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1.
Nat Prod Res ; : 1-10, 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34727811

RESUMO

Chemical investigation of the ethanol extract from the whole plant of Plectranthus glandulosus led to the isolation of a new nor-triterpenoid (1) along with seventeen known compounds (2-18) including seven triterpenoids, nine flavonoids and one steroid. Their structures were established on the basis of 1D- and 2D-NMR, IR, and MS experiments, and by comparison of their spectroscopic data with those of similar compounds reported in the literature. The EtOH extract and some isolated triterpenoids (1-4 and 13) were subjected to in vitro antimicrobial assays against a panel of pathogenic microorganisms, including Gram-positive and Gram-negative bacteria, and fungi using broth microdilution method. The EtOH extract displayed moderate activity (MIC = 512 µg/mL) against Staphylococcus aureus MSSA1, Shigella flexneri SDINT and Cryptococcus neoformans H99. Compounds 1, 4 and 13 showed the most potent antimicrobial effect with MICs of 32-256 µg/mL.

2.
Molecules ; 26(21)2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34770962

RESUMO

To scientifically clarify the hepatoprotective constituents of Fructus Schizandrae chinensis, eleven batches samples of total dibenzocyclooctadiene lignans (TDL) from Schisandra chinensis were prepared by using the optimum extraction technique. Characteristic high-performance liquid chromatography (HPLC) chromatograms were obtained through HPLC analysis technology, and the hepatoprotective effects of the eleven batches of TDL were evaluated by MTT assay. Based on the chemical and biological activity results, the spectrum-effect relationship between the characteristic HPLC fingerprints and the hepatoprotective effect of TDL was established using Minitab 16.0 data analysis software. On the basis of the spectrum-effect relationship, thirteen compounds (1-13) were obtained from the TDL by chemical natural product chemical separation and purification technology, and their structures were identified on the basis of the spectral data and the literature. Based on these compounds, thirteen common peaks among the thirty-three chromatographic peaks in the above HPLC fingerprints were identified. Our findings showed that some components, including, schisandrin B (2), schisandrin A (3), and schisandrol B (7) had significant roles in promoting hepatoprotective activity. Preliminary verification of the spectrum-effect relationship of TDL from S. chinensis was carried out, and the results confirmed that the activity of a composite of these three key components in optimal ratios was better than that of any individual compound, which potentially confirmed the reliability of the spectrum-effect relationship and the synergistic effects of traditional Chinese medicine.

3.
Eur J Med Chem ; 227: 113966, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34749200

RESUMO

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unprecedented in human history. As a major structural protein, nucleocapsid protein (NPro) is critical to the replication of SARS-CoV-2. In this work, 17 NPro-targeting phenanthridine derivatives were rationally designed and synthesized, based on the crystal structure of NPro. Most of these compounds can interact with SARS-CoV-2 NPro tightly and inhibit the replication of SARS-CoV-2 in vitro. Compounds 12 and 16 exhibited the most potent anti-viral activities with 50% effective concentration values of 3.69 and 2.18 µM, respectively. Furthermore, site-directed mutagenesis of NPro and Surface Plasmon Resonance (SPR) assays revealed that 12 and 16 target N-terminal domain (NTD) of NPro by binding to Tyr109. This work found two potent anti-SARS-CoV-2 bioactive compounds and also indicated that SARS-CoV-2 NPro-NTD can be a target for new anti-virus agents.

4.
Natl Sci Rev ; 8(4): nwaa105, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34691607

RESUMO

To evaluate the phylogenetic patterns of the distribution and evolution of plant secondary metabolites (PSMs), we selected 8 classes of PSMs and mapped them onto an updated phylogenetic tree including 437 families of seed plants. A significant phylogenetic signal was detected in 17 of the 18 tested seed-plant clades for at least 1 of the 8 PSM classes using the D statistic. The phylogenetic signal, nevertheless, indicated weak clustering of PSMs compared to a random distribution across all seed plants. The observed signal suggests strong diversifying selection during seed-plant evolution and/or relatively weak evolutionary constraints on the evolution of PSMs. In the survey of the current phylogenetic distributions of PSMs, we found that multiple origins of PSM biosynthesis due to external selective forces for diverse genetic pathways may have played important roles. In contrast, a single origin of PSMs seems rather uncommon. The distribution patterns for PSMs observed in this study may also be useful in the search for natural compounds for medicinal purposes.

