Ho Sik Rho

A Highly Reactive and Enantioselective Bifunctional Organocatalyst for the Methanolytic Desymmetrization of Cyclic Anhydrides : Prevention of Catalyst Aggregation

At present, there is much interest in organocatalysts, as they tend to be less toxic and more environmentally friendly than traditional metal-based catalysts. Although much progress has been made, the development of chiral organocatalysts that are as reactive and stereoselective as some of the best transition-metal catalysts remains a considerable challenge. To attain reasonable reaction rates and stereoselectivity with organocatalysts, a large catalyst loading is often required. One way to address this difficulty is to design bifunctional or multifunctional organocatalysts with functional groups that work cooperatively to stabilize the transition state and accelerate the rate of the reaction. It has been shown that ureaor thiourea-based bifunctional organocatalysts are effective in facilitating a variety of useful organic reactions, including the methanolytic desymmetrization of cyclic anhydrides. However, we showed recently that ureaand thiourea-based organocatalysts can form hydrogen-bonded aggregates, which results in a strong dependence of reactivity and enantioselectivity on concentration and temperature. X-ray crystal structures of monofunctional and bifunctional (thio)urea derivatives show that they form aggregates through hydrogen bonding between the (thio)urea NH groups and the (thio)urea sulfur or oxygen atom in an intermolecular fashion. A recent NMR spectroscopic study also showed that the thiourea IV exists as a dimer, even in solution. Furthermore, thiourea groups tend to degrade under thermal conditions. Herein we present a thermally robust sulfonamide-based bifunctional organocatalyst I (Scheme 1), which shows unprecedented catalytic activity and excellent enantioselectivity in the methanolytic desymmetrization of meso cyclic anhydrides. A detailed mechanistic and computational approach to the design of I resulted in a catalyst that does not self-aggregate to any appreciable extent. To the best of our knowledge, I is the first quinineand sulfonamide-based bifunctional organocatalyst. The quinuclidine group of I may be able to function as a general-base catalyst to activate the nucleophile, and the sulfonamide group may be able to activate the electrophile simultaneously by hydrogen bonding. To investigate the catalytic activity and enantioselectivity of the cinchona-alkaloid-based sulfonamide catalyst I, we examined the asymmetric methanolysis of cis-1,2-cyclohexanedicarboxylic anhydride (1a) in Et2O with various amounts of I at ambient temperature. The results are summarized in Table 1, together with the results obtained with other cinchona-alkaloid-based catalysts (quinine (II), (DHQ)2AQN (III), and the quinine-based thiourea catalyst IV; Scheme 1). The desymmetrization of 1a with I (10 mol%) proceeded surprisingly fast; the reaction was complete within 1 h to Scheme 1. Structures of cinchona-alkaloid-based organocatalysts.

Ginsenoside Rp1, a Ginsenoside Derivative, Blocks Promoter Activation of iNOS and COX-2 Genes by Suppression of an IKKβ-mediated NF-кB Pathway in HEK293 Cells.

Ginsenoside (G) Rp1 is a ginseng saponin derivative with anti-cancer and anti-inflammatory activities. In this study, we examined the mechanism by which G-Rp1 inhibits inflammatory responses of cells. We did this using a strategy in which DNA constructs containing cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) promoters were transfected into HEK293 cells. G-Rp1 strongly inhibited the promoter activities of COX-2 and iNOS; it also inhibited lipopolysaccharide induced upregulation of COX-2 and iNOS mRNA levels in RAW264.7 cells. In HEK293 cells G-Rp1 did not suppress TANK binding kinase 1-, Toll-interleukin-1 receptor-domain-containing adapter-inducing interferon-β (TRIF)-, TRIFrelated adaptor molecule (TRAM)-, or activation of interferon regulatory factor (IRF)-3 and nuclear factor (NF)-кB by the myeloid differentiation primary response gene (MyD88)-induced. However, G-Rp1 strongly suppressed NF-кB activation induced by IкB kinase (IKK)β in HEK293 cells. Consistent with these results, G-Rp1 substantially inhibited IKKβ-induced phosphorylation of IкBɑ and p65. These results suggest that G-Rp1 is a novel anti-inflammatory ginsenoside analog that can be used to treat IKKβ/NF-кB-mediated inflammatory diseases.

