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Isolation of Betulinic Acid, its Methyl Ester and Guaiane Sesquiterpenoids with Protein Tyrosine Phosphatase 1B Inhibitory Activity from the Roots of Saussurea lappa C.B.Clarke

Activity-guided fractionation of a MeOH extract of the roots of Saussurea lappa C.B.Clarke (Compositae), using an in vitro protein tyrosine phosphatase 1B (PTP1B) inhibition assay, led to the isolation of four active constituents: betulinic acid (1), betulinic acid methyl ester (2), mokko lactone (3) and dehydrocostuslactone (4), along with nine inactive compounds. Our findings indicate that betulinic acid (1) and its methyl ester 2, as well as the two guaiane sesquiterpenoids 3 and 4 are potential lead moieties for the development of new PTP1B inhibitors.

Lanostane triterpenes from the fruiting bodies of Ganoderma lucidum and their inhibitory effects on adipocyte differentiation in 3T3-L1 Cells.

Four new lanostane triterpenes, butyl ganoderate A (1), butyl ganoderate B (2), butyl lucidenate N (3), and butyl lucidenate A (4), were isolated from the fruiting bodies of Ganoderma lucidum together with 14 known compounds (5-18). The structures of the new triterpenes were established by extensive spectroscopic studies and chemical evidence. In addition, the inhibitory effect of isolated compounds on adipocyte differentiation in 3T3-L1 cells was examined.

Acetylcholinesterase inhibitory effect of lignans isolated from Schizandra chinensis.

The hexane extract of the fruit ofSchizandra chinensis (Schisandraceae) was found to show significant inhibition of the activity of acetylcholinesterase enzyme (AChE). In further studies, fourteen lignans were isolated, and evaluated for their inhibitory effect on AChE. The compounds having both aromatic methylenedioxy and hydroxyl groups on their cyclooctadiene ring, such as gomisin C (6), gomisin G. (7), gomisin D (8), schisandrol B (11) and gomisin A (13), entirely inhibited AChE in dose dependent manners, with IC50 values of 6.71 ± 0.53, 6.55 ± 0.31, 7.84 ± 0.62, 12.57 ± 1.07 and 13.28 ± 1.68 ¼M, respectively. These results indicate that the lignans could potentially be a potent class of AChE inhibitors.

Triterpenoids and diarylheptanoids from Alnus hirsuta inhibit HIF-1 in AGS cells.

Bioassay-guided fractionation and purification of the EtOAc soluble fraction from the MeOH extract of the stem bark of Alnus hirsuta (Betulaceae), using an in vitro HIF-1 assay, led to the isolation of four triterpenoids (1–4) and six diarylheptanoids (5–10). Their structures were determined by comparison with the physicochemical and spectroscopic data in the literature. These compounds were investigated for their effects on the hypoxia-induced HIF-1 activation using an HIF-1 a mediated reporter gene assay in AGS cells. Among them, two diarylheptanoids, 2-oxatrycyclo[13.2.2.13,7]eicosa-3,5,7(20),15,17,18-hexaen-10-16-diol (6) and 2-oxatrycyclo [13.2.2.13,7]eicosa-3,5,7-(20), 15, 17, 18-hexaen-10-one (7), inhibited HIF-1 activation dose-dependently with IC50 values of 11.2 μM and 12.3 μM, respectively. These two compounds had no significant cytotoxicity to the AGS cells at the effective concentration for the inhibition of HIF-1 activation.

Isoprenylated flavonoids from the stem bark of Erythrina abyssinica

Three new prenylated flavanones, abyssinoflavanones V, VI, and VII (1-3), together with eight known flavanones (4-11) and two chalcones (12-13), were isolated from the stem bark of Erythrina abyssinica. Their structures were elucidated on the basis of spectroscopic and physicochemical analyses. All the isolates, with the exception of 1 and 8, strongly inhibited PTP1B activity in an in vitro assay with IC50 values ranging from 14.2 +/- 1.7 to 26.7 +/- 1.2 microM.

PTP1B inhibitory activity of kaurane diterpenes isolated from Siegesbeckia glabrescens

Protein tyrosine phosphatase 1B (PTP1B) is considered as a therapeutic target for the treatment of diabetes and obesity. In our preliminary screening study, a MeOH extract of the aerial part of Siegesbeckia glabrescens was found to inhibit PTP1B activity at 30 μg/mL. Bioassay‐guided fractionation led to the isolation of two active diterpenes, ent-16βH,17-isobutyryloxy-kauran-19-oic acid (1) and ent-16βH,17-acetoxy-18-isobutyryloxy-kauran-19-oic acid (2), along with ent-16βH,17-hydroxy-kauran-19-oic acid (3). Compounds 1 and 2 inhibited the PTP1B activity with IC50 values of 8.7 ± 0.9 and 30.6 ± 2.1 μM, respectively. Kinetic studies suggest that both 1 and 2 are non-competitive inhibitors of PTP1B. However, compound 3 substituted with a hydroxyl group at C-17 in kaurane-type showed no inhibitory effects towards PTP1B.

