Yong Sup Lee

Neuroprotective effects of antioxidative flavonoids, quercetin, (+)-dihydroquercetin and quercetin 3-methyl ether, isolated from Opuntia ficus-indica var. saboten.

The flavonoids quercetin, (+)-dihydroquercetin, and quercetin 3-methyl ether were isolated from the ethyl acetate fractions of the fruits and stems of Opuntia ficus-indica var. saboten. In the present study, we evaluated their protective effects against oxidative neuronal injuries induced in primary cultured rat cortical cells and their antioxidant activities by using three different cell-free bioassays. Quercetin was found to inhibit H(2)O(2)- or xanthine (X)/xanthine oxidase (XO)-induced oxidative neuronal cell injury, with an estimated IC(50) of 4-5 micro g/ml. However, it was no more protective at concentrations of 30 micro g/ml and above. (+)-Dihydroquercetin concentration-dependently inhibited oxidative neuronal injuries, but it was less potent than quercetin. On the other hand, quercetin 3-methyl ether potently and dramatically inhibited H(2)O(2)- and X/XO-induced neuronal injuries, with IC(50) values of 0.6 and 0.7 micro g/ml, respectively. All three principles markedly inhibited lipid peroxidation and scavenged 1,1-diphenyl-2-picrylhydrazyl free radicals. In addition, quercetin and quercetin 3-methyl ether were shown to inhibit XO activity in vitro, with respective IC(50) values of 10.67 and 42.01 micro g/ml. These results indicate that quercetin, (+)-dihydroquercetin, and quercetin 3-methyl ether are the active antioxidant principles in the fruits and stems of Opuntia ficus-indica var. saboten exhibiting neuroprotective actions against the oxidative injuries induced in cortical cell cultures. Furthermore, quercetin 3-methyl ether appears to be the most potent neuroprotectant of the three flavonoids isolated from this plant.

Caffeic acid phenethyl ester inhibits nitric oxide synthase gene expression and enzyme activity

Since nitric oxide (NO) synthesized by inducible nitric oxide synthase (iNOS) has been known to be involved in inflammatory and autoimmune-mediated tissue destruction, modulation of NO synthesis or action represents a new approach to the treatment of inflammatory and autoimmune diseases. Caffeic acid phenethyl ester (CAPE), an active component of honeybee propolis, has been identified to show anti-inflammatory, anti-viral and anti-cancer activities. The present study, therefore, examined effects of CAPE on iNOS expression and activity of iNOS enzyme itself. Treatment of RAW 264.7 cells with CAPE significantly inhibited NO production and iNOS protein expression induced by lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma). CAPE also inhibited iNOS mRNA expression and nuclear factor-kappa B (NF-kappaB) binding activity in a concentration-dependent manner. Furthermore, transfection of RAW 264.7 cells with iNOS promoter linked to a chloramphenicol acetyltransferase reporter gene, revealed that CAPE inhibited the iNOS promoter activity induced by LPS plus IFN-gamma through the NF-kappaB sites of the iNOS promoter. In addition, CAPE directly interfered with the catalytic activity of murine recombinant iNOS enzyme. These results suggest that CAPE may exert its anti-inflammatory effect by inhibiting the iNOS gene expression at the transcriptional level through the suppression of NF-kappaB activation, and by directly inhibiting the catalytic activity of iNOS.

Constituents of the stems and fruits of Opuntia ficus-indica var. saboten

From the stems and fruits ofOpuntia ficus-indica var.saboten, eight flavonoids, kaempferol (1), quercetin (2), kaempferol 3-methyl ether (3), quercetin 3-methyl ether (4), narcissin (5), (+)-dihydrokaempferol (aromadendrin,6), (+)-dihydroquercetin (taxifolin,7), eriodictyol (8), and two terpenoids, (6S,9S)-3-oxo-α-ionol-|β-D-glucopyranoside (9) and corchoionoside C (10) were isolated and identified by means of chemical and spectroscopic. Among these isolates, compounds3–5 and8–10 were reported for the first time from the stems and fruits of O.ficusindica var.saboten.

Sulfuretin isolated from heartwood of Rhus verniciflua inhibits LPS-induced inducible nitric oxide synthase, cyclooxygenase-2, and pro-inflammatory cytokines expression via the down-regulation of NF-κB in RAW 264.7 murine macrophage cells

It has been reported that Rhusverniciflua exhibits anti-inflammatory, anti-oxidant and anti-cancer activities. However, little is known about biological activity of sulfuretin, a flavonoid isolated from R.verniciflua. In the present study, we investigated the anti-inflammatory effect and the underlying molecular mechanisms of sulfuretin in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Sulfuretin dose-dependently reduced the productions of nitric oxide (NO), prostaglandin E(2) (PGE(2)), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 beta (IL-1 beta) induced by LPS. Consistent with these findings, sulfuretin significantly suppressed the LPS-induced expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-alpha, and IL-1 beta. In addition, sulfuretin attenuated LPS-induced DNA binding and the transcriptional activities of nuclear factor-kappa B (NF-kappaB), which was accompanied by a parallel reduction of degradation and phosphorylation of inhibitory kappa B-alpha (I kappaB-alpha) and consequently by decreased nuclear translocation of p65 subunit of NF-kappaB. Furthermore, pretreatment with sulfuretin significantly inhibited the LPS-stimulated activation of I kappaB kinase beta (IKK beta). Taken together, these results suggest that the anti-inflammatory effect of sulfuretin in LPS-treated RAW 264.7 macrophages is associated with the suppression of NF-kappaB transcriptional activity via the inhibitory regulation of IKKbeta phosphorylation.