5.
Org Biomol Chem ; 19(44): 9637-9640, 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34714900

RESUMO

Two new quassinoids (1 and 2) were isolated from the twigs of Harrisonia perforata (Blanco) Merr. Perforalactone E (2) possesses an uncommon hexacyclic 1α,12α:5α,13α-dicyclo-9ßH-picrasane skeleton. Its structure was determined based on spectroscopic data and X-ray crystallography. Compounds 1 and 2 could significantly induce lysosomal biogenesis through transcriptional activation of lysosomal genes.

6.
Eur J Med Chem ; 227: 113919, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34688010

RESUMO

Twenty-one new schisanhenol derivatives were synthesized, and their hepatoprotective effects against liver injury induced by concanavalin A (Con A) were evaluated in vitro using an MTT assay. The data indicated that most derivatives exhibited equivalent or better protective activity than the positive control (dimethyl dicarboxylate biphenyl, DDB) under the same conditions. Among them, compound 1b showed the most potent hepatoprotective activity against Con A-induced immunological injury. Mechanistic studies in vitro revealed that 1b inhibited cell apoptosis and inflammatory responses caused by Con A treatment via IL-6/JAK2/STAT3 signaling pathway. Consistently, it also exhibited significant hepatoprotective activity in mice with Con A-induced immunological liver injury. These results clearly indicated that 1b might be a highly potent hepatoprotective agent targeting IL-6/STAT3 signaling pathway.

7.
Phytochemistry ; 193: 112970, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34689099

RESUMO

Hypericum monogynum L. (Hypericaceae) has been used as a folk Chinese medicine for the treatment of inflammatory related diseases. Cyclooxygenase-2 (COX-2) is a crucial target for the development of agents to treat inflammation. To search for anti-inflammatory compounds from traditional Chinese medicines, a chemical constituent study along with COX-2 inhibitory activity analysis was performed for this plant. In this study, sixteen chemical monomers, including three undescribed oxidative degradation polycyclic polyprenylated acylphloroglucinols (PPAPs, hypemoins C-E), two undescribed PPAPs (hypemoins A and B), and 11 known compounds, were identified from the flowers of H. monogynum. Their structures were characterized by HRESIMS, NMR techniques, ECD, and single crystal X-ray diffraction. Four flavonoid derivatives showed remarkable COX-2 inhibitory activities, with IC50 values ranging from 0.220 ± 0.006 to 1.655 ± 0.098 µM. Among these compounds, the possible recognition mechanism between quercetin 3-(6″-O-caffeoyl)-ß-3-D-galactoside and COX-2 was predicted by molecular docking analysis. Moreover, the multidrug resistance reversal activities for the selected compounds were evaluated.

8.
Nat Prod Res ; : 1-6, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34583594

RESUMO

Two new monoterpenoid indole alkaloids, (2 R, 7 R, 16 R, 20 R, 21S)-12-hydroxypleiocarpine (1) and (2S, 7 R, 16S, 20 R, 21S)-N-methoxycarbonyl-11,12-methylenedioxy-Δ14,15-kopsinaline (2), along with six known alkaloids were isolated from the methanol extract of the kernels of Kopsia arborea. Their structures including the absolute configurations were elucidated by HRESIMS, NMR spectroscopy, and quantum computational methods. Their cytotoxicity against two human cancer cell lines were also evaluated.

9.
Nat Prod Res ; : 1-4, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34498970

RESUMO

Fourteen sesquiterpene lactones were isolated from the whole plant of Carpesium abrotanoides L. Their structures were determined on the basis of comprehensive spectroscopic data analysis. All compounds were screened for their cytotoxic activity, and compound 6 showed the strongest activity (IC50 2.73 - 7.21 µM) against five human cancer cell lines, including A549, HepG2, HCT116, MDA-MB-231, and CNE2. Compound 6 was further investigated. Compound 6 effectively induced G2/M cell cycle arrest and ROS accumulation in a dose-dependent manner, which further led to apoptosis in cancer cells. Interestingly, compounds 1 and 6 could also activate protective autophagy, which was reported for the first time in sesquiterpene isolated from Carpesium abrotanoides. In addition, compounds 1 and 6 could induce lysosomal biogenesis by 173.2% and 163.7%, respectively. In sum, sesquiterpene lactones from Carpesium abrotanoides could induce apoptosis and protective autophagy in cancer cells, which provide a serial of compounds with potential clinical applications.

