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
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
Two new ent-clerodane diterpenoids, named isoscoparins R and S (1 and 2), were isolated from the aerial parts of Isodon scoparius. Their structures were characterized mainly by analyzing the NMR and HRESIMS data, and the relative configuration of compound 1 was determined by single-crystal X-ray diffraction. Compound 2 showed weak activity as an autophagic inhibitor.
Assuntos
Diterpenos Clerodânicos/química , Diterpenos Clerodânicos/farmacologia , Isodon/química , Antineoplásicos Fitogênicos/química , Autofagia/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/química , Células HEK293 , Células HeLa , Humanos , Imunossupressores/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Componentes Aéreos da Planta/química , Espectrometria de Massas por Ionização por Electrospray , Difração de Raios XRESUMO
Adenanthin, a natural ent-kaurane diterpenoid extracted from the herb Isodon adenantha, has been reported to increase intracellular reactive oxygen species in leukemic and hepatocellular carcinoma cells. However, the function and mechanism of the compound in adipogenesis and the development of obesity is still unknown. In this study, we demonstrated that adenanthin inhibited adipogenesis of 3T3-L1 and mouse embryonic fibroblasts, and the underlying mechanism included two processes: a delayed mitotic clonal expansion via G0/G1 cell cycle arrest by inhibiting the RB-E2F1 signaling pathway and a reduced C/EBPß signaling by inhibiting the expression and activity of C/EBPß during mitotic clonal expansion. Furthermore, adenanthin significantly reduced the growing body weight and adipose tissue mass during high-fat diet-inducing obesity of mice, indicating the beneficial effects of adenanthin as a potential agent for prevention of obesity.
Assuntos
Adipogenia/efeitos dos fármacos , Diterpenos do Tipo Caurano/isolamento & purificação , Diterpenos do Tipo Caurano/farmacologia , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Isodon/química , Obesidade/metabolismo , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Dieta Hiperlipídica , Diterpenos do Tipo Caurano/química , Medicamentos de Ervas Chinesas/química , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Masculino , Camundongos , Obesidade/tratamento farmacológico , Obesidade/etiologia , Obesidade/patologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
A phytochemical investigation of an ethyl acetate extract of the aerial parts of Isodon pharicus led to the isolation of 21 new 7α,20-epoxy-ent-kaurane diterpenoids, pharicins C-W (1-21), and 29 known (22-50) analogues. The structural characterization of 1-21 and assignment of their relative configurations were accomplished by spectroscopic data interpretation, while the structures of 1 and 16 were confirmed by X-ray crystallography. The absolute stereostructure of 1 was confirmed by electronic circular dichroism data analysis. Twenty-five of the diterpenoids were screened for their cytotoxic activities against a panel of tumor cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW-480. Compounds 11, 16, 38, and 48 exhibited inhibitory activities against these tumor cell lines with IC50 values ranging from 1.01 to 9.62 µM, while 2, 15, 29, and 47 exhibited moderate cytotoxic potency.
Assuntos
Diterpenos do Tipo Caurano/química , Isodon/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X/métodos , Diterpenos do Tipo Caurano/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Células HL-60 , Humanos , Células MCF-7 , Componentes Aéreos da Planta/químicaRESUMO
Fourteen new diterpenoids (1-14) based on four skeletal types and two known analogues (15 and 16) were isolated from the aerial parts of Isodon scoparius. Compound 2 is the first ent-kaurane diterpenoid featuring a 1,11-ether bridge, and the structures of these new compounds were established mainly by NMR and MS methods. The absolute configurations of 1 and 5 and the relative configuration of 3 were determined using single-crystal X-ray diffraction. The absolute configuration of 14 was determined by comparison of the experimental and calculated electronic circular dichroism spectra. Compounds 1, 4, and 15 were active against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW-480), and they also inhibited NO production in LPS-stimulated RAW264.7 cells, with IC50 values of 1.0, 3.1, and 1.8 µM, respectively.
