ABSTRACT
Emerging evidence suggests the regulation of microglial phenotype balance between M1 and M2 will be a potential therapeutic strategy for microglia-mediated neuroinflammation in Alzheimer's disease (AD). Herein, we evaluated the anti-neuroinflammatory effects and the underlying mechanism of a natural cyathane diterpenoid sarcodonin A (1) derived from the mushroom Sarcodon scabrosus and its six new derivatives (2-7). Lipopolysaccharide (LPS)-activated primary microglia and microglia cell lines were used as models. The nitrite test and immunostaining showed that the derivative named 6 was more effective in inhibiting neuroinflammation. qRT-PCR, ELISA, and western blotting revealed that 6 showed more significant suppression on mRNA and protein expression of proinflammatory M1 markers of TNF-α, IL-6, IL-1ß, iNOS, and COX-2, while more obvious potentiation on mRNA and protein levels of anti-inflammatory M2 markers of IL-10 and ARG-1. In mechanism, western blotting demonstrated that 6 inhibited LPS-induced activation of MAPK, and prevented LPS-stimulated nuclear translocation of NF-κB p65. Molecular docking revealed that 1 and 6 constructed interactions with iNOS. Collectively, the present study indicated that 1 and 6 might support neuroprotection by reversing LPS-induced microglia M1 polarization, implying that sarcodonin A can be a promising candidate for developing new therapeutics against AD by targeting microglia-mediated neuroinflammation.
Subject(s)
Microglia , NF-kappa B , Basidiomycota , Lipopolysaccharides/metabolism , Lipopolysaccharides/pharmacology , Molecular Docking Simulation , NF-kappa B/metabolism , RNA, Messenger/metabolism , TerpenesABSTRACT
Phosphoglycerate dehydrogenase (PHGDH) is abnormally expressed in numerous malignant tumor cells and catalyzes the first step of serine biosynthesis, thus becoming a key drug target for antitumor treatment. In this study, compound B2 bearing a benzene-1,3-diamine scaffold was identified by structure-based virtual screening as a novel PHGDH inhibitor with moderate enzymatic activity. The structure-activity relationship study led to the discovery of compound C25 possessing improved enzymatic inhibitory activity and potent inhibitory activity on the proliferation of cells overexpressing PHGDH. The enzyme kinetic assay confirmed that C25 inhibited PHGDH in a nicotinamide adenine dinucleotide (NAD+) competitive manner. Molecular docking and mutagenesis experiment on PHGDH collectively revealed the binding site and key interaction residues of C25 in the PHGDH catalytic site. Taken together, this study provides information on the structural diversity for a further development of potent PHGDH inhibitors.
Subject(s)
Enzyme Inhibitors , Phosphoglycerate Dehydrogenase , Cell Line, Tumor , Enzyme Inhibitors/chemistry , Molecular Docking Simulation , Serine , Structure-Activity RelationshipABSTRACT
During our continuous efforts to pursue antifungal agents, some calycanthaceous alkaloid analogs showed diverse and promising bioactivities. Therefore, 34 new calycanthaceous alkaloid derivatives were further prepared and screened for bioactivities. As a result of the evaluation against a great deal of plant pathogen fungi, bacteria and human pathogenic fungi, a majority of them displayed potent bioactivity. In particular, compound b6 displayed remarkably activity and might be novel potential leading compound for further development of antifungal agent. The relationship between structure and biological activity was also discussed.
Subject(s)
Alkaloids , Fungi , Alkaloids/pharmacology , Antifungal Agents/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity RelationshipABSTRACT
Signal transducer and activator of transcription 3 (STAT3) is identified as a promising target for multiple cancer therapy and attracts widespread concern. Herein, we reported the discovery of a series of 2-acetyl-7-phenylamino benzofuran derivatives as STAT3 inhibitors using scaffold fusion strategy. Further structure activity relationship study led to the discovery of compound C6, which displayed the most potent anti-proliferation activities against MDA-MB-468 cells (IC50 = 0.16 µM). Western blot assay demonstrated that C6 inhibited the activation of STAT3 (Tyr705) without influencing the phosphorylation of STAT1 (Tyr701). Further mechanistic studies indicated that C6 caused a notable G2/M cycle-arresting and early apoptosis in a concentration-dependent manner in MDA-MB-468 cells. Finally, molecular modelling study elucidated the binding mode of C6 in STAT3 SH2 domain.