Anti-inflammatory activity of AP-SF, a ginsenoside-enriched fraction, from Korean ginseng

Background Korean ginseng is an ethnopharmacologically valuable herbal plant with various biological properties including anticancer, antiatherosclerosis, antidiabetic, and anti-inflammatory activities. Since there is currently no drug or therapeutic remedy derived from Korean ginseng, we developed a ginsenoside-enriched fraction (AP-SF) for prevention of various inflammatory symptoms. Methods The anti-inflammatory efficacy of AP-SF was tested under in vitro inflammatory conditions including nitric oxide (NO) production and inflammatory gene expression. The molecular events of inflammatory responses were explored by immunoblot analysis. Results AP-SF led to a significant suppression of NO production compared with a conventional Korean ginseng saponin fraction, induced by both lipopolysaccharide and zymosan A. Interestingly, AP-SF strongly downregulated the mRNA levels of genes for inducible NO synthase, tumor necrosis factor-α, and cyclooxygenase) without affecting cell viability. In agreement with these observations, AP-SF blocked the nuclear translocation of c-Jun at 2 h and also reduced phosphorylation of p38, c-Jun N-terminal kinase, and TAK-1, all of which are important for c-Jun translocation. Conclusion Our results suggest that AP-SF inhibits activation of c-Jun-dependent inflammatory events. Thus, AP-SF may be useful as a novel anti-inflammatory remedy.

Syk/Src Pathway-Targeted Inhibition of Skin Inflammatory Responses by Carnosic Acid

Carnosic acid (CA) is a diterpene compound exhibiting antioxidative, anticancer, anti-angiogenic, anti-inflammatory, anti-metabolic disorder, and hepatoprotective and neuroprotective activities. In this study, the effect of CA on various skin inflammatory responses and its inhibitory mechanism were examined. CA strongly suppressed the production of IL-6, IL-8, and MCP-1 from keratinocyte HaCaT cells stimulated with sodium lauryl sulfate (SLS) and retinoic acid (RA). In addition, CA blocked the release of nitric oxide (NO), tumor necrosis factor (TNF)-α, and prostaglandin E2 (PGE2) from RAW264.7 cells activated by the toll-like receptor (TLR)-2 ligands, Gram-positive bacterium-derived peptidoglycan (PGN) and pam3CSK, and the TLR4 ligand, Gram-negative bacterium-derived lipopolysaccharide (LPS). CA arrested the growth of dermatitis-inducing Gram-positive and Gram-negative microorganisms such Propionibacterium acnes, Pseudomonas aeruginosa, and Staphylococcus aureus. CA also blocked the nuclear translocation of nuclear factor (NF)-κB and its upstream signaling including Syk/Src, phosphoinositide 3-kinase (PI3K), Akt, inhibitor of κBα (IκBα) kinase (IKK), and IκBα for NF-κB activation. Kinase assays revealed that Syk could be direct enzymatic target of CA in its anti-inflammatory action. Therefore, our data strongly suggest the potential of CA as an anti-inflammatory drug against skin inflammatory responses with Src/NF-κB inhibitory properties.

Kaempferol and Kaempferol Rhamnosides with Depigmenting and Anti-Inflammatory Properties

The objective of this study was to examine the biological activity of kaempferol and its rhamnosides. We isolated kaempferol (1), α-rhamnoisorobin (2), afzelin (3), and kaempferitrin (4) as pure compounds by far-infrared (FIR) irradiation of kenaf (Hibiscus cannabinus L.) leaves. The depigmenting and anti-inflammatory activity of the compounds was evaluated by analyzing their structure-activity relationships. The order of the inhibitory activity with regard to depigmentation and nitric oxide (NO) production was kaempferol (1) > α-rhamnoisorobin (2) > afzelin (3) > kaempferitrin (4). However, α-rhamnoisorobin (2) was more potent than kaempferol (1) in NF-κB-mediated luciferase assays. From these results, we conclude that the 3-hydroxyl group of kaempferol is an important pharmacophore and that additional rhamnose moieties affect the biological activity negatively.

3-(4-(tert-Octyl)phenoxy)propane-1,2-diol suppresses inflammatory responses via inhibition of multiple kinases

Novel anti-inflammatory compounds were synthesised by derivatization of militarin, a compound isolated from Cordyceps militaris that is an ethnopharmacologically well-known herbal medicine with multiple benefits such as anti-cancer, anti-inflammatory, anti-obesity, and anti-diabetic properties. In this study, we explored the in vitro and in vivo anti-inflammatory potencies of these compounds during inflammatory responses, their inhibitory mechanisms, and acute toxicity profiles. To do this, we studied inflammatory conditions using in vitro lipopolysaccharide-treated macrophages and several in vivo inflammatory models such as dextran sodium sulphate (DSS)-induced colitis, EtOH/HCl-induced gastritis, and arachidonic acid-induced ear oedema. Methods used included real-time PCR, immunoblotting analysis, immunoprecipitation, reporter gene assays, and direct kinase assays. Of the tested compounds, compound III showed the highest nitric oxide (NO) inhibitory activity. This compound also inhibited the production of prostaglandin (PG)E(2) at the transcriptional level by suppression of Syk/NF-κB, IKKɛ/IRF-3, and p38/AP-1 pathways in lipopolysaccharide (LPS)-activated RAW264.7 cells and peritoneal macrophages. Consistent with these findings, compound III strongly ameliorated inflammatory symptoms in colitis, gastritis, and ear oedema models. In acute toxicity tests, there were no significant differences in body and organ weights, serum parameters, and stomach lesions between the untreated and compound III-treated mice. Therefore, this compound has the potential to be served as a lead chemical for developing a promising anti-inflammatory drug candidate with multiple kinase targets.

