RESUMO
Exploitation of key protected wild plant resources makes great sense, but their limited populations become the major barrier. A particular strategy for breaking this barrier was inspired by the exploration of a resource-saving fungal endophyte Penicillium sp. DG23, which inhabits the key protected wild plant Schisandra macrocarpa. Chemical studies on the cultures of this strain afforded eight novel indole diterpenoids, schipenindolenes A-H (1-8), belonging to six diverse skeleton types. Importantly, semisyntheses suggested some key nonenzymatic reactions constructing these molecules and provided targeted compounds, in particular schipenindolene A (Spidâ A, 1) with low natural abundance. Remarkably, Spidâ A was the most potent HMG-CoA reductase (HMGCR) degrader among the indole diterpenoid family. It degraded statin-induced accumulation of HMGCR protein, decreased cholesterol levels and acted synergistically with statin to further lower cholesterol. Mechanistically, transcriptomic and proteomic profiling suggested that Spidâ A potentially activated the endoplasmic reticulum-associated degradation (ERAD) pathway to enhance the degradation of HMGCR, while simultaneously inhibiting the statin-activated expression of many key enzymes in the cholesterol and fatty acid synthesis pathways, thereby strengthening the efficacy of statins and potentially reducing the side effects of statins. Collectively, this study suggests the potential of Spidâ A for treating cardiovascular disease.
Assuntos
Acil Coenzima A , Inibidores de Hidroximetilglutaril-CoA Redutases , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Degradação Associada com o Retículo Endoplasmático , Proteômica , Colesterol/metabolismo , IndóisRESUMO
Scopariusicides D-M (1-10), ten new ent-clerodane-based meroditerpenoids with a cyclobutane-fused γ/δ-lactone core, were isolated from Isodon scoparius. Their structures were determined by comprehensive analysis of spectroscopic data, single-crystal X-ray diffraction, chemical transformation, and TDDFT ECD calculation. A plausible biosynthetic pathway of 1-10 was proposed in which the asymmetrical cyclobutane ring was formed via a crossed "head-to-tail" intermolecular [2 + 2] cycloaddition in anti/syn facial approaches between an ent-clerodane lactone and a cis-4-hydroxycinnamic acid. Bioactivity evaluation manifested that 5 exhibited significant neuroprotective effect against corticosterone-induced injury in PC12 cells, while 6 and 7 exhibited moderate immunosuppressive activity against human T cell proliferation stimulated by anti-CD3/anti-CD28 mAb.
Assuntos
Antineoplásicos Fitogênicos , Ciclobutanos , Diterpenos Clerodânicos , Isodon , Animais , Antineoplásicos Fitogênicos/farmacologia , Ciclobutanos/farmacologia , Diterpenos Clerodânicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isodon/química , Lactonas/farmacologia , Estrutura Molecular , RatosRESUMO
Twelve new diterpenoids, isoresbins A-L (1-12), together with twenty-eight known ones, were isolated from the aerial parts of Isodon oresbius. Their diverse structures included 6,7-seco-ent-kaurane, 7,20-epoxy-ent-kaurane, 6,7:8,15-diseco-ent-kaurane, and abietanes skeletons, which were elucidated by spectroscopic data interpretation, single-crystal X-ray diffraction, and quantum chemical calculation. Isoresbins A (1) and B (2) possessed a new rearranged 15(8 â 11)-abeo-6,7-seco-ent-kaurane skeleton. 1 and 5 promoted lysosomal function, which was evaluated by LysoTracker Red staining and DQ-ovalbumin dequenching assay. 1 showed cytotoxicity against six human tumor cell lines with IC50 values in 2.07-4.04 µM range. Moreover, 1 induced damage of mitochondrial membrane potential, G2/M cell cycle arrest and apoptosis in SW480 cells.
Assuntos
Antineoplásicos Fitogênicos , Diterpenos do Tipo Caurano , Diterpenos , Isodon , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Diterpenos/farmacologia , Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isodon/química , Estrutura MolecularRESUMO
Natural products possessing unique scaffolds may have antiviral activity but their complex structures hinder facile synthesis. A pharmacophore-oriented semisynthesis approach was applied to (-)-maoelactoneâ A (1) and oridonin (2) for the discovery of anti-SARS-CoV-2 agents. The Wolff rearrangement/lactonization cascade (WRLC) reaction was developed to construct the unprecedented maoelactone-type scaffold during semisynthesis of 1. Further mechanistic study suggested a concerted mechanism for Wolff rearrangement and a water-assisted stepwise process for lactonization. The WRLC reaction then enabled the creation of a novel family by assembly of the maoelactone-type scaffold and the pharmacophore of 2, whereby one derivative inhibited SARS-CoV-2 replication in HPA EpiC cells with a low EC50 value (19±1â nM) and a high TI value (>1000), both values better than those of remdesivir.