Subject(s)
Antineoplastic Agents/chemistry , Benzofurans/chemistry , STAT3 Transcription Factor/antagonists & inhibitors , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Benzofurans/metabolism , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Design , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , Molecular Docking Simulation , Phosphorylation/drug effects , STAT3 Transcription Factor/metabolism , Structure-Activity Relationship , src Homology DomainsABSTRACT
A novel sesquiterpenoid dimer, named multistalide C (1), together with two known congeners, shizukaols C (2) and D (3), was isolated from the whole plant of Chloranthus japonicus Sieb. The structures of compounds 1-3 were elucidated by extensive HR-ESI-MS, 1D, and 2D NMR spectroscopic analysis. Compounds 1-3 exhibited significant toxic effects on brine shrimp larvae (Artemia salina). The absolute configuration of 1 was established by CD/TDDFT calculations. The related compound chlorahololide A was also reinvestigated. The previous assignment of the absolute configuration of chlorahololide A and several related sesquiterpenoid dimers, based on an incorrect application of the exciton chirality method, is criticized.
Subject(s)
Magnoliopsida/chemistry , Plant Extracts/chemistry , Sesquiterpenes/chemistry , Circular Dichroism , Dimerization , Magnetic Resonance Spectroscopy , Molecular Structure , Plant Extracts/isolation & purification , Quantum Theory , StereoisomerismABSTRACT
Degos disease also known as malignant atrophic papulosis (MAP), is an autoinflammatory disease that mainly affects small- to medium-sized arteries. Gastrointestinal and nervous system are most commonly affected systems. Herein, we reported a case of Degos disease with disease onset during infantile and had severe neurological involvement.
ABSTRACT
The title compound, C14H12N2O4, was obtained from 2-acetyl-6-amino-naphthalene through two-step reactions of acetyl-ation and nitration. The mol-ecule comprises the naphthalene ring system consisting of functional systems bearing a acetyl group (C-2), a nitro group (C-5), and an acetyl-amino group (C-6). In the crystal, the mol-ecules are assembled into two-dimensional sheet-like structures by inter-molecular N-Hâ¯O and C-Hâ¯O hydrogen-bonding inter-actions. Hirshfeld surface analysis illustrates that the most important contributions to the crystal packing are from Oâ¯H/Hâ¯O (43.7%), Hâ¯H (31.0%), and Câ¯H/Hâ¯C (8.5%) contacts.
ABSTRACT
The title compound, C12H10N2O3, was obtained by the de-acetyl-ation reaction of 1-(6-amino-5-nitro-naphthalen-2-yl)ethanone in a concentrated sulfuric acid methanol solution. The mol-ecule comprises a naphthalene ring system bearing an acetyl group (C-3), an amino group (C-7), and a nitro group (C-8). In the crystal, the mol-ecules are assembled into a two-dimensional network by Nâ¯H/Hâ¯N and Oâ¯H/Hâ¯O hydrogen-bonding inter-actions. n-π and π-π stacking inter-actions are the dominant inter-actions in the three-dimensional crystal packing. Hirshfeld surface analysis indicates that the most important contributions are from Oâ¯H/Hâ¯O (34.9%), Hâ¯H (33.7%), and Câ¯H/Hâ¯C (11.0%) contacts. The energies of the frontier mol-ecular orbitals were computed using density functional theory (DFT) calculations at the B3LYP-D3BJ/def2-TZVP level of theory and the LUMO-HOMO energy gap of the mol-ecule is 3.765â eV.
ABSTRACT
A novel cyathane diterpenoid, designated scabronine M (1), was isolated from the fruiting bodies of the mushroom Sarcodon scabrosus together with 10 known compounds. The structure of the new compound was elucidated on the basis of extensive spectroscopic analysis including 2D-NMR. Among these compounds, only scabronine M (1) significantly inhibited dose-dependently NGF-induced neurite outgrowth in PC12 cells without cytotoxicity, possibly through suppressing the phosphorylation of the receptor Trk A and the extracellular signal regulated kinases (ERK). This is the first report of novel neurite outgrowth-inhibiting activity in PC12 cells of this group of diterpenoids.
