ABSTRACT
Current periodontal treatment focuses on the mechanical removal of the source of infection, such as bacteria and their products, and there is no approach to control the host inflammatory response that leads to tissue destruction. In order to control periodontal inflammation, we have previously reported the optimization of (+)-terrein synthesis methods and the inhibitory effect of (+)-terrein on osteoclast differentiation in vitro. However, the pharmacological effect of (+)-terrein in vivo in the periodontitis model is still unknown. In this study, we investigated the effect of synthetic (+)-terrein on inflammatory bone resorption using a ligature-induced periodontitis mouse model. Synthetic (+)-terrein (30 mg/kg) was administered intraperitoneally twice a week to the mouse periodontitis model. The control group was treated with phosphate buffer. One to two weeks after the induction of periodontitis, the periodontal tissues were harvested for radiological evaluation (micro-CT), histological evaluation (HE staining and TRAP staining), and the evaluation of inflammatory cytokine production in the periodontal tissues and serum (quantitative reverse-transcription PCR, ELISA). The synthetic (+)-terrein-treated group suppressed alveolar bone resorption and the number of osteoclasts in the periodontal tissues compared to the control group (p < 0.05). In addition, synthetic (+)-terrein significantly suppressed both mRNA expression of TNF-α in the periodontal tissues and the serum concentration of TNF-α (both p < 0.05). In conclusion, we have demonstrated that synthetic (+)-terrein abrogates alveolar bone resorption via the suppression of TNF-α production and osteoclast differentiation in vivo. Therefore, we could expect potential clinical effects when using (+)-terrein on inflammatory bone resorption, including periodontitis.
ABSTRACT
The enhanced reaction rate in the epoxidation of cyclohexene with air as an oxidant was discovered without any added catalyst utilizing a continuous flow reactor constructed with readily available stainless steel parts and devices. This continuous-flow process demonstrates a significant improvement in reaction time for highly selective epoxide production over the batch process due to the efficient mass transfer between the liquid phase and air. The flow process discovered was operated continuously with good operational stability, evaluated by a constant high yield of cyclohexene oxide, to obtain the desired product with high productivity.
ABSTRACT
Osteoporosis is a common disease characterized by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. Severe bone loss due to osteoporosis triggers pathological fractures and consequently decreases the daily life activity and quality of life. Therefore, prevention of osteoporosis has become an important issue to be addressed. We have reported that the fungal secondary metabolite (+)-terrein (TER), a natural compound derived from Aspergillus terreus, has shown receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation by suppressing nuclear factor of activated T-cell 1 (NFATc1) expression, a master regulator of osteoclastogenesis. TER has been shown to possess extensive biological and pharmacological benefits; however, its effects on bone metabolism remain unclear. In this study, we investigated the effects of TER on the femoral bone metabolism using a mouse-ovariectomized osteoporosis model (OVX mice) and then on RANKL signal transduction using mouse bone marrow macrophages (mBMMs). In vivo administration of TER significantly improved bone density, bone mass, and trabecular number in OVX mice (p < 0.01). In addition, TER suppressed TRAP and cathepsin-K expression in the tissue sections of OVX mice (p < 0.01). In an in vitro study, TER suppressed RANKL-induced phosphorylation of PKCα/ßII, which is involved in the expression of NFATc1 (p < 0.05). The PKC inhibitor, GF109203X, also inhibited RANKL-induced osteoclastogenesis in mBMMs as well as TER. In addition, TER suppressed the expression of osteoclastogenesis-related genes, such as Ocstamp, Dcstamp, Calcr, Atp6v0d2, Oscar, and Itgb3 (p < 0.01). These results provide promising evidence for the potential therapeutic application of TER as a novel treatment compound against osteoporosis.
ABSTRACT
The first Cu-catalyzed dehydrogenative C-O cyclization for the synthesis of furan-fused thienoacenes is described. A variety of heteroacenes including a thieno[3,2-b]furan or a thieno[2,3-b]furan skeleton were synthesized by intramolecular C-H/O-H coupling. The use of a mixed solvent of N-methyl-2-pyrrolidone, ethylene glycol monomethyl ether, and toluene was essential for suppressing side reactions and efficiently promoting the reaction. Double C-O cyclization was also conducted to afford highly π-expanded furan-fused thienoacenes.