Flavonoids and Isoflavonoids from Sophorae Flos Improve Glucose Uptake in Vitro

Glucose uptake assay-guided fractionations on the methanol extract of Sophorae Flos led to the isolation of the flavonoids rutin (1), narcissin (2), quercetin (3), tamarixetin (4), and kaempferol (5) and the isoflavonoids cajanin (6), genistein (7), orobol (8), and pratensein (9). Among them, 1, 4, 5, 6, 8, and 9 significantly improved basal glucose uptake in HepG2 cells. Their improving effects were concentration dependent. Compounds 4, 5, 6, and 9 exhibited effects stronger than that of rosiglitazone, which has been used as an antidiabetic drug. However, 2, 3, and 7 did not show any improving effects. Stimulating glucose uptake into peripheral cells may be responsible for reducing the level of blood glucose in the circulation. Therefore, these findings demonstrate a potential to develop these flavonoids and isoflavonoids as hypoglycemic drugs.

Kahalalides V–Y Isolated from a Hawaiian Collection of the Sacoglossan Mollusk Elysia rufescens

Four new kahalalides, V (1), W (2), X (3), and Y (4), as well as six previously characterized kahalalides have been isolated from a two-year collection of the sacoglossan mollusk Elysia rufescens. Curiously, kahalalide B, previously isolated in high yield from E. rufescens, was found to be essentially absent from these collections despite identical collection sites and times with previous collections. In addition, kahalalide K, which to date has only been reported from Bryopsis sp., was found in this collection of E. rufescens, suggesting that the production of these metabolites could potentially be from a microbial association with the mollusk and algae, and this relationship is continuously evolving in response to changes in the environment and predation. The structures of new peptides have been established on the basis of extensive 1D and 2D NMR spectroscopic data analysis. Kahalalide V (1) was ascertained to be an acyclic derivative of kahalalide D (5), while kahalalide W (2) was determined to have a 4-hydroxy-L-proline residue instead of the proline in 5. The arginine residue of kahalalide X (3), an acyclic derivative of kahalalide C, was determined to have an L configuration. Kahalalide Y (4) was found to have an L-proline residue instead of the hydroxyproline in kahalalide K. It is clear from this collection of E. rufescens that the discovery of new kahalalide-related metabolites is still highly feasible.

Effect of Lanostane Triterpenes from the Fruiting Bodies of Ganoderma lucidum on Adipocyte Differentiation in 3T3-L1 Cells

Two new lanostane triterpenes, methyl lucidenate N ( 1) and T-butyl lucidenate B ( 2), were isolated from the fruiting bodies of GANODERMA LUCIDUM together with five known compounds ( 3- 7). The structures of the two new triterpenes were established as methyl 3 β,7 β-dihydroxy-4,4,14 α-trimethyl-11,15-dioxo-5 α-chol-8-en-24-oate ( 1) and T-butyl 7 β,12 β-dihydroxy-4,4,14 α-trimethyl-3,11,15-trioxo-5 α-chol-8-en-24-oate ( 2) by extensive spectroscopic studies and chemical evidence. The effect of the isolated compounds ( 1- 7) on triglyceride (TG) accumulation, an indicator of adipocyte differentiation, during the differentiation of 3T3-L1 preadipocytes was examined. T-Butyl lucidenate B ( 2) reduced the TG accumulation significantly by 72 % at 80 µM compared to the untreated group. Furthermore, compound 2 effectively suppressed the GPDH activity in the cells. Consistent with the decrease in TG accumulation and GPDH activity, compound 2 suppressed the gene expressions of PPAR γ, C/EBP α, and SREBP-1c in a dose-dependent manner during differentiation. Our findings demonstrate that the lanostane triterpenes isolated in this study contribute to the inhibitory effect of the fruiting bodies of G. LUCIDUM on adipocyte differentiation in 3T3-L1 cells.

Pentacyclic Triterpenoids from Astilbe rivularis that Enhance Glucose Uptake via the Activation of Akt and Erk1/2 in C2C12 Myotubes.

Glucose uptake into insulin-sensitive tissues is important for the regulation of blood glucose. This study has investigated whether the pentacyclic triterpenoids substituted with a carboxylic acid at the C-27 position isolated from Astilbe rivularis can enhance glucose uptake and subsequently to also examine their underlying molecular mechanisms. The structure of the new pentacyclic triterpenoid 1 was assigned by spectroscopic data interpretation. To evaluate the activity of compounds 1 and 2, glucose uptake and glucose transporter 4 (GLUT4) translocation were measured in C2C12 myotubes. The C-27-carboxylated triterpenoids 1 and 2 significantly increased basal and insulin-stimulated glucose uptake and GLUT4 translocation to plasma membrane. Both compounds stimulated the phosphorylation of insulin receptor substrate-1 (IRS-1), protein kinase B (Akt), and extracellular signal-regulated kinase 1/2 (Erk1/2). Pretreatment with the Akt inhibitor triciribine or the Erk1/2 inhibitor U0126 decreased the ability of both compounds to enhance basal- and insulin-stimulated glucose uptake and stimulate GLUT4 translocation. These results indicate that compounds 1 and 2 activated both the IRS-1/Akt and Erk1/2 pathways and subsequently stimulated GLUT4 translocation, leading to enhanced glucose uptake. Thus, these observations suggest that C-27-carboxylated-pentacyclic triterpenoids may serve as scaffolds for development as agents for the management of blood glucose levels in disease states such as diabetes.