Assuntos
Produtos Biológicos , Tratamento Farmacológico da COVID-19 , Antivirais/química , Antivirais/farmacologia , Produtos Biológicos/farmacologia , Humanos , SARS-CoV-2RESUMO
Autophagy is a conserved lysosomal degradation process, and abnormal autophagy has been associated with various pathological processes, e.g., neurodegeneration, cancer, and pathogen infection. Small chemical modulators of autophagy show the potential to treat autophagy-associated diseases. Diterpenoids, nature products found in various plants, exhibit a wide range of bioactivity, and we have recently isolated and characterized over 150 diterpenoids from Isodon species distributed in China. Here, we applied a high-content fluorescence imaging-based assay to assess these diterpenoids' ability to affect autophagic flux in HeLa cells. We found that enanderinanin J, an ent-kauranoid dimer, is an autophagy inhibitor, manifested by its ability to increase lysosomal pH and inhibit the fusion between autophagosomes and lysosomes. Autophagy has been shown to be either positively or negatively involved in the life cycle of Zika virus (ZIKV), Japanese encephalitis virus (JEV), Dengue virus (DENV), and enterovirus-A71 (EV-A71). We found that enanderinanin J significantly inhibited the infection of ZIKV, DENV, JEV, or EV-A71. Interestingly, although ATG5 knockdown inhibited ZIKV or JEV infection, enanderinanin J further inhibited the infection of ZIKV or JEV in ATG5-knockdown cells. Taken together, our data indicate that enanderinanin J inhibits autophagosome-lysosome fusion and is a potential antiviral agent.
Assuntos
Diterpenos , Isodon , Infecção por Zika virus , Zika virus , Antivirais/farmacologia , Autofagia , Diterpenos/farmacologia , Células HeLa , HumanosRESUMO
(-)-Isoscopariusinâ A was isolated from the aerial parts of Isodon scoparius. Chemical synthesis and spectroscopic analysis established its structure as an unsymmetrical meroditerpenoid bearing a sterically congested 6/6/4 tricyclic carbon skeleton with seven continuous stereocenters. A gram-scale synthesis was achieved in 12 steps from commercially available (+)-sclareolide. A cobalt catalyzed, hydrogen atom transfer-based olefin isomerization was used to prepare a trisubstituted alkene, which underwent stereoselective [2+2] cycloaddition with a substituted keteniminium ion generated in situ from the corresponding amide. The cyclobutanone product was further elaborated into the fully substituted cyclobutane core through face-selective homologation, and the two side chains were installed by using nickel-catalyzed cross-electrophile coupling and carbodiimide-mediated esterification, respectively. (-)-Isoscopariusinâ A displayed selective inhibition of T-cell proliferation.
Assuntos
Imunossupressores/síntese química , Isodon/química , Animais , Proliferação de Células/efeitos dos fármacos , Imunossupressores/química , Imunossupressores/farmacologia , Camundongos , Conformação Molecular , Componentes Aéreos da Planta/química , Linfócitos T/efeitos dos fármacosRESUMO
Eight new diterpenoids (1-8) with varied structures were isolated from the aerial parts of Isodon xerophilus. Among them, xerophilsin A (1) was found to be an unusual meroditerpenoid representing a hybrid of an ent-kauranoid and a long-chain aliphatic ester, xerophilsins B-D (2-4) are dimeric ent-kauranoids, while xerophilsins E-H (5-8) are new ent-kauranoids. The structures of 1-8 were elucidated mainly through the analyses of their spectroscopic data. The absolute configurations of 2, 6, and 8 were confirmed by single-crystal X-ray diffraction, and the configuration of C-16 in 7 was established through quantum chemical calculation of NMR chemical shifts, as well as modeling of key interproton distances. Bioactivity evaluation of all isolated compounds revealed that 2, 3, and 5 inhibited NO production in LPS-stimulated RAW264.7 cells.
Assuntos
Diterpenos do Tipo Caurano/isolamento & purificação , Diterpenos/isolamento & purificação , Isodon/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Dimerização , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Eleven undescribed schinortriterpenoids (SNTs) and one known analogue (12) were isolated from the stems and leaves of Schisandra henryi. Their diverse structures included preschisanartane (1), 18-norschiartane (2-5, 12), schiartane (6 and 7), and schisanartane (8-11) skeletons, which were elucidated by comprehensive NMR, MS, electronic circular dichroism analyses, single crystal X-ray diffraction and biogenetic considerations. 1 was the first case of preschisanartane-type SNT with six-membered lactone ring, and 2 was one of the most highly oxygenated 18-norschiartane SNTs. Three types of the highly oxygenated SNTs, 1, 4, 10 and 11, effectively prevent apoptosis induced by corticosterone in PC12 cells. In addition, 11 showed neurite outgrowth-promoting activity.