Assuntos
Antineoplásicos Fitogênicos , Diterpenos do Tipo Caurano , Isodon/química , Componentes Aéreos da Planta/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Cristalografia por Raios X , Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/isolamento & purificação , Diterpenos do Tipo Caurano/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Células HL-60 , Humanos , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Estrutura Molecular , Óxido Nítrico/biossíntese , Ressonância Magnética Nuclear BiomolecularRESUMO
Four new ent-abietane diterpenoids, along with four known ones were isolated from the aerial parts of Isodon serra, a traditional Chinese folk medicine. The new diterpenoids were named as serrin K (1), xerophilusin XVII (2), and enanderianins Q and R (3 and 4), while the known ones were identified as rubescansin J (5), (3α,14ß)-3,18-[(1-methylethane-1,1-diyl)dioxy]-ent-abieta-7,15(17)-diene-14,16-diol (6), xerophilusin XIV (7), and enanderianin P (8), respectively. Their structures were elucidated by extensive spectroscopic analysis and comparison with the literature. Compound 1 showed remarkable inhibitory activity towards NO production in LPS-stimulated RAW264.7 cells (IC50 = 1.8 µM) and weak cytotoxicity towards five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480).
Assuntos
Abietanos/química , Abietanos/isolamento & purificação , Isodon/química , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Abietanos/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Óxido Nítrico/biossíntese , Componentes Aéreos da Planta/química , Extratos Vegetais/farmacologiaRESUMO
The phytochemical investigation on 1 g of materials from Gypsoplacamacrophylla (Zahlbr.) Timdal resulted in the discovery of gypmacrophin A, a rare pentacyclic sesterterpenoid; brialmontin III, a new polysubstituted depside and two known ones, brialmontins I and II. The structure and absolute configurations of gypmacrophin A were elucidated by spectroscopic analyses and computational methods. Gypmacrophin A showed weak inhibition of AchE with an IC50 value of 32.03 µM. The four compounds provided new chemical evidence for G. macrophylla identification.
Assuntos
Ascomicetos/isolamento & purificação , Depsídeos/química , Sesterterpenos/química , Acetilcolinesterase , Modelos Moleculares , Estrutura Molecular , Fragmentos de Peptídeos/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
Oxidative stress is a major component of harmful cascades activated in neurodegenerative disorders. Coenzyme Q10 (CoQ10), an essential component in the mitochondrial respiratory chain, has recently gained attention for its potential role in the treatment of neurodegenerative disease. Here, we investigated the possible protective effects of CoQ10 on H2O2-induced neurotoxicity in PC12 cells and the underlying mechanism. CoQ10 showed high free radical-scavenging activity as measured by a DPPH and TEAC. Pre-treatment of cells with CoQ10 diminished intracellular generation of ROS in response to H2O2. H2O2 decreased viability of PC12 cells which was reversed by pretreatment with CoQ10 according to MTT assay. H2O2-induced lipid peroxidation was attenuated by CoQ10 as shown by inhibition of MDA formation. Furthermore, pre-incubation of the cells with CoQ10 also restored the activity of cellular antioxidant enzymes which had been altered by H2O2. Moreover, CoQ10 induced Nrf2 nuclear translocation, the upstream of antioxidant enzymes. These findings suggest CoQ10 augments cellular antioxidant defense capacity through both intrinsic free radical-scavenging activity and activation of Nrf2 and subsequently antioxidant enzymes induction, thereby protecting the PC12 cells from H2O2-induced oxidative cytotoxicity.
Assuntos
Antioxidantes/metabolismo , Peróxido de Hidrogênio/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ubiquinona/análogos & derivados , Animais , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sequestradores de Radicais Livres/farmacologia , Espaço Intracelular/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Células PC12 , Transporte Proteico/efeitos dos fármacos , Ratos , Ubiquinona/farmacologiaRESUMO
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
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.