10.
Int J Biol Sci ; 17(11): 2703-2717, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34345202

RESUMO

Rationale: Colorectal cancer (CRC) is a common malignant tumor of the digestive system. However, the efficacy of surgery and chemotherapy is limited. Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of regulated cell death (RCD) and plays a vital role in tumor suppression. Ferroptosis inducing agents have been studied extensively as a novel promising way to fight against therapy resistant cancers. The aim of this study is to investigate the mechanism of action of tagitinin C (TC), a natural product, as a novel ferroptosis inducer in tumor suppression. Methods: The response of CRC cells to tagitinin C was assessed by cell viability assay, clonogenic assay, transwell migration assay, cell cycle assay and apoptosis assay. Molecular approaches including Western blot, RNA sequencing, quantitative real-time PCR and immunofluorescence were employed as well. Results: Tagitinin C, a sesquiterpene lactone isolated from Tithonia diversifolia, inhibits the growth of colorectal cancer cells including HCT116 cells, and induced an oxidative cellular microenvironment resulting in ferroptosis of HCT116 cells. Tagitinin C-induced ferroptosis was accompanied with the attenuation of glutathione (GSH) levels and increased in lipid peroxidation. Mechanistically, tagitinin C induced endoplasmic reticulum (ER) stress and oxidative stress, thus activating nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). As a downstream gene (effector) of Nrf2, heme oxygenase-1 (HO-1) expression increased significantly with the treatment of tagitinin C. Upregulated HO-1 led to the increase in the labile iron pool, which promoted lipid peroxidation, meanwhile tagitinin C showed synergistic anti-tumor effect together with erastin. Conclusion: In summary, we provided the evidence that tagitinin C induces ferroptosis in colorectal cancer cells and has synergistic effect together with erastin. Mechanistically, tagitinin C induces ferroptosis through ER stress-mediated activation of PERK-Nrf2-HO-1 signaling pathway. Tagitinin C, identified as a novel ferroptosis inducer, may be effective chemosensitizer that can expand the efficacy and range of chemotherapeutic agents.

11.
Fitoterapia ; 153: 104989, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34252513

RESUMO

Ten new nortriterpenes, euphorbiumrins A-J (1-10), together with three known analogues (11-13) were isolated from the latex of Euphorbia resinifera. Their structures were established on the basis of extensive spectroscopic analyses (IR, UV, HRESIMS, 1D and 2D NMR). Their inhibitions on tomato yellow leaf curl virus (TYLCV) were evaluated and compound 5 exhibited significant anti-TYLCV activity with an inhibition rate of 71.7% at concentration of 40 µg/mL.


Assuntos
Begomovirus/efeitos dos fármacos , Euphorbia/química , Doenças das Plantas/prevenção & controle , Triterpenos/farmacologia , China , Látex/química , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Doenças das Plantas/virologia , Tabaco/virologia , Triterpenos/isolamento & purificação
12.
BMC Chem ; 15(1): 44, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301301

