrid of dearomatized isoprenylated acylphloroglucinol (DIAP) and monoterpenoid, hypatone A (1), together with its biosynthetic analogues 2-4 is characterized from Hypericum patulum. Structurally, 1 possesses an unprecedented spiro[bicyclo[3.2.1]octane-6,1'-cyclohexan]-2',4',6'-trione core as elucidated by extensive spectroscopic and X-ray crystallographic analyses. Biological studies reveal that compounds 1 and 2-4 produce opposite effects on Cav3.1 low voltage-gated Ca2+ channel, with 1 and 4, respectively, being the most potent Cav3.1 agonist and antagonist from natural products. Further studies suggest that compound 1 and its biogenetical precursor, 2, have the same binding site on Cav3.1 and that the rigid cagelike moiety at C-5 and C-6 is a key structural feature responsible for 1 being an agonist. Furthermore, 1 can normalize the pathological gating of a mutant Cav3.1 channel found in spinocerebellar ataxia 42 (SCA42), a hereditary neurodegenerative disorder with no available therapy. Collectively, our findings provide valuable tools for future studies on Cav3.1 physiology and pathophysiology, as well as afford possible leads for developing new drugs against SCA42, epilepsy, and pain.
Assuntos
Agonistas dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Monoterpenos/farmacologia , Floroglucinol/análogos & derivados , Floroglucinol/farmacologia , Animais , Agonistas dos Canais de Cálcio/isolamento & purificação , Canais de Cálcio Tipo T/genética , Células HEK293 , Humanos , Hypericum/química , Ativação do Canal Iônico/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Monoterpenos/isolamento & purificação , Mutação , Floroglucinol/isolamento & purificaçãoRESUMO
Adamantane polycyclic polyprenylated acylphloroglucinols (PPAPs) with caged architecture, a special class of hybrid natural products, is specifically rich in the plant family Guttiferae, especially Hypericum or Garcinia genus. Hypersampsone P is one of Adamantane PPAPs compounds extracted from Hypericum subsessile. Here we have chosen, screened ten PPAPs and identified one of them showed an activity in inhibiting of adipocytes differentiation. Particularly, the compound, hypersampsone P, blunted the adipocyte differentiation dose-dependently. Moreover, hypersampsone P down-regulated the expressions of several key regulators for adipogenesis, including PPARγ and FABP4. The treatment of cells at the early stage of adipogenesis by hypersampsone P induced the greatest blunting of adipocyte differentiation and the effect might be involved in the LKB1-AMPK signaling pathway.
RESUMO
A series of dearomatized isoprenylated acylphloroglucinols derivatives, hyperhenols A-E (1-5), as well as seven known analogues (6-12), were characterized from Hypericum henryi. Their structures were determined by combination of NMR, ECD spectroscopy, and X-ray diffraction analysis. Compounds 1 and 6-8 were tested to exhibit potential antitumor properties, of which 6 and 7 inhibited cell growth through inducing apoptosis and cell cycle arrest. In addition, these compounds could induce autophagy and PINK1/Parkin-mediated mitophagy in cancer cell lines, as well as suppress lung cancer A549 cells metastasis in vitro.
RESUMO
In the original publication the corresponding author appeared incorrectly as Xin-Wen Zhang. The corrected text is given below: The corresponding author of the article is Gang Xu.
RESUMO
Six new polyphenols with different isoprenylated xanthones, isoprenylated acylphloroglucinols, and chromone architectures, hyperfaberols A-F (1-6), were isolated from the whole plants of Hypericum faberi along with seven other related known compounds. In which hyperfaberols A/B (1/2) and 12-13 were isoprenylated xanthones, hyperfaberols C-E (3-5) and 8-11 were seven isoprenylated acylphloroglucinol derivatives, while 6-7 were two chromones. Their structures were elucidated by comprehensive analysis of their spectroscopic data as well as detailed comparison with the literature data. Compounds 1 and 11 showed cytotoxities against the human esophageal cancer cell line (ECA-109) and the pancreatic tumor cell line (PANC-1) in vitro, respectively.
RESUMO
Garsubelone A (1), the first dimeric polycyclic polyprenylated acylphloroglucinols type metabolite featuring a complicated 6/6/6/6/6/6/6 heptacyclic architecture containing 10 stereogenic centers, was isolated from Garcinia subelliptica. Biogenetically, this compound was constructed by the plausible monomeric precursor, garsubelone B (2) and secohyperforin, via a key Diels-Alder cycloaddition to form an unique 2-oxabicyclo[3.3.1]nonane core. Their structures and absolute configurations were determined by comprehensive spectroscopic and X-ray diffraction techniques. The cytotoxic activities of these isolates were also evaluated.