Sang-Hun Jung

Inhibitory action of novel aromatic diamine compound on lipopolysaccharide-induced nuclear translocation of NF-κB without affecting IκB degradation

4‐Methyl‐N 1‐(3‐phenyl‐propyl)‐benzene‐1,2‐diamine (JSH‐23) is a novel chemically synthetic compound. The aromatic diamine JSH‐23 compound exhibited inhibitory effect with an IC50 value of 7.1 μM on nuclear factor (NF)‐κB transcriptional activity in lipopolysaccharide (LPS)‐stimulated macrophages RAW 264.7, and interfered LPS‐induced nuclear translocation of NF‐κB without affecting IκB degradation. This mechanism of action is very rare for controlling NF‐κB activation. Furthermore, the compound inhibited not only LPS‐induced expressions of tumor necrosis factor‐α, interleukin (IL)‐1β, IL‐6 and inducible nitric oxide synthase and cyclooxygenase‐2 but also LPS‐induced apoptosis of the RAW 264.7 cells.

Structural requirement of isoflavonones for the inhibitory activity of interleukin-5.

Sophoricoside isolated from Sophora japonica is a glycoside of isoflavonone as an inhibitor of interleukin (IL)-5. To identify structural requirements of this isoflavonone for its inhibitory activity against IL-5, isoflavonones, isoflavanones, and their glycosides were prepared and their inhibitory activity was tested against IL-5. Among them, 5-benzyloxy-3-(4-hydroxyphenyl)chromen-4-one (4b, 87.9% inhibition at 50 microM, IC(50)=15.3 microM) shows the most potent activity, comparable with that of sophoricoside. The important structural requirements of these isoflavonone analogs exhibiting the inhibitory activity against IL-5 were recognized as (1) planarity of chromen-4-one ring, (2) existence of phenolic hydroxyl at 4-position of B ring, and (3) introduction of benzyloxy at 5-position, which may act as a bulky group for occupying hydrophobic pocket in putative binding site. However the glucopyranosyl moiety of sophoricoside is not an essential motif for the activity.

A novel stereo-selective sulfonylurea, 1-[1-(4-aminobenzoyl)-2,3-dihydro-1H-indol-6-sulfonyl]-4-phenyl-imidazolidin-2-one, has antitumor efficacy in in vitro and in vivo tumor models.

The antitumor activities of novel 1-[1-(4-aminobenzoyl)-2,3-dihydro-1H-indol-6-sulfonyl]-4-phenyl-imidazolidin-2-ones were studied to determine the potential of these compounds as antitumor candidates. The agents studied were: DW2143 (1-[1-(4-aminobenzoyl)-2,3-dihydro-1H-indol-6-sulfonyl]-4-phenyl-imidazolidin-2-one), a racemic mixture, and DW2282 [(4S)-1-[1-(4-aminobenzoyl)-2,3-dihydro-1H-indol-6-sulfonyl]-4-phenyl-imidazolidin-2-one], an S-isomer. DW2143 and DW2282 suppressed the in vitro growth of tumor cells at lower concentrations than doxorubicin, but tumor specificity was not observed between the compounds. These compounds when administered orally were not active in syngeneic models of murine Colon 26 adenocarcinoma and L1210 leukemia. However, DW2143 suppressed the growth of SW620 (human colon cancer) and NCI-H23 (human lung cancer) cells in nude mice, inhibiting tumor growth by 87 and 67%, respectively. DW2282 was a more potent inhibitor of SW620 tumor cell growth in nude mice and was also lower in toxicity than DW2143. Moreover, DW2282 did not produce a series of toxic symptoms caused by the aniline metabolites of sulfonylureas, including hypoglycemia. These results suggest that DW2282, an S-isomer, could be a novel antitumor candidate with higher specificity and lower toxicity than other orally active sulfonylureas.