RESUMO

Zanthoxylum nitidium (Roxb.) DC (Rutaceae) is well known for inhibiting the proliferation of human gastric, liver, kidney and lung cancer cells, though research on its potential use in treating leukaemia is relatively rare. Twenty-six compounds were isolated from the chloroform and petroleum ether extracts of the roots and leaves of Z. nitidium (Zanthoxylum nitidium). They were ( +)-9'-O-transferuloyl-5, 5'-dimethoxylaricriresinol (1), 8-(3'-oxobut-1'-en-1'-yl)-5, 7-dimethoxy-coumarin (2), 5, 7, 8-trimethoxy-coumarin (3), 5-(3', 3'-dimethyl-2'-butenyloxy)-7, 8-dimethoxy-coumarin (4), 2-(5-methoxy-2-methyl-1H-indol-3-yl) methyl acetate (5), 2'-(5, 6-dihydrochleletrythrine-6-yl) ethyl acetate (6), 6-acetonyldi-hydrochelerythrine (7), 6ß-hydroxymethyldihydronitidine (8), bocconoline (9), zanthoxyline (10), O-methylzanthoxyline (11), rhoifoline B (12), N-nornitidine (13), nitidine (14), chelerythrine (15), 4-hydroxyl-7,8-dimethoxy-furoquinoline (16), dictamnine (17), γ-fagarine (18), skimmianine (19), robustine (20), R-( +)-platydesmine (21), 4-methoxyl-1-methyl-2-quinoline (22), 4-methoxy-2-quinolone (23), liriodenine (24), aurantiamide acetate (25), 10-O-demethyl-12-O-methylarnottianamide (26). Four among them, compounds 4 - 6 and 16, were first confirmed in this study by UV, IR, 1D, 2D NMR and HR-ESI-MS spectra. Compounds 1 - 2 and 11 were isolated from Z. nitidium for the first time. Of the assayed compounds, 1, 2, 9, 10, 14, 15 and 24, exhibited good inhibitory activities in the leukaemia cell line HEL, whereas compound 14 (IC50: 3.59 µM) and compound 24 (IC50: 15.95 µM) exhibited potent inhibitory activities. So, to further investigate the possible mechanisms, cell cycle and apoptosis assays were performed, which indicated that compound 14 causes obvious S-phase arrest in HEL cells and induced apoptosis, whereas compound 24 only induced apoptosis. The present results suggested both compounds 14 and 24 are promising potential anti-leukaemia drug candidates.

13.
BMC Cancer ; 21(1): 680, 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34107900

RESUMO

BACKGROUND: Cholesterol plays vital roles in human physiology; abnormal levels have deleterious pathological consequences. In cancer, elevated or reduced expression of cholesterol biosynthesis is associated with good or poor prognosis, but the underlying mechanisms are largely unknown. The limonoid compounds A1542 and A1543 stimulate ERK/MAPK by direct binding, leading to leukemic cell death and suppression of leukemia in mouse models. In this study, we investigated the downstream consequences of these ERK/MAPK agonists in leukemic cells. METHODS: We employed RNAseq analysis combined with Q-RT-PCR, western blot and bioinformatics to identify and confirm genes whose expression was altered by A1542 and A1543 in leukemic cells. ShRNA lentiviruses were used to silence gene expression. Cell culture and an animal model (BALB/c) of erythroleukemia induced by Friend virus were utilized to validate effects of cholesterol on leukemia progression. RESULTS: RNAseq analysis of A1542-treated cells revealed the induction of all 18 genes implicated in cholesterol biosynthesis. Expression of these cholesterol genes was blocked by cedrelone, an ERK inhibitor. The cholesterol inhibitor lovastatin diminished ERK/MAPK activation by A1542, thereby reducing leukemic cell death induced by this ERK1/2 agonist. Growth inhibition by cholesterol was observed both at the intracellular level, and when orally administrated into a leukemic mouse model. Both HDL and LDL also suppressed leukemogenesis, implicating these lipids as important prognostic markers for leukemia progression. Mechanistically, knockdown experiments revealed that the activation of SREBP1/2 by A1542-A1543 was responsible for induction of only a sub-set of cholesterol biosynthesis genes. Induction of other regulatory factors by A1542-A1543 including EGR1, AP1 (FOS + JUN) LDLR, IER2 and others may cooperate with SREBP1/2 to induce cholesterol genes. Indeed, pharmacological inhibition of AP1 significantly inhibited cholesterol gene expression induced by A1542. In addition to leukemia, high expression of cholesterol biosynthesis genes was found to correlate with better prognosis in renal cancer. CONCLUSIONS: This study demonstrates that ERK1/2 agonists suppress leukemia and possibly other types of cancer through transcriptional stimulation of cholesterol biosynthesis genes.