Subject(s)
Basidiomycota/chemistry , Diterpenes/isolation & purification , Fruiting Bodies, Fungal/chemistry , Nerve Growth Factors/antagonists & inhibitors , Neurites/drug effects , Animals , Diterpenes/chemistry , Diterpenes/pharmacology , Dose-Response Relationship, Drug , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Magnetic Resonance Spectroscopy , Molecular Structure , Nerve Growth Factors/pharmacology , Neurites/physiology , PC12 Cells , Phosphorylation/drug effects , RatsABSTRACT
Secoscabronine M (1) is a hemiacetal cyathane diterpenoid that was isolated from the fruiting bodies of the basidiomycete Sarcodon scabrosus (Fr.) Karst. Compound 1 possesses a novel structure with a bond cleavage between C-3 and C-4. The structure of the new compound was elucidated by means of spectroscopic methods, including two-dimensional nuclear magnetic resonance experiments. The absolute configuration of 1 was established by analysis of circular dichroism spectroscopy and also by employing time-dependent density functional theory calculations. In addition, compound 1 was confirmed to be an equilibrium mixture of two epimers (15S and 15R) at position C-15 in polar solvents by one-dimensional nuclear magnetic resonance analysis.
Subject(s)
Basidiomycota/chemistry , Diterpenes/chemistry , Animals , Circular Dichroism , Diterpenes/isolation & purification , Diterpenes/pharmacology , Drug Evaluation, Preclinical , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Neurites/drug effects , PC12 Cells , RatsABSTRACT
The structure of the title com-pound, C17H20O4 [systematic name: (1aS,3aR,4aS,5aR)-15-(acet-oxy)linden-7(11),8-trieno-12,8-lactone or (4aR,5S,5aR,6aS,6bR)-5-(acet-oxy-meth-yl)-4a,5,5a,6,6a,6b-hexa-hydro-3,6b-di-methyl-cyclo-propa[2,3]indeno-[5,6-b]furan-2(4H)-one, ent-chloranthalactone C], a natural product iso-lated from the whole plant Chloranthus japonicus Sieb., is a typical lin-den-ane-type sesquiterpenoid. The mol-ecule com-prises a bi-cyclo-[3.1.0]hexane ring (A/B system) bearing an acetoxymethyl (C-4) group, a bi-cyclo-[4.3.0]nonane ring (B/C system) containing a double bond (C-8/9) and a chiral quaternary carbon (C-10), and a 7(11)-en-12,8-olide structural moiety on the cyclo-hexan-8-ene (C ring). In the tetra-cyclic skeleton, the 1,3-cyclo-propane ring has a ß-con-figuration, and atoms H-5 and H3-14 have α- and ß-orientations, respectively. In the crystal, the mol-ecules are assembled into a two-dimensional network by weak Oâ¯H/Hâ¯O inter-actions. Hirshfeld surface analysis illustrates that the greatest contributions are from Hâ¯H (55.2%), Oâ¯H/Hâ¯O (34.6%) and Câ¯H/Hâ¯C (8.9%) contacts.
ABSTRACT
Microbial transformation of diosgenin (3ß-hydroxy-5-spirostene) using white-rot fungus Coriolus versicolor afforded four previously unreported polyhydroxylated steroids, 25(R)-spirost-5-en-3ß,7α,15α,21-tetraol (5), 25(R)-spirost-5-en-3ß,7ß,12ß,21-tetrol (6), (25R)-spirost-5-en-3ß,7α,12ß,21-tetraol (7), and (25R)-spirost-5-en-3ß,7ß,11α,21-tetraol (8), along with three known congeners, 25(R)-spirost-5-en-3ß,7ß-diol (2), 25(R)-spirost-5-en-3ß,7ß,21-triol (3), and 25(R)-spirost-5-en-3ß,7ß,12ß-triol (4). These structures were elucidated by 1D and 2D NMR as well as HR-ESIMS analysis. In addition, we provide evidence for two new microbial hydroxylations of diosgenin: C-21 primary carbon hydroxylation and C-15 hydroxylation. The 3ß-hydroxyl group and double bond in the B-ring of diosgenin were found to be important structural determinants for their activity.