Costunolide Triggers Apoptosis in Human Leukemia U937 Cells by Depleting Intracellular Thiols

We have previously demonstrated that costunolide, a biologically active compound that was isolated from the stem bark of Magnolia sieboldii, induced apoptosis in human cancer cells. In the present study, we investigated the underlying mechanisms and suggest that costunolide induces apoptosis in human promonocytic leukemia U937 cells by depleting the intracellular thiols. Costunolide treatment rapidly depleted the intracellular reduced glutathione (GSH) and protein thiols, and this preceded the occurrence of apoptosis. Pretreatment with sulfhydryl compounds such as GSH, N‐acetyl‐L‐cysteine, dithiothreitol and 2‐mercaptoethanol almost completely blocked the costunolide‐induced apoptosis, highlighting the significance of the intracellular thiol level in the process. Furthermore, overexpression of Bcl‐2 also significantly attenuated the effects of costunolide. The apoptosis‐inducing activity of costunolide is likely to depend on the exomethylene moiety because derivatives in which this group was reduced, such as dihydrocostunolide and saussurea lactone, did not deplete the cellular thiols and showed no apoptotic activity. Taken together, the present study demonstrates that the costunolide‐induced apoptosis depends on intracellular thiols contents, which are modulated by Bcl‐2.

Angiotensin converting enzyme inhibitory phenylpropanoid glycosides from Clerodendron trichotomum.

The stems of Clerodendron trichotomum have been traditionally used for treatment of hypertension in far East Asia including China, Korea, and Japan. Bioassay-guided fractionation and purification of the EtOAc-soluble extract of Clerodendron trichotomum afforded acteoside (1), leucosceptoside A (2), martynoside (3), acteoside isomer (4), and isomartynoside (5). The angiotensin converting enzyme (ACE) activities were significantly inhibited by the addition of these phenylpropanoid glycosides (1-5) in a dose-dependent manner of which IC(50) values were 373+/-9.3 microg/ml, 423+/-18.8 microg/ml, 524+/-28.1 microg/ml, 376+/-15.6 microg/ml, 505+/-26.7 microg/ml, respectively. These results suggest that the antihypertensive effect of Clerodendron trichotomum may be, at least in part, due to ACE inhibitory effect of phenylpropanoid glycosides.

HIV-1 integrase inhibitory phenylpropanoid glycosides from Clerodendron trichotomum.

Seven phenylpropanoid glycosides named acteoside (1), acteoside isomer (2), leucosceptoside A (3), plantainoside C (4), jionoside D (5), martynoside (6), and isomartynoside (7) were isolated from Clerodendron trichotomum. Compounds 1 and 2 showed potent inhibitory activities against HIV-1 integrase with IC50 values of 7.8 +/- 3.6 and 13.7 +/- 6.0 microM, respectively.

New imidazo[2,1-b]thiazole derivatives: Synthesis, in vitro anticancer evaluation, and in silico studies

A series of 18 new imidazo[2,1-b]thiazole derivatives was synthesized. Their in vitro antiproliferative activities against A375P human melanoma cell line and NCI-60 cell line panel were tested. Compounds 15, 16, 18, 22, 26-28, and 31 showed superior potency against A375P to sorafenib. In addition, compounds 26 and 27 showed selectivity toward melanoma cell lines than for other cancer types. Both compounds exerted sub-micromolar IC(50) values over 7 (including A375P) and 6 melanoma cell lines, respectively. In silico studies are also reported. ADME profiling, in silico toxicity, drug-likeness, and drug-score data of compounds 26 and 27 are promising.

A Prenylated Flavonol, Sophoflavescenol: A Potent and Selective Inhibitor of cGMP Phosphodiesterase 5

During the search for naturally occurring cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) inhibitors, it was found that the extracts from Sophora flavescens exhibit potent inhibitory activity against cGMP PDE5 prepared from rat diaphragm. Therefore, the inhibitory activities of five flavonoids, kushenol H (1), kushenol K (2), kurarinol (3), sophoflavescenol (4) and kuraridine (5), isolated from S. flavescens were measured against cGMP PDE5 to identify potent cGMP PDE5 inhibitory constituents. Among tested compounds, sophoflavescenol (4), a C-8 prenylated flavonol, showed the most potent inhibitory activity (IC(50)=0.013 microM) against cGMP PDE5 with 31.5- and 196.2-fold selectivity over PDE3 and PDE4, respectively. Kinetic analysis revealed that sophoflavescenol was a mixed inhibitor of PDE5 with a K(i) value of 0.005 microM.

FORMATION OF PYRAZINOISOQUINOLINE RING SYSTEM BY THE TANDEM AMIDOALKYLATION AND N-ACYLIMINIUM ION CYCLIZATION : AN EFFICIENT SYNTHESIS OF PRAZIQUANTEL

Abstract An efficient synthesis of pyrazinoisoquinoline derivatives including Praziquantel has been accomplished by the tandem amidoalkylaion and N-acyliminium ion cyclization of amido-acetals.