ABSTRACT
We developed an efficient acylative kinetic resolution of 3-hydroxy-3-substituted 2-oxindoles by a chiral DMAP derivative having a 1,1'-binaphthyl with two tert-alcohols units. A wide range of 3-hydroxy-3-substituted oxindoles having various functional groups were efficiently resolved (14 examples, up to s = 60) in the presence of 1 mol % of catalyst within 3-9 h. Multigram-scale reactions (10 g) also proceeded with a high s-factor (s = 43) within 5 h.
ABSTRACT
Pathophysiological bone resorption is commonly associated with periodontal disease and involves the excessive resorption of bone matrix by activated osteoclasts. Receptor activator of nuclear factor (NF)-κB ligand (RANKL) signaling pathways have been proposed as targets for inhibiting osteoclast differentiation and bone resorption. The fungal secondary metabolite (+)-terrein is a natural compound derived from Aspergillus terreus that has previously shown anti-interleukin-6 properties related to inflammatory bone resorption. However, its effects and molecular mechanism of action on osteoclastogenesis and bone resorption remain unclear. In the present study, we showed that 10 µM synthetic (+)-terrein inhibited RANKL-induced osteoclast formation and bone resorption in a dose-dependent manner and without cytotoxicity. RANKL-induced messenger RNA expression of osteoclast-specific markers including nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), the master regulator of osteoclastogenesis, cathepsin K, tartrate-resistant acid phosphatase (Trap) was completely inhibited by synthetic (+)-terrein treatment. Furthermore, synthetic (+)-terrein decreased RANKL-induced NFATc1 protein expression. This study revealed that synthetic (+)-terrein attenuated osteoclast formation and bone resorption by mediating RANKL signaling pathways, especially NFATc1, and indicated the potential effect of (+)-terrein on inflammatory bone resorption including periodontal disease.
Subject(s)
Aspergillus/metabolism , Cyclopentanes/pharmacology , Osteoclasts/metabolism , RANK Ligand/metabolism , Signal Transduction/drug effects , Acid Phosphatase/metabolism , Animals , Aspergillus/chemistry , Bone Marrow Cells/drug effects , Bone Resorption/genetics , Bone Resorption/metabolism , Cathepsin K/metabolism , Cell Differentiation/drug effects , Dose-Response Relationship, Drug , Isoenzymes/metabolism , Macrophages/drug effects , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , NFATC Transcription Factors/metabolism , Osteoclasts/cytology , Osteoclasts/drug effects , Osteogenesis/drug effects , RANK Ligand/drug effectsABSTRACT
The first electrochemical dehydrogenative C-S bond formation leading to thienoacene derivatives is described. Several thienoacene derivatives were synthesized by dehydrogenative C-H/S-H coupling. The addition of n Bu4 NBr, which catalytically promoted the reaction as a halogen mediator, was essential.
ABSTRACT
The first synthesis of dithieno-1,2-oxaborine derivatives was achieved via iodide-mediated or iodide-catalyzed demethylation of 3-methoxy-2,2'-bithiophene and subsequent C-H borylation. A wide variety of thiophene-fused oxaborines could be synthesized by the procedure.
ABSTRACT
An efficient enantioselective acyl migration reaction of furanyl carbonates was developed to construct all-carbon quaternary stereogenic centers. In some cases, the reactions required only 0.05â mol % (minimum 500â ppm) of catalyst and showed a high turnover frequency value (TOF; 3640â h-1 ). Multigram-scale reactions (10â grams) also proceeded with high enantioselectivity (>99:1 e.r.) in quantitative yield. The catalyst was robust and easily recovered in 98 % yield. A wide range of functional groups were tolerated (15â examples, >98 % yield, up to >99:1 e.r.), and a variety of optically active 3,3'-disubstituted benzofuranone derivatives, which are useful intermediates for the synthesis of natural products and pharmaceuticals, were efficiently obtained. Control experiments on the catalyst structure (e.g., catalyst 1 a vs. 1 a' and 1 a'') and computational calculations revealed that both the catalytic activity and enantioselectivity should be enhanced by hydrogen bonding between catalyst and substrate. Moreover, this system was applied to the challenging γ-selective acyl migration reaction of furanyl carbonates with high γ-selectivity and high enantioselectivity (α:γ=10:90, 95:5 e.r.).