Subject(s)
Basidiomycota/chemistry , Diosgenin/metabolism , Steroids/isolation & purification , Basidiomycota/metabolism , Biotransformation , Diosgenin/chemistry , Diosgenin/pharmacology , Humans , Molecular Structure , NF-kappa B/drug effects , NF-kappa B/metabolism , Nuclear Magnetic Resonance, Biomolecular , Steroids/chemistry , Steroids/pharmacologyABSTRACT
Two new highly oxygenated fasciculol-type lanostane derivatives, fasciculols H and I (1 and 2, resp.), together with five known compounds, 3-7, were isolated from the fruiting bodies of the Chinese toxic mushroom Naematoloma fasciculare. Their structures were elucidated on the basis of spectroscopic analyses including 2D-NMR (HMBC, HSQC, NOESY, (1)H,(1)H-COSY). Compounds 5-7 were identified for the first time in this mushroom. Compounds 1, 3, 4, and 5 were evaluated for inhibitory activity against human glioma cell line U87 and nuclear factor-κB.
Subject(s)
Agaricales/chemistry , Triterpenes/chemistry , Triterpenes/pharmacology , Antineoplastic Agents, Alkylating , Cell Line, Tumor , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/pathology , Drug Screening Assays, Antitumor , Fruiting Bodies, Fungal/chemistry , Glioma/drug therapy , Glioma/pathology , Humans , Magnetic Resonance Spectroscopy , Molecular Structure , NF-kappa B p50 Subunit/antagonists & inhibitors , Triterpenes/isolation & purificationABSTRACT
In the title compound, C(15)H(12)F(2)O(2), the dihedral angle between the aromatic rings is 70.43â (4)°. The crystal packing exhibits no significantly short inter-molecular contacts.
ABSTRACT
The title compound, C(13)H(11)Cl(2)N(3)O(2), was obtained by the reaction of eugenol and cyanuric chloride. The dihedral angle between the benzene and triazine rings is 87.56â (4)°. Two C atoms of the allyl group are disordered over two sites in a 0.72â (2):0.28â (2) ratio.
ABSTRACT
Persistently activated signal transducer and activator of transcription 3 (STAT3) plays an important role in the development of multiple cancers, and therefore is a potential therapeutic target for cancer prevention. Herein, we report the rational design, synthesis, and biological evaluation of novel potent STAT3 inhibitors based on BBI608. Among them, compound A11 exhibited the most potent in vitro tumor cell growth inhibitory activities toward MDA-MB-231, MDA-MB-468 and HepG2 cells with IC50 values as low as 0.67 ± 0.02 µM, 0.77 ± 0.01 µM and 1.24 ± 0.16 µM, respectively. Fluorescence polarization (FP) assay validated the binding of compound A11 in STAT3 SH2 domain with the IC50 value of 5.18 µM. Further mechanistic studies indicated that A11 inhibited the activation of STAT3 (Y705), and thus reduced the expression of STAT3 downstream genes CyclinD1 and C-Myc. Simultaneously, it induced cancer cell S phase arrest and apoptosis in a concentration-dependent manner. An additional in vivo study revealed that A11 suppressed the MDA-MB-231 xenograft tumor growth in mice at the dose of 10 mg/kg (i.p.) without obvious body-weight loss. Finally, molecular docking study further elucidated the binding mode of A11 in STAT3 SH2 domain.
Subject(s)
Antineoplastic Agents/therapeutic use , Benzofurans/therapeutic use , Naphthoquinones/therapeutic use , Neoplasms/drug therapy , STAT3 Transcription Factor/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Apoptosis/drug effects , Benzofurans/chemical synthesis , Benzofurans/metabolism , Cell Line, Tumor , Drug Design , Female , Humans , Mice, Inbred BALB C , Molecular Docking Simulation , Molecular Structure , Naphthoquinones/chemical synthesis , Naphthoquinones/metabolism , Protein Binding , S Phase Cell Cycle Checkpoints/drug effects , STAT3 Transcription Factor/metabolism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Sarcodonin G, one of the cyathane diterpenoids isolated from the mushroom Sarcodon scabrosus, possesses pronounced neurotrophic activity but ambiguous mechanical understanding. In this work, sarcodonin G was chosen as a lead compound to prepare a series of 19- O-benzoyl derivatives by semisynthesis and their neuritogenic activities were evaluated. 6 and 15 (10 µM) were investigated with opposite effects in PC12 cells. 6 exhibited a superior activity to sarcodonin G by promoting NGF-induced neurite outgrowth, while 15 showed an inhibitory effect. Supportingly, 6 and 15 (20 µM) significantly induced and suppressed neurite extension in primary cultured rat cortical neurons, respectively. In mechanism, the two derivatives were revealed to influence NGF-induced neurite outgrowth in PC12 cells through the regulation of PKC-dependent and -independent ERK/CREB signaling as well as the upstream TrkA receptor phosphorylation. Furthermore, a possible pattern of interaction among NGF, 6/15 and TrkA was presented using molecular simulations. It revealed that 6/15 may contribute to the stabilization of the NGF-TrkAd5 complex by establishing several hydrophobic and hydrogen-bond interactions with NGF and TrkA, respectively. Taken together, 6 and 15 modulate PKC-dependent and -independent ERK/CREB signaling pathways possibly by influencing the binding affinity of NGF to the receptor TrkA, and finally regulate neurite outgrowth in PC12 cells.