Assuntos
Fármacos Neuroprotetores/química , Extratos Vegetais/química , Folhas de Planta/química , Caules de Planta/química , Schisandra/química , Triterpenos/química , Animais , Corticosterona/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Lactonas/química , Estrutura Molecular , Fármacos Neuroprotetores/farmacologia , Oxigênio/química , Células PC12 , Ratos , Triterpenos/farmacologiaRESUMO
Penicilfuranone A (1), a novel furancarboxylic acid, and its proposed biosynthetic precursor, gregatin A (2), were isolated from the cultures of the fungus Penicillium sp. sh18 endophytic to the stems of Isodon eriocalyx var. laxiflora guided by HPLC-MS. X-ray crystallography was applied to the structure determination of furancarboxylic acid for the first time, allowing unambiguous assignment of 1. Penicilfuranone A displays a significant antifibrotic effect in activated hepatic stellate cells via negative regulation of transforming growth factor-ß (TGF-ß)/Smad signaling.
Assuntos
Ácidos Carboxílicos/isolamento & purificação , Ácidos Carboxílicos/farmacologia , Furanos/isolamento & purificação , Furanos/farmacologia , Penicillium/química , Animais , Western Blotting , Ácidos Carboxílicos/química , Cristalografia por Raios X , Furanos/química , Isodon/microbiologia , Conformação Molecular , Estrutura Molecular , Ratos , Fator de Crescimento Transformador beta/efeitos dos fármacosRESUMO
Cyclobutanes are distributed widely in a large class of natural products featuring diverse pharmaceutical activities and intricate structural frameworks. The [2 + 2] cycloaddition is unequivocally the primary and most commonly used method for synthesizing cyclobutanes. In this review, we have summarized the application of the [2 + 2] cycloaddition with different reaction mechanisms in the chemical synthesis of selected cyclobutane-containing natural products over the past decade.
RESUMO
Scoparodane C (1), a diterpenoid with a rare 3,4-seco-3-nor-2,11-epoxy-ent-clerodane scaffold, was obtained from the aerial parts of Isodon scoparius, along with isocopariusines A-E (2-6), five ent-clerodanoids featuring a 5/6-fused ring system, and isocopariusines F-H (7-9), three common ent-clerodanoids. The structures of these previously undescribed compounds were established by a combination of spectroscopic analysis, X-ray diffraction, chemical derivatization, and quantum chemical calculation. Remarkably, isocopariusine B (3) showed strong resistance reversal activity against fluconazole-resistant Candida albicans.
Assuntos
Candida albicans , Isodon , Componentes Aéreos da Planta , Componentes Aéreos da Planta/química , Isodon/química , Estrutura Molecular , Candida albicans/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Antifúngicos/farmacologia , Antifúngicos/química , Antifúngicos/isolamento & purificação , Diterpenos Clerodânicos/química , Diterpenos Clerodânicos/farmacologia , Diterpenos Clerodânicos/isolamento & purificação , Modelos MolecularesRESUMO
Isoxerophilusins A (1) and B (2), two unprecedented diterpene heterodimers biogenetically from ent-atisanes and abietanes, were isolated from the rhizomes of Isodon xerophilus. Their structures were determined by extensive spectroscopic analysis and single-crystal X-ray diffraction. Selective esterification of 1 generated 11 new derivatives. All derivatives showed excellent α-glucosidase inhibitory activity in comparison to acarbose. Compounds 12 and 13 demonstrated significant inhibition against α-glucosidase with IC50 values of 4.92 and 3.83 µM, respectively.
Assuntos
Diterpenos , Inibidores de Glicosídeo Hidrolases , Isodon , alfa-Glucosidases , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Diterpenos/química , Diterpenos/farmacologia , Diterpenos/isolamento & purificação , alfa-Glucosidases/metabolismo , Estrutura Molecular , Isodon/química , Dimerização , Cristalografia por Raios X , Relação Estrutura-Atividade , Rizoma/químicaRESUMO
[4 + 2] cycloaddition has led to diverse polycyclic chiral architectures, serving as novel sources for organic synthesis and biological exploration. Here, an unprecedented class of cadinane sesquiterpene [4 + 2] dimers, henryinins A-E (1-5), with a unique 6/6/6/6/6-fused pentacyclic system, were isolated from Schisandra henryi. The divergent total syntheses of compounds 1-5 and their enantiomers (6-10) were concisely accomplished in eight linear steps using a protection-free approach. Mechanistic studies illustrated the origin of selectivity in the key [4 + 2] cycloaddition as well as the inhibition of reaction pathway bifurcation via desymmetrization. The chemical proteomics results showed that a pair of enantiomers shared common targets (PRDX5 C100 and BLMH C73) and had unique targets (USP45 C588 for 4 and COG7 C419 for 9). This work provides experimental evidence for the discovery of unprecedented cadinane dimers from selective Diels-Alder reaction and a powerful strategy to explore the biological properties of natural products.