ABSTRACT
Control of bacterial infection-induced inflammatory responses is one of the effective therapeutic approaches of periodontal diseases. Natural products such as lipid mediators and metabolites from microorganisms have been used for decreasing inflammation. We previously reported that (+)-terrein inhibited activation of STAT3 and ERK1/2 in interleukin-6 (IL-6) signaling cascade, leading to prevent vascular endothelial growth factor (VEGF) secretion in human gingival fibroblasts (HGFs). However, little is still known about the role of (+)-terrein on inflammatory responses. In this study, we provided the possibility of novel action that (+)-terrein inhibits activation of Janus-activated kinase 1 (JAK1), which has a central function in IL-6 signaling cascade, and alters expression of mRNAs and proteins induced by IL-6/soluble IL-6 receptor (sIL-6R) stimulation in HGFs. First, we performed PCR array to examine IL-6/sIL-6R-induced mRNA expression, and then expression of mRNA and protein of colony stimulating factor-1 (CSF1) and VEGF were clearly determined by quantitative RT-PCR and ELISA, respectively. Treatment with (+)-terrein suppressed expression of mRNA and protein of CSF1 and VEGF by IL-6/sIL-6R stimulation. Next, to test the effect of (+)-terrein on IL-6/sIL-6R signaling cascade, we demonstrated whether (+)-terrein affects phosphorylation of JAK1 and its downstream proteins, Akt and SHP-2. Western blotting revealed that (+)-terrein inhibited IL-6/sIL-6R-induced phosphorylation of JAK1, Akt, and SHP-2. Therefore, (+)-terrein suppresses IL-6/sIL-6R-induced expression of CSF1 and VEGF via inhibition of JAK1, Akt, and SHP-2. Based on our results, we suggest that (+)-terrein is a candidate compound for anti-inflammatory effect associated with IL-6 signaling.
ABSTRACT
The first synthesis of dithieno[3,2- b:2',3'- e][1,4]azaborinine (DTAB) derivatives has been achieved by Buchwald-Hartwig coupling and subsequent Friedel-Crafts-type C-H borylation. A facile method for further π-extension of DTAB was also developed via stannylation and subsequent Kosugi-Migita-Stille cross-coupling reaction. The fundamental properties of DTAB derivatives were also investigated.
ABSTRACT
In this study, six-membered N-acyliminium ions were generated by the "indirect cation pool" method and reacted with several nucleophiles. These reactions afforded disubstituted piperidine derivatives with high diastereoselectivities and good to excellent yields. The conformations of the obtained N-acyliminium ions were studied by low temperature NMR analyses and DFT calculations and were found to be consistent with the Steven's hypothesis.
ABSTRACT
A dynamic kinetic resolution (DKR) of azlactones in the presence of benzoic acid and a binaphthyl-based N, N-4-dimethylaminopyridine (DMAP) derivative 1i having two amide groups at the 3,3'-positions of a binaphthyl unit is developed. The reaction proceeded smoothly with a wide range of azlactones to provide α-amino acid derivatives with good to high enantiomeric ratios (er's). A multigram-scale reaction (2.5 g) for the DKR of azlactone 2d was also demonstrated, and the resulting product was converted to unnatural α-amino acid 6d'.
ABSTRACT
We developed an acylative desymmetrization of meso-1,2-diols using a binaphthyl-based N,N-4-dimethylaminopyridine (DMAP) derivative 1h with tert-alcohol substituents. The reaction proceeds with a wide range of acyclic meso-1,2-diols and six-membered-ring meso-1,2-diols to provide a monoacylate selectively with a high enantiomeric ratio (er). Only 0.1 mol % of the catalyst facilitated the reaction within a short reaction time (3 h) to afford enantio-enriched monoacylated products in moderate to good yield. Several control experiments revealed that the tert-alcohol units of catalyst 1h play a significant role in achieving high catalytic activity, chemoselectivity of monoacylation, and enantioselectivity.
ABSTRACT
The synthesis of 3-benzo[b]thienyl 3-thienyl ether and its dehydrogenative cyclization leading to benzodithienofuran (BDTF; [1]benzothieno[3,2-b]thieno[2,3-d]furan) are described for the first time. Further transformation of BDTF to more π-extended BDTF derivatives and their fundamental physical properties are also studied.
