Yong Nam Han

Antinociceptive and anti-rheumatoidal effects of Kalopanax pictus extract and its saponin components in experimental animals

In the present study, we have attempted to elucidate the active components for rheumatoidal arthritis using chloroform (CHCl(3)), ethylacetate (EtOAc) and n-butanol (BuOH) fractions of the methanol extract (MeOH) of Kalopanax pictus. Kalopanaxsaponin-A and -I (KPS-A and -I, hederagenin monodesmoside) were isolated from EtOAc fraction and kalopanaxsaponin-B, -H and -K (KPS-B, -H and -K, hederagenin bisdesmosides) obtained from BuOH fraction, respectively. MeOH extract, EtOAc fraction (250, 500 mg/kg, p.o.) and KPS-A and -I (5, 10, 20 mg/kg, i.p.) exhibited significant antinociceptive effects, which were determined by acetic acid-induced writhing test and hot plate test. On Freunds complete adjuvant reagent-induced rheumatoidal arthritis in rats, the administration of EtOAc fraction and KPS-A and -I inhibited edema, agglutination, vascular permeability and trypsin inhibitor. In addition, LD(50) of the MeOH extract was shown to be 4.033 mg/kg. These results suggest that anti-rheumatoidal effects of KPS-A and -I contribute to the inhibition of kinin formation by suppression of trypsin inhibitor activity.

Tissue factor inhibitory flavonoids from the fruits ofChaenomeles sinensis

Tissue factor (TF, tissue thromboplastin or coagulation factor III) accelerates the blood clotting, activating both the intrinsic and the extrinsic pathways to serve as a cofactor. In order to isolate TF inhibitors from the fruits ofChaenomeles sinensis, an activity-guided purification utilizing a bio-assay method of prothrombin time prolongation, was carried out to yield five active flavoniods such as hovetrichoside C (1) (IC50 = 14.0 μg), luteolin-7-O-β-D-glucuronide (3) (IC50 = 31.9 μg), hyperin (4) (IC50 = 20.8 μg), avicularin (6) (IC50 = 54.8 μg) and quercitrin (10) (IC50 = 135.7 μg), along with other inactive compounds such as (±)-(2E,4E)-O-α-D-glucopyranosyl-4′-hydroxy-β-ionylideneacetic acid ester (2), genistein-7-O-β-D-glucopyranoside (5), luteolin-3′-methoxy-4′-O-β-D-glucopyranoside (7), luteolin-7-O-β-D-glucuronide methyl ester (8), tricetin-3′-methoxy-4′-O-p-D-glucopyranoside (selagin-4′-O-β-D-glucopyranoside) (9), (-)-epicatechin (11), luteolin-4′-O-β-D-glucopyranoside (12) and apigenin-7-O-β-D-glucuronide methyl ester (13). The structures of the isolated compounds were elucidated through spectral analysis. Among them, compounds1 to9,12 and13 were isolated for the first time from the fruits of this plant and the compound9 is a new flavonoid.

Apoptosis-inducing Costunolide and a novel acyclic monoterpene from the stem bark ofMagnolia sieboldii

In a course of obtaining more amount of bioactive costunolide and successive phytochemical isolation fromMagnolia sieboldii (Magnoliaceae), a novel acyclic monoterpene 1 named deoxygeraniol (2,6(E)-dimethyl-2, 6-octadiene) was isolated along with β-sitosterol 3-O-linoleate (2), trilinolein (3) and high amount of costunolide (4) in the pure state. The structure of compound1 was determined on the basis of spectroscopic data. Costunolide was found to induce apoptotic cell death in a dose-dependent manner by nucleosomal DNA ladder and flow cytometric analysis. Immunoblot analysis showed that the level of the anti-apoptotic protein, Bcl-2, was decreased, whereas the cleavage of poly-(ADP-ribose) polymerase was activated. Furthermore, the N-acetyl-L-cysteine antioxidant effectively prevented costunolide-induced cytotoxicity. These results suggest that costunolide-induced cell death is mediated by reactive oxygen species Received March 20, 2001

Yomogin, an inhibitor of nitric oxide production in LPS-activated macrophages.

In activated macrophages the inducible form of nitric oxide synthase (i-NOS) generates high amounts of toxic mediator, nitric oxide (NO) which contributes to the circulatory failure associated with septic shock. A sesquiterpene lactone compound (yomogin) isolated from medicinal plantArtemisia princeps Pampan inhibited the production of NO in LPS-activated RAW 264.7 cells by suppressing i-NOS enzyme expression. Thus, yomogin may be a useful candidate for the development of new drugs to treat endotoxemia and inflammation accompanied by the overproduction of NO.