Subject(s)
Benzene Derivatives/pharmacology , Central Nervous System Agents/pharmacology , Diterpenes/pharmacology , Nerve Growth Factor/metabolism , Neuronal Outgrowth/drug effects , Animals , Benzene Derivatives/chemical synthesis , Central Nervous System Agents/chemical synthesis , Cerebral Cortex/cytology , Cerebral Cortex/drug effects , Cerebral Cortex/physiology , Cyclic AMP Response Element-Binding Protein/metabolism , Dose-Response Relationship, Drug , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Neuronal Outgrowth/physiology , PC12 Cells , Primary Cell Culture , Rats , Receptor, trkA/metabolism , Signal Transduction/drug effectsABSTRACT
Placentation, which is critical for maternal-fetal exchange of nutrients and gases, is a complicated process comprising stepwise vasculogenesis and angiogenesis. Hypoxia caused by impaired trophoblast invasion may cause various angiogenic abnormalities in human placenta. The Notch1 signaling pathway plays an important role in the regulation of angiogenesis. The angiogenesis of human umbilical vein endothelial cells (HUVECs) under normal/hypoxic conditions and the mRNA/protein level of Notch1/Dell4/Jagged1 were investigated in this study. The effects of DAPT/JAG-1 on the migration of HUVECs were also assessed by cell wound healing assay, so as to discover the possible role of notch1 signaling pathway in the angiogenesis of human placenta. The results showed that angiogenic ability of HUVECs was seriously reduced under hypoxic conditions. The mRNA and protein levels of Notch1/Dell4/Jagged1 were decreased in the hypoxic group compared to the control one. In addition, the migration capability of HUVECs was significantly obstructed when treated with DAPT and under hopoxic condition, but promoted when treated with JAG-1. The above results demonstrate that hypoxia downregulates the angiogenesis in human placenta via Notch1 signaling pathway.
Subject(s)
Down-Regulation , Hypoxia/genetics , Neovascularization, Physiologic , Placenta/metabolism , Receptor, Notch1/metabolism , Signal Transduction , Cell Hypoxia/genetics , Cell Movement/genetics , Down-Regulation/genetics , Female , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Hypoxia/pathology , Jagged-1 Protein/metabolism , Pregnancy , RNA, Messenger/genetics , RNA, Messenger/metabolism , Time FactorsABSTRACT
Two new sesquiterpenes, namely, 1ß,10ß-dihydroxy-eremophil-7(11), 8-dien-12,8-olide (1) and 8,12-epoxy-1ß-hydroxyeudesm-3,7,11-trien-9-one (2), together with three known sesquiterpenoids, shizukolidol (3), 4α-hydroxy-5α(H)-8ß-methoxy-eudesm-7(11)-en-12,8-olide (4), and neolitacumone B (5), and two known monoterpenes, (3R,4S,6R)-p-menth-1-en-3,6-diol (6) and (R)-p-menth-1-en-4,7-diol (7), were isolated from the whole plant of Chloranthus japonicus Sieb. Their structures were elucidated on the basis of spectroscopic data analysis and comparison with those of related known compounds. Compounds 4-7 were isolated from this plant for the first time.
Subject(s)
Magnoliopsida/chemistry , Sesquiterpenes/isolation & purification , Animals , Artemia/drug effects , Medicine, Chinese Traditional , Plant Extracts/analysis , Sesquiterpenes/chemistry , Sesquiterpenes/toxicityABSTRACT
The title compound, C15H22O3·H2O, is a natural producr isolated from Chloranthus japonicus, which is a eudesmane sesquiterpenoid. The two trans-fused six-membered rings have chair confomations. In the crystal, O-Hâ¯O hydrogen bonds link the components into corrugated layers parallel to the bc plane. There are C-Hâ¯O inter-actions present within and between the layers.