RESUMO
Four previously undescribed chamigrane sesquiterpenes, namely steccherins A-D, have been isolated from the fungus Steccherinum ochraceum. Their structures were elucidated by extensive spectroscopic analysis, as well as computational methods and single crystal X-ray diffraction. Steccherins A and B possess previously undescribed backbones which might be derived from normal chamigrane sesquiterpenes, especially that steccherin A possesses a spiro[5.6]dodecane carbon skeleton via a ring-rearrangement. Steccherins A, C, and D showed immunosuppressive activity with IC50 values ranging from 6.2 to 37.8 µM. The data suggested that these chamigrane sesquiterpenes have potential selective inhibition on LPS-induced B lymphocyte proliferation.
Assuntos
Fungos , Sesquiterpenos , Proliferação de Células , Sesquiterpenos/farmacologia , Linfócitos BRESUMO
(+)-Isoscopariusins B (1) and C (2), two meroditerpenoids containing a 6/6/4 tricyclic carbon skeleton and seven continuous stereocenters, were identified from Isodon scoparius. The structures were determined by nuclear magnetic resonance analysis and concise biomimetic syntheses from readily available alkene 5 in seven and six steps, respectively. An intermolecular [2+2] photocycloaddition with cooperative catalysis of a Lewis acid and an Ir photocatalyst was used to construct a cyclobutane core with four stereogenic centers.
Assuntos
Ciclobutanos , Isodon , Estrutura Molecular , Biomimética , Espectroscopia de Ressonância Magnética , Isodon/química , Catálise , EstereoisomerismoRESUMO
Cytochalasans from the endophytic fungi featured structure diversity. Our previous study has disclosed that cytochalasans from the endophytic fungus Phomopsis sp. shj2 exhibited an antimigratory effect. Further chemical investigation on Phomopsis sp. shj2 has led to the discovery of seven new cytochalasans (1-7), together with four known ones. Their structures were elucidated through extensive spectroscopic data interpretation and single-crystal X-ray diffraction analysis. Compounds 1-3 and 8-11 exhibited antimigratory effects against MDA-MB-231 in vitro with IC50 values in the range of 1.01-10.42 µM.
RESUMO
Rugosiformisin A, a skeleton-rearranged abietane-type diterpenoid with a spiro[4.5]decane motif, was isolated from Isodon rugosiformis. Its structure was unambiguously established via NMR spectroscopic analysis and single-crystal X-ray diffraction. A bioinspired asymmetric synthesis of rugosiformisin A was achieved in 15 steps with 2.7% overall yield. The synthesis features an iridium-catalyzed asymmetric polyene cyclization and a semipinacol rearrangement.
Assuntos
Diterpenos , Isodon , Isodon/química , Abietanos/química , Espectroscopia de Ressonância Magnética , Extratos Vegetais/química , Esqueleto , Estrutura Molecular , Diterpenos/químicaRESUMO
Three new diterpene alkaloids, tangutidines A-C (1-3), and four known alkaloids (4-7) were isolated from the whole plant of Aconitum tanguticum, from which amphoteric diterpene alkaloids (1-3) were obtained for the first time. The structures of 1-3 were elucidated by detailed interpretation of spectroscopic data, including MS and NMR data. All of them were evaluated for their cytotoxic activities.
RESUMO
Scospirosins A (1) and B (2), two unprecedented spiro ent-clerodane dimers with 6/6/10/6 and 6/6/6/6/6 ring systems, respectively, were isolated from Isodon scoparius. Their structures were unambiguously established by spectroscopic, X-ray crystallographic, and chemical approaches. A bioinspired protecting-group-free strategy for their synthesis was achieved on a gram scale and featured the application of green methods, including neat reaction, sensitized photooxygenation, and electrochemical oxidation. 2 exhibited selective immunosuppressive activity against the proliferation of T lymphocytes (IC50 = 1.42 µM).
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Diterpenos Clerodânicos/síntese química , Diterpenos Clerodânicos/farmacologia , Imunossupressores/farmacologia , Isodon/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Biomimética , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Diterpenos Clerodânicos/análise , Imunossupressores/química , Imunossupressores/isolamento & purificação , Concentração Inibidora 50 , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Linfócitos T/efeitos dos fármacosRESUMO
Six new ent-kaurane diterpenoids, isorugosiformins A-F (1-6), were isolated from the aerial parts of Isodon rugosiformis Hand.-Mazz. Hara. Their structures were elucidated by spectroscopic data interpretation, single crystal X-ray diffraction, and quantum chemical calculation of NMR parameters. The absolute configuration of 5 as 6R was the first case in the known 6,7:8,15-diseco-7,20-olide-6,8-cyclo-ent-kaurane diterpenoids.