Kojyl thioether derivatives having both tyrosinase inhibitory and anti-inflammatory properties

This study was conducted to examine the tyrosinase inhibitory and anti-inflammatory activities of kojic acid derivatives. A series of kojic acid derivatives containing thioether, sulfoxide, and sulfone linkages were synthesized. In the tyrosinase assay, kojyl thioether derivatives containing appropriate lipophilic alkyl chains (pentane, hexane, and cyclohexane) showed potent inhibitory activity. However, sulfoxides and sulfones exhibited decreased activity. Similar experimental results were obtained with inhibitory activities of NO production being induced by LPS. The presence of thioether linkage and appropriated lipophilic acid moiety was critical for the tyrosinase inhibitory and anti-inflammatory activities.

Inhibitory activity of novel kojic acid derivative containing trolox moiety on melanogenesis.

A novel kojic acid derivative containing a trolox moiety, (±)-5-hydroxy-4-oxo-4H-pyran-2-yl methyl 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylate (3a), was synthesized. The two biologically active compounds, namely, kojic acid and trolox, were conjugated via an ester bond as they are expected to behave synergistically. The antioxidant activity and the tyrosinase inhibitory activity of this novel kojic acid derivative on melanogenesis were evaluated. Compound 3a exhibited potent tyrosinase inhibitory activity and radical scavenging activity. Limited structure-activity relationship (SAR) investigations indicated that the tyrosinase inhibitory activities may originate from the kojic acid moiety, and the radical scavenging activity may be due to the phenolic hydroxyl group of trolox. Compound 3a also exhibited potent depigmenting activity in a cell-based assay. The limited SAR investigations revealed that the depigmenting activity of 3a may be due to the synergistic activities of kojic acid and its trolox moiety.

Studies on depigmenting activities of dihydroxyl benzamide derivatives containing adamantane moiety.

Six diphenolic compounds containing adamantane moiety were synthesized and evaluated as potent inhibitors on tyrosinase activity and melanin formation in Melan-A cells. The inhibitory activity of 4-adamantyl resorcinol 1 was similar to that of 4-n-butyl resorcinol in both assays. However, dihydroxyl benzamide derivatives 6a-e showed different inhibitory patterns. All derivatives significantly suppressed the cellular melanin formation without tyrosinase inhibitory activities. These behaviors indicated that the introduction of amide bond changes the binding mode of dihydroxyl groups to tyrosinase. Among derivatives, 6d (3,4-dihydroxyl compound) and 6e (2,3-dihydroxyl compound) showed stronger inhibitory activities (IC(50)=1.25 microM and 0.73 microM, respectively) as compared to 4-n-butyl resorcinol (IC(50)=21.64 microM) and hydroquinone (IC(50)=3.97 microM). This study showed that the position of dihydroxyl substituent at aromatic ring is important for the intercellular inhibition of melanin formation, and also amide linkage and adamantane moiety enhance the inhibition.

Radical Scavenging Activity-Based and AP-1-Targeted Anti-Inflammatory Effects of Lutein in Macrophage-Like and Skin Keratinocytic Cells

Lutein is a naturally occurring carotenoid with antioxidative, antitumorigenic, antiangiogenic, photoprotective, hepatoprotective, and neuroprotective properties. Although the anti-inflammatory effects of lutein have previously been described, the mechanism of its anti-inflammatory action has not been fully elucidated. Therefore, in the present study, we aimed to investigate the regulatory activity of lutein in the inflammatory responses of skin-derived keratinocytes or macrophages and to elucidate the mechanism of its inhibitory action. Lutein significantly reduced several skin inflammatory responses, including increased expression of interleukin-(IL-) 6 from LPS-treated macrophages, upregulation of cyclooxygenase-(COX-) 2 from interferon-γ/tumor necrosis-factor-(TNF-) α-treated HaCaT cells, and the enhancement of matrix-metallopeptidase-(MMP-) 9 level in UV-irradiated keratinocytes. By evaluating the intracellular signaling pathway and the nuclear transcription factor levels, we determined that lutein inhibited the activation of redox-sensitive AP-1 pathway by suppressing the activation of p38 and c-Jun-N-terminal kinase (JNK). Evaluation of the radical and ROS scavenging activities further revealed that lutein was able to act as a strong anti-oxidant. Taken together, our findings strongly suggest that lutein-mediated AP-1 suppression and anti-inflammatory activity are the result of its strong antioxidative and p38/JNK inhibitory activities. These findings can be applied for the preparation of anti-inflammatory and cosmetic remedies for inflammatory diseases of the skin.