SYNTHESIS AND EVALUATION OF CYTOTOXIC ACTIVITY OF NOVEL ARYLSULFONYLIMIDAZOLIDINONES

Abstract Synthesis of novel arylsulfonylimidazolidinones 3 and 4 containing sulfonylurea pharmacophore and evaluation of their in vitro cytotoxicity against human cell lines were investigated. As a result, a series of 4-phenyl-1(N)-arylsulfonylimidazolidinones have been found to be the potential anticancer agent.

Enantioselective stabilization of inclusion complexes of metoprolol in carboxymethylated β-cyclodextrin

The inclusion complexes of metoprolol (MT) and carboxymethyl-beta-cyclodextrin (CMCD) were prepared and the stability constants of the complexes were determined. Binding studies performed using high performance liquid chromatography (HPLC), UV spectrometry and capillary electrophoresis (CE) indicated that a complex with 1:1 stoichiometry is predominant in the solution. The enantiomers of MT possess relatively high affinity towards CMCD with stability constants of 288 and 262 per M for (R)- and (S)-MT, respectively. Through nuclear magnetic resonance (NMR) analysis, MT was predicted to be a bent structure with phenyl ring of MT inserted in the shielding cavity of CMCD during complex formation. The NMR data suggested that the chiral side chain and the methoxyethyl moiety of MT are aligned in the deshielding zone, above and below the CMCD torus ring.

Design and synthesis of novel 2-(indol-5-yl)thiazole derivatives as xanthine oxidase inhibitors

Xanthine oxidase (XO) inhibitors have been widely used for the treatment of gout. Indole rings are frequently used as active scaffold in designing inhibitors for enzymes. Herein, we describe the structure-activity relationship for novel xanthine oxidase inhibitors based on indole scaffold. A series of novel tri-substituted 2-(indol-5-yl)thiazole derivatives were synthesized, and their in vitro inhibitory activities against xanthine oxidase and in vivo efficacy lowering uric acid level in blood were measured. Among them, 2-(3-cyano-2-isopropylindol-5-yl)-4-methylthiazole-5-carboxylic acid exhibits the most potent XO inhibitory activity (IC50 value: 3.5nM) and the excellent plasma uric acid lowering activity. Study of structure activity relationship indicated that hydrophobic moiety (e.g., isopropyl) at 1-position and electron withdrawing group (e.g., CN) at 3-position of indole ring and small hydrophobic group (CH3) at 4-position of the thiazole ring enhanced the XO inhibitory activity. Hydrophobic substitution such as isopropyl at 1-position of the indole moiety without any substitution at 2-position has an essential role for enhancing bioavailability and therefore for high in vivo efficacy.

Anti-inflammatory mode of isoflavone glycoside sophoricoside by inhibition of interleukin-6 and cyclooxygenase-2 in inflammatory response.

Soy, high dietary intake for the oriental population, is a main source of isoflavonoids. Sophoricoside (SOP) an isoflavone glycoside was isolated from immature fruits ofSophora japonica (Leguminosae family) and its inhibitory effect on chemical mediators involved in inflammatory response was investigated in this study. SOP inhibited the interleukin (IL)-6 bioactivity with an IC50 value of 6.1 μM whereas it had no effects on IL-1(3 and TNF-α bioactivities. SOP was identified as a selective inhibitor of cyclooxygenase (COX)-2 activity with an IC50 value of 4.4 μM, but did not show inhibitory effect on the synthesis of COX-2. However, SOP had no effect on the production of reactive oxygen species including superoxide anions and nitric oxide. These results revealed thatin vitro anti-inflammatory action of SOP is significantly different from that of genistein known as a phytoestrogen of soy products. This experimental study has documented an importance of dietary soy isoflavonoids as multifunctional agents beneficial to human health, and will help to clarify protective mechanisms of SOP against inflammatory con-ditions.