Assuntos
Colesterol/metabolismo , Leucemia/genética , Limoninas/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Animais , Feminino , Humanos , Leucemia/mortalidade , Masculino , Camundongos , Transdução de Sinais , Análise de Sobrevida , Transfecção
14.
Nat Prod Res ; : 1-6, 2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34100676

RESUMO

Two new cycloartane triterpenoids, (24 R)-cycloartane-3ß,24,25,30-tetrol (1) and (24 R)-24,25,30-trihydroxy-9,19-cycloartane-3-one (2), along with three known compounds (3-5) were isolated from leaves and twigs of Aphanamixis polystachya. The new compounds were elucidated based on comprehensive spectroscopic analysis, including 1 D, 2 D NMR and HREIMS. The in vitro cytotoxic activities evaluation of five human cancer cell lines revealed that compound 1 exhibited cytotoxic activity on all of tested human cancer cell lines, while compound 2 only had specific activity on SMMC-7721 cell line.

15.
Nat Prod Bioprospect ; 11(4): 453-457, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33977511

RESUMO

One new Daphniphyllum alkaloid, daphnioldhanol A (1), together with three known ones, were isolated from the stem part of Daphniphyllum angustifolium Hutch. Their structures were elucidated by spectroscopic methods and comparing with the literature data. Compound 2 is a new natural product, but known by synthesis as a racemate. Compound 1 exhibited week cytotoxic activity against Hela cell line with IC50 of 31.9 µM.

16.
Org Lett ; 23(8): 3125-3129, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33818113

RESUMO

Hymoins A-D (1-4), two pairs of light-induced transformative polyprenylated acylphloroglucinols with an unprecedented pentacyclic skeleton, were isolated from the flowers of Hypericum monogynum. The first decarbonylative ring contraction of complex natural products was investigated by light irradiation. Their structures were elucidated by nuclear magnetic resonance analysis, X-ray crystallography, and electronic circular dichroism calculations. In addition, compound 3 showed moderate inhibition efficacy of the platelet-activating-factor-induced aggregation of rabbit platelets.


Assuntos
Hypericum/química , Floroglucinol/química , Animais , Dicroísmo Circular , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Floroglucinol/isolamento & purificação , Coelhos
17.
J Org Chem ; 86(10): 7021-7027, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33881865

RESUMO

Hypermonins A-D (1-4), four rearranged nor-polycyclic polyprenylated acylphloroglucinols (PPAPs) with unprecedented skeletons, together with two new biosynthesis related PPAPs (5 and 6) were isolated and identified from the flowers of Hypericum monogynum. Hypermoins A-D represented the first examples of highly modified norPPAPs characterized by a rare 7/6/6/5-tetracyclic system. From the biogenic synthesis pathway analysis, all isolates shared the same biosynthetic intermediate, and the addition of two methyls or one methyl to this intermediate through methyltranferase could generate different types of PPAPs (1-7). Their planner structures as well as absolute configuration were confirmed via spectroscopic analysis, ECD calculation, and X-ray crystallography. All isolates potentially reversed multidrug resistance (MDR) activity in both two cancer cells, HepG2/ADR and MCF-7/ADR. Specifically, hypermoin E (5) and hyperielliptone HA (7) were found to be the best MDR modulators with the reversal fold ranging from 41 to 236, which is higher than the positive control verapamil.


Assuntos
Hypericum , Cristalografia por Raios X , Flores , Estrutura Molecular , Floroglucinol/farmacologia
18.
Fitoterapia ; 151: 104876, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33675885

RESUMO

Six rocaglaol derivatives were isolated from Dysoxylum gotadhora, and those compounds showed good cytotoxic activity with IC50 values ranging from 10 to 350 ng/mL against five different cancer cells. Obviously, further total synthesis of rocaglaol derivatives for medical chemistry study is of great significance. Then, twenty six rocaglaol derivatives including 25 new compounds were designed, synthesized, and evaluated for their cytotoxic activities against three human cancer cell lines: human colon cancer cells (HCT116), colorectal cancer stem cells (P6C), and human red leukocyte leukemia cells (HEL), using MTT assay. Most of derivatives showed good cytotoxic activities, with the lowest IC50 being 3.2 nM for HEL cells, which was 169 times stronger than that of the positive control (doxorubicin). Further mechanism study indicated that 11k could significantly suppress MAPK pathway in HCT116 cells, which may responsible for induction of apoptosis and cell cycle arrest.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Benzofuranos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Meliaceae/química , Antineoplásicos Fitogênicos/isolamento & purificação , Benzofuranos/isolamento & purificação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , China , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia
19.
Front Immunol ; 12: 607836, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717090