Monoamine oxidase B inhibitors from the fruits ofOpuntia ficus-indica var.saboten

Three varieties of methyl citrate and 1-methyl malate were isolated from the fruits ofOpuntia ficus-indica var.saboten Makino throughin vitro bioassay-guided isolation for the inhibition on monoamine oxidase(MAO). The IC50 values for MAO-B of 1-monomethyl citrate, 1,3-dimethyl citrate, trimethyl citrate and 1-methyl malate were 0.19, 0.23, 0.61 and 0.25 mM, respectively. However, on MAO-A, their inhibitions showed only marginal activity.

Tissue factor inhibitory sesquiterpene glycoside from Eriobotrya japonica.

Tissue factor (TF, tissue thromboplastin) is a membrane bound glycoprotein, which accelerates the blood clotting, activating both the intrinsic and the extrinsic pathways to serve as a cofactor for activated factor VII (Vlla). The TF-factor Vlla complex (TF/Vlla) proteolytically activates factors IX and X, which leads to the generation of thrombin and fibrin clots. In order to isolate TF inhibitors, by means of a bioassay-directed chromatographic separation technique, from the leaves ofEriobotrya japonica Lindley (Rosaceae), a known sesquiterpene glycoside (2) and ferulic acid (3) were isolated as inhibitors that were evaluated using a single-clotting assay method for determining TF activity. Another sesquiterpene glycoside (1) was also isolated but was inactive in the assay system. Compound3 was yielded by alkaline hydrolysis of compound2. The structures of compounds1, 2, and3 were identified by means of spectral analysis as 3-O-α-L-rhamnopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→6)]-β-D-glucopyranosyl nerolidol (1), 3-O-α-L-rhamnopyranosyl-(1→4)-α-L-rhamnopyr-anosyl-(1→2)-[α-L-(4-trans-feruloyl)-rhamnopyranosyl-(1→6)]-β-D-glucopyranosyl nerolidol (2) and ferulic acid (3), respectively. Compounds2 and3 inhibited 50% of the TF activity at concentrations of 2 and 369 μM/TF units, respectively.

Inhibition of calmodulin-dependent Calcium-ATPase and phosphodiesterase by various cyclopeptides and peptide alkaloids from the zizyphus species

The effects of various sedative cyclopeptides and peptide alkaloids from the Zizyphus species on calmodulin-dependent Ca2+-ATPase and phosphodiesterase were investigated. Calmodulin-induced activation of Ca2+-ATPase was strongly inhibited by sanjoinine-A dialdehyde (IC50, 2.3 μM), -Ah1 (IC50, 4.0 μM), -A (IC50, 4.6 μM), and -G2 (IC50, 7.2 μM), while calmodulin-induced activation of phosphodiesterase was strongly inhibited by both deachuine S10 (IC50, 4.9 μM) and sanjoinine-D (IC50, 9.0 μM). The inhibitory activity of the various cyclopeptides and peptide alkaloids on Ca2+-ATPase was found to correlate well with their sedative activity.

Inhibition of calmodulin-dependent protein kinase II by cyclic and linear peptide alkaloids fromZizyphus species

The effects of sedative peptide alkaloids fromZizyphus species on calmodulin-dependent protein kinase II were investigated. Protein kinase II activity was assayed on the basis of its ability to activate tryptophan 5-monooxygenase as its substrate in the presence of calmodulin. All thirteen alkaloids tested were stronger inhibitors than chlorpromazine (IC50, 98 μM) on calmodulin-dependent protein kinase II. Among them, the most potent inhibitor was daechuine S27 (IC50 2.95 μM), which was stronger than pimozide (IC50 15.0 μM).

Anti-lipid peroxidative principles from the stem bark ofKalopanax pictus Nakai

Hepatic lipid peroxide contents were examined in bromobenzene-treated rats firstly after the oral administration of MeOH extract ofKalopanax pictus stem bark, its n-BuOH fraction, EtOAc fraction and an alkaline hydrolysate of the n-BuOH fraction, and secondly after the intraperitoneal administration of hederagenin monodesmosides and bisdesmosides. Two hederagenin monodesmosides, kalopanaxsaponin A (KPS-A) and sapindoside C, exhibited significant anti-lipid peroxidation effects after intraperitoneal administration at doses of 10-30 μmole/kg, whereas their bisdesmosides did not exhibit any significant activity. These results suggest that it is the hederagenin monodesmosides that are responsible for anti-lipid peroxidationin vivo. The activity of KPS-A was established by the observation of decreased aminopyrine N-demethylase activity and increased epoxide hydrolase activity.

3-Amino-1,2-benzisoxazoles: A new family of potent inhibitors of LTB4 binding to the human neutrophils

Abstract A new family of 3-amino-1,2-benzisoxazoles was designed and synthesized to be a potent inhibitors of LTB4 binding to the human neutrophils. HS-1141 appears to be one of the strongest inhibitors of LTB4 binding reported so far (IC50=7nM).