RESUMO
Ten spirocyclic polycyclic polyprenylated acylphloroglucinols (PPAP), hunascynols A-J (1-10), and 12 known analogs were isolated from the aerial parts of Hypericum ascyron Linn. Compounds 1 and 2, which share a 1,2-seco-spirocyclic PPAP skeleton, could be derived from spirocyclic PPAP, with a common octahydrospiro[cyclohexan-1,5'-indene]-2,4,6-trione core, through a cascade of Retro-Claisen, keto-enol tautomerism, and esterification reactions. Aldolization of normal spirocyclic PPAP yielded 3, which has a caged framework with a 6/5/6/5/6 ring system. The structures of these compounds were determined using spectroscopy and X-ray diffraction. The inhibitory activities of all isolates were tested in three human cancer cell lines and a zebrafish model. Compounds 1 and 2 displayed moderate cytotoxicity against HCT116 cells (IC50 6.87 and 9.86 µM, respectively). The mechanisms of these compounds were evaluated using Western blot assays. Compounds 3 and 5 inhibited the growth of sub-intestinal vessels in zebrafish embryos. Further, the target genes were screened using real-time PCR.
Assuntos
Hypericum , Humanos , Animais , Estrutura Molecular , Hypericum/química , Peixe-Zebra , Linhagem Celular , FloroglucinolRESUMO
(+)-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
Carascynol A, an unprecedented 4/9/8 ring system hybrid with a peroxide bridge, was characterized from Hypericum ascyron. The architecture contains a caryophyllane-type moiety and a C6 unit derived from polyprenylated acylphloroglucinols. Its structure and absolute configuration were determined by comprehensive spectroscopic and X-ray diffraction data. Biologically, compound 1 inhibited cell proliferation in LoVo, SW480, and HCT116 cell lines (IC50 = 12.30-24.57 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
A series of novel scopariusicide derivatives were designed and synthesized starting from the main diterpenoid from the aerial parts of Isodon scoparius. Sis-25 was the most effective compound among them. The potential mechanism(s) of its immunosuppressive activity in vitro, as well as its effects on delayed type hypersensitivity (DTH) reaction and imiquimod-induced dermatitis in vivo were investigated in this study. Sis-25 inhibited anti-CD3/anti-CD28 mAbs, PHA or alloantigen-induced T cell proliferation without obvious cytotoxicity. Sis-25 was a highly selective inhibitor of GSK3-ß and inhibited the mTOR/p70S6K pathway but not the PI3K/Akt, p38 MAPK/ERK 1/2 and JAK3/STAT5 pathways. Furthermore, Sis-25 significantly inhibited IFN-γ, IL-6 and IL-17 expression but not IL-10 expression in activated T cells. Finally, Sis-25 treatment mitigated the DNFB-induced DTH reaction and ameliorated imiquimod-induced dermatitis. In summary, Sis-25 exerted significant immunosuppressive activity by targeting GSK3ß in vitro and in vivo. Sis-25 may guide the design of new drugs for more effective and safer treatments of autoimmune diseases and provide new insight into developing utilizations of Isodon scoparius.
Assuntos
Ciclobutanos , Dermatite , Proliferação de Células , Ciclobutanos/farmacologia , Quinase 3 da Glicogênio Sintase , Glicogênio Sintase Quinase 3 beta , Humanos , Imiquimode , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismoRESUMO
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
Nineteen preschisanartane-type schinortriterpenoids (SNTs), among which eleven ones were previously undescribed, were isolated from two Schisandra species, S. sphaerandra and S. rubriflora. Their structures were determined using 1D and 2D NMR spectroscopic analyses, NMR data comparison, quantum chemical calculation of NMR parameters, electronic circular dichroism (ECD), X-ray single crystal diffraction, and chemical derivation. Furthermore, structural re-examination of a few previously reported preschisanartane-type SNTs led to the structural revision of preschisanartanin J. Besides, it is suggested that the reported structures of arisanlactone D and schilancidilactone W should be re-checked. Finally, a few isolated SNTs were found to possess neurite outgrowth-promoting activities, and protective activities against neural injuries.
Assuntos
Schisandra/química , Triterpenos/química , Triterpenos/isolamento & purificação , China , Dicroísmo Circular , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Componentes Aéreos da Planta/químicaRESUMO
A detailed chemical investigation of the secondary metabolites produced by the endophytic fungus Xylaria sp. isolated from the stems of Isodon sculponeatus afforded six new compounds, xylariahgins A-F (1-6), two new natural products (7 and 8), along with two known compounds (9 and 10) (Fig. 1). The structures of all compounds were unambiguously established by analyzing their spectroscopic data or referring to pertinent literature. Compounds 1-8 were tested for their cytotoxic activity against five human tumor cell lines.