RESUMO

Wiskott-Aldrich Syndrome, WAS/WAVE, is a rare, X-linked immune-deficiency disease caused by mutations in the WAS gene, which together with its homolog, N-WASP, regulates actin cytoskeleton remodeling and cell motility. WAS patients suffer from microthrombocytopenia, characterized by a diminished number and size of platelets, though the underlying mechanism is not fully understood. Here, we identified FLI1 as a direct transcriptional regulator of WAS and its binding partner WIP. Depletion of either WAS or WIP in human erythroleukemic cells accelerated cell proliferation, suggesting tumor suppressor function of both genes in leukemia. Depletion of WAS/WIP also led to a significant reduction in the percentage of CD41 and CD61 positive cells, which mark committed megakaryocytes. RNAseq analysis revealed common changes in megakaryocytic gene expression following FLI1 or WASP knockdown. However, in contrast to FLI1, WASP depletion did not alter expression of late-stage platelet-inducing genes. N-WASP was not regulated by FLI1, yet its silencing also reduced the percentage of CD41+ and CD61+ megakaryocytes. Moreover, combined knockdown of WASP and N-WASP further suppressed megakaryocyte differentiation, indicating a major cooperation of these related genes in controlling megakaryocytic cell fate. However, unlike WASP/WIP, N-WASP loss suppressed leukemic cell proliferation. WASP, WIP and N-WASP depletion led to induction of FLI1 expression, mediated by GATA1, and this may mitigate the severity of platelet deficiency in WAS patients. Together, these results uncover a crucial role for FLI1 in megakaryocyte differentiation, implicating this transcription factor in regulating microthrombocytopenia associated with Wiskott-Aldrich syndrome.


Assuntos
Proteínas do Citoesqueleto/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína Proto-Oncogênica c-fli-1/metabolismo , Trombopoese/genética , Proteína da Síndrome de Wiskott-Aldrich/metabolismo , Síndrome de Wiskott-Aldrich/etiologia , Síndrome de Wiskott-Aldrich/metabolismo , Animais , Sequência de Bases , Biomarcadores , Linhagem Celular , Sequenciamento de Cromatina por Imunoprecipitação , Modelos Animais de Doenças , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Humanos , Leucemia/genética , Leucemia/metabolismo , Leucemia/patologia , Camundongos , Camundongos Knockout , Regiões Promotoras Genéticas , Proteína Proto-Oncogênica c-fli-1/genética , Transdução de Sinais
20.
J Nat Prod ; 84(4): 1175-1184, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33760626

RESUMO

Porcine epidemic diarrhea virus (PEDV) has become increasingly problematic around the world, not only for its hazards to livestock but also due to the possibility that it is a zoonotic disease. Although vaccine therapy has made some progress toward PEDV control, additional effective therapeutic strategies against PEDV are needed, such as the development of chemotherapeutic agents. The aim of this work was to identify novel anti-PEDV agents by designing and synthesizing a series of phenanthridine derivatives. Among them, three compounds (compounds 1, 2, and 4) were identified as potent anti-PEDV agents exhibiting suppression of host cell heat shock cognate 70 (Hsc70) expression. Mechanism studies revealed that host Hsc70 is involved in the replication of PEDV, and its expression can be suppressed by destabilization of the mRNA, resulting in inhibition of PEDV replication. Activity against PEDV in vivo in PEDV-infected piglets suggested that phenanthridine derivatives are the first host-acting potential anti-PEDV agents.


Assuntos
Antivirais/farmacologia , Proteínas de Choque Térmico HSC70/metabolismo , Fenantridinas/farmacologia , Vírus da Diarreia Epidêmica Suína/efeitos dos fármacos , Animais , Antivirais/síntese química , Linhagem Celular , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/veterinária , Desenho de Fármacos , Estrutura Molecular , Fenantridinas/síntese química , Suínos
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