Differential regulation of interleukin-12 and tumour necrosis factor-α by phosphatidylinositol 3-kinase and ERK 1/2 pathways during Mycobacterium tuberculosis infection

Interleukin (IL)‐12 and tumour necrosis factor (TNF)‐α are both thought to be critical factors in the defence against mycobacteria but are known to play different roles. In this study, we investigated the regulatory pathways for IL‐12 and TNF‐α expression in human monocyte‐derived macrophages (MDMs) after treatment with Mycobacterium tuberculosis H37Rv or the Triton X‐100 solubilized proteins (TSP) purified from M. tuberculosis. We found a rapid phosphorylation of Akt and extracellular signal‐regulated kinase (ERK), albeit with differential activation kinetics, in human MDMs treated with M. tuberculosis or TSP. Studies using inhibitors selective for phosphatidylinositol 3‐kinase (PI 3‐K) and ERK 1/2 show that both pathway plays an essential role in the induction of TNF‐α at both the transcriptional and translational levels in human MDMs. In contrast, blockade of the PI 3‐K/Akt or ERK 1/2 pathways significantly increased M. tuberculosis‐ or TSP‐induced IL‐12 p40 and p35 mRNA and bioactive p70 protein. The enhancement of IL‐12 levels by inhibition of PI 3‐K and ERK 1/2 was not reversed by neutralization of TNF‐α or addition of rhTNF‐α, suggesting that the negative regulation of IL‐12 is not mediated by concomitant TNF‐α suppression. Further, PI 3‐K activity is required for the M. tuberculosis‐ or TSP‐induced phosphorylation of ERK 1/2 activation. TSP from M. tuberculosis shows a similar dependency on the PI 3‐K and ERK 1/2 pathways to those by M. tuberculosis. Collectively, these data suggest that the Th1‐driving cytokine IL‐12 and proinflammatory cytokine TNF‐α are differentially regulated by PI 3‐K and ERK 1/2 pathways in human MDMs during mycobacterial infection. These results may provide therapeutic targets for precise and specific fine‐tuning of cytokine responses.

Enantioselective Preparation of Metoprolol and Its Major Metabolites

To obtain the standard compounds of metoprolol for a pharmacokinetic study, a convenient synthetic procedure to prepare enantiomers of metoprolol (3a) and its major metaboites, 2-4-(2-hydroxy-3-isopropylamino)propoxyphenylethanol (3b) and 4-(2-hydroxy-3-isopropylamino) pro-poxyphenylacetic acid (4), was developed from their respective starting materials, 4-(2-methoxyethyl)phenol (1a), 4-(2-hydroxyethyl)phenol (1b) and methyl 4-hydroxyphenylacetate (1c). These phenolic compounds (1a, b, c) were convertedin situ to their corresponding phenoxides with sodium hydroxide treatment followed by (R)- or (S)-epichlorohydrin treatment. The resulting epoxides2 were transformed to3 through reaction with isopropylamine. Ester3c was hydrolyzed to the metabolite4. Measured using the HPLC method on chiral column without any derivatization, the optical purity of enantiomers of metoprolol and o-demethylated metabolite3b ranged between 96–99% ee and that of enantiomers of carboxylic acid metabolite4 ranged 91% ee.

Synthesis and Evaluation of Cytotoxicity of Novel Arylsulfonylimidazolidinones Containing Sulfonylurea Pharmacophore

Design and synthesis of novel 4-phenyl-1-arylsulfonylimidazolones3 and 4-phenyl-3-arylsulfonylimidazolones4 and evaluation of their cytotoxic activity against eleven human cancer cell lines and two murine leukemia cell linesin vitro were performed. As a result, a series of 4-phenyl-1(N)-arylsulfonylimidazolones (3) has been found to be the potential anticancer agent. Compounds3b, 3c, and3d exhibit strong activity as indicated by their IC50 values 0.39, 3.19, 0.31 μg/mL against A549 and 0.80, 0.48, 0.0007 μg/mL against SK-Mel-2, respectively. These compounds also possess much more potent activity (10–1000 times) than LY186641 against eleven other cell lines.