ABSTRACT
Straightforward syntheses leading to π-extended benzosilolothiophene (BST) derivatives by Rh-catalyzed dehydrogenative cyclization reactions have been developed. Electron-deficient ligands were effective for the reactions, and dppe-F20 gave the best result. This method could be applied to the synthesis of highly π-extended ladder-type BST derivatives, which exhibited fluorescence.
ABSTRACT
Catalysts that can promote acyl transfer processes are important to enantioselective synthesis and their development has received significant attention in recent years. Despite noteworthy advances, discovery of small-molecule catalysts that are robust, efficient, recyclable and promote reactions with high enantioselectivity can be easily and cost-effectively prepared in significant quantities (that is, >10 g) has remained elusive. Here, we demonstrate that by attaching a binaphthyl moiety, appropriately modified to establish H-bonding interactions within the key intermediates in the catalytic cycle, and a 4-aminopyridyl unit, exceptionally efficient organic molecules can be prepared that facilitate enantioselective acyl transfer reactions. As little as 0.5 mol% of a member of the new catalyst class is sufficient to generate acyl-substituted all-carbon quaternary stereogenic centres in quantitative yield and in up to 98:2 enantiomeric ratio (er) in 5 h. Kinetic resolution or desymmetrization of 1,2-diol can be performed with high efficiency and enantioselectivity as well.
ABSTRACT
BACKGROUND/AIM: Head and neck cancers are the fifth most common cancer type worldwide, affecting more than half a million patients annually. Development of effective therapeutic drugs is, therefore, required for this type of disease. This study assessed the effects of synthetic terrein on head and neck cancer. MATERIALS AND METHODS: Synthetic terrein was prepared by using the modified Altenhach's procedure. The effect of synthetic terrein on cell proliferation of head and neck cancer cells and HUVECs was assessed. Angiogenin secretion and ribosome biogenesis were examined by ELISA and silver staining of the nucleolar organizer region. A mouse xenograft model was prepared by inoculating mice with suspensions of cells of the human head and neck cancer cell line OSC-19 subcutaneously into the dorsal region of each mouse. Ki-67, CD31 and angiogenin expression in xenografted tumors was examined by immunohistochemistry. RESULTS: Synthetic terrein inhibited the growth of various head and neck cancer cells. In addition, an in vivo experiment revealed that synthetic terrein inhibited a xenograft tumor growth in athymic mice. Immunohistochemical analysis revealed that expression of Ki-67, CD31 and ANG was down-regulated in synthetic terrein-treated tumors, compared to controls. Synthetic terrein suppressed the ANG secretion and ribosome biogenesis in cancer cells, and cell proliferation in vascular endothelial cells. CONCLUSION: The mechanism underlying the anti-tumor effects of synthetic terrein against head and neck cancer consists of the inhibition of both tumor cell proliferation and angiogenesis via the suppression of ANG production.
Subject(s)
Antineoplastic Agents/pharmacology , Cyclopentanes/pharmacology , Head and Neck Neoplasms/pathology , Ribonuclease, Pancreatic/antagonists & inhibitors , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Progression , Head and Neck Neoplasms/metabolism , Human Umbilical Vein Endothelial Cells , Humans , Neovascularization, Pathologic/prevention & control , Ribonuclease, Pancreatic/biosynthesisABSTRACT
Chiral N,N-4-(dimethylamino)pyridine (DMAP) derivatives, which can be readily prepared by the Ugi multicomponent reaction in a one-pot manner, have been efficiently applied to the enantioselective Steglich rearrangement of oxindole derivatives to give the desired products bearing a quaternary carbon center in high yield (>98% yield) and with high enantioselectivity (up to 99:1 er).
ABSTRACT
A method for the facile synthesis of ethene-bridged terthiophenes (EBTTs) in two steps has been developed. The first step is a double Sonogashira coupling between 3',4'-dibromo-2,2':5',2â³-terthiophene and terminal alkynes to give dialkynylated terthiophenes, and the second step is a cyclization reaction to afford EBTTs. The fundamental physical properties of EBTTs were also studied.