Bisindole alkaloids from Voacanga grandifolia leaves.

Two new bisindole alkaloids, 12'-O-demethyl-vobtusine-5-lactam and isovobtusine-N-oxide (1 and 2), were isolated from the leaves of Voacanga grandifolia, together with two known bisindole alkaloids. Their structures were elucidated on the basis of 1D and 2D NMR data. 1 and 2 showed potent antimalarial activity against Plasmodium falciparum 3D7 and very low cytotoxic activity against a human cell line, HepG2 cells.

Antiviral activities of Indonesian medicinal plants in the East Java region against hepatitis C virus.

BACKGROUND: Hepatitis C virus (HCV) is a major cause of liver disease and a potential cause of substantial morbidity and mortality worldwide. The overall prevalence of HCV infection is 2%, representing 120 million people worldwide. Current standard treatment using pegylated interferon and ribavirin is effective in only 50% of the patients infected with HCV genotype 1, and is associated with significant side effects. Therefore, it is still of importance to develop new drugs for treatment of HCV. Antiviral substances obtained from natural products, including medicinal plants, are potentially good targets to study. In this study, we evaluated Indonesian medicinal plants for their anti-HCV activities. METHODS: Ethanol extracts of 21 samples derived from 17 species of medicinal plants explored in the East Java region were tested. Anti-HCV activities were determined by a cell culture method using Huh7.5 cells and HCV strains of 9 different genotypes (1a to 7a, 1b and 2b). RESULTS: Four of the 21 samples tested showed antiviral activities against HCV: Toona sureni leaves (TSL) with 50% inhibitory concentrations (IC50) of 13.9 and 2.0 µg/ml against the HCV J6/JFH1-P47 and -P1 strains, respectively, Melicope latifolia leaves (MLL) with IC50 of 3.5 and 2.1 µg/ml, respectively, Melanolepis multiglandulosa stem (MMS) with IC50 of 17.1 and 6.2 µg/ml, respectively, and Ficus fistulosa leaves (FFL) with IC50 of 15.0 and 5.7 µg/ml, respectively. Time-of-addition experiments revealed that TSL and MLL inhibited both at the entry and post-entry steps while MMS and FFL principally at the entry step. TSL and MLL inhibited all of 11 HCV strains of all the genotypes tested to the same extent. On the other hand, FFL showed significantly weaker inhibitory activities against the HCV genotype 1a strain, and MMS against the HCV strains of genotypes 2b and 7a to a lesser extent, compared to the other HCV genotypes. CONCLUSIONS: Ethanol extracts of TSL, MLL, MMS and FFL showed antiviral activities against all the HCV genotypes tested with the exception that some genotype(s) showed significant resistance to FFL and to MMS to a lesser extent. These plant extracts may be good candidates for the development of anti-HCV drugs.

Sanjecumins A and B: new limonoids from Sandoricum koetjape.

Two new limonoids, sanjecumins A (1) and B (2), have been isolated from the leaves of Sandoricum koetjape, together with sandoripins A (3) and B (4). Their structures and absolute configurations were elucidated on the basis of NMR and CD data. Sandoripins A (3) and B (4) moderately inhibited nitric oxide production in mouse macrophage-like cell line J774.1 stimulated by lipopolysaccharide.

Alstiphyllanines I-O, ajmaline type alkaloids from Alstonia macrophylla showing vasorelaxant activity.

Seven new ajmaline type alkaloids, alstiphyllanines I-O (1-7) were isolated from the leaves of Alstonia macrophylla together with six related alkaloids (8-13). Structures and stereochemistry of 1-7 were fully elucidated and characterized by 2D NMR analysis. A series of alstiphyllanines I-O (1-7) as well as the known ajmaline type alkaloids (8-13) showed that they relaxed phenylephrine (PE)-induced contractions against rat aortic ring. Among them, vincamedine (10) showed potent vasorelaxant activity, which may be mediated through inhibition of Ca(2+) influx through voltage-dependent Ca(2+) channels (VDCs) and/or receptor-operated Ca(2+) channels (ROCs) as well as partially mediated the NO release from endothelial cells. The presence of substituents at both N-1 and C-17 may be important to show vasorelaxation activity.

Melidianolic acid A and B, new antimalarial acyclic diterpenes from Aphanamixis grandifolia.

Two new acyclic diterpenes, melidianolic acids A (1) and B (2), have been isolated from the bark of Aphanamixis grandifolia. Their structures were elucidated on the basis of spectroscopic and chemical methods. Melidianolic acids A (1) and B (2) showed antimalarial activity against Plasmodium falciparum 3D7 with IC50 of 6.1 and 7.3 microg/mL, respectively.

Inhibitors of nitric oxide production from Stemona javanica.

In our screening program for bioactive natural products from our library of tropical plants, the extract prepared from the roots of Stemona javanica inhibited NO production in mouse macrophage-like cell line J774.1 stimulated by lipopolysaccharide (LPS). Bioassay-guided fractionation of the extract from S. javanica led to the isolation of two active compounds, stemofoline (1) and stemanthrene C (2). The inhibition mechanism of 1 was proposed to suppress iNOS expression in J774.1 cells stimulated by LPS, whereas that of 2 was due to potent radical scavenging activity resulting in NO inhibitory activity.

Biscarpamontamines A and B, an aspidosperma-iboga bisindole alkaloid and an aspidosperma-aspidosperma bisindole alkaloid, from Tabernaemontana sphaerocarpa.

Two new bisindole alkaloids, biscarpamontamine A (1), possessing an aspidosperma-iboga-type skeleton, and biscarpamontamine B (2), having an aspidosperma-aspidosperma-type skeleton, were isolated from stems of Tabernaemontana sphaerocarpa, and their structures were elucidated on the basis of spectroscopic data analysis. The absolute configuration of biscarpamontamine B (2) was established by comparison of its CD spectrum and with that of vobtusine (3). Biscarpamontamine B (2) showed potent cytotoxicity against various human cancer cell lines.

Dose dependent elevation of plasma tocotrienol levels and its effect on arterial compliance, plasma total antioxidant status, and lipid profile in healthy humans supplemented with tocotrienol rich vitamin E.

UNLABELLED: Tocotrienols are a class of vitamin E reported to be potent antioxidants, besides having the ability to inhibit the HMG-CoA reductase enzyme. This study assessed the effects of 3 doses of tocotrienol-rich vitamin E (TRE) on plasma tocotrienol isomer concentration, arterial compliance, plasma total antioxidant status (TAS), aortic systolic blood pressure (ASBP), serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) in healthy males. METHODOLOGY: This randomised, blinded end-point, placebo-controlled clinical trial with a parallel design involved 36 healthy male subjects who took either an oral placebo or TRE at doses of 80, 160 or 320 mg daily for 2 mo. Baseline and end-of-treatment measurements of vitamin E concentration, arterial compliance [assessed by aortic femoral pulse wave velocity (PWV) and augmentation index (AI)], ASBP, plasma TAS, serum TC and LDL-C were taken. RESULTS: Baseline tocotrienol isomer concentrations were low and not detectable in some subjects. Upon supplementation, all TRE-treated groups showed significant difference from placebo for their change in alpha, gamma and delta tocotrienol concentrations from baseline to end of treatment. There was a linear dose and blood level relationship for all the isomers. There was no significant difference between groups for their change in PWV, AI, plasma TAS, ASBP, TC or LDL-C from baseline to end of treatment. Groups 160 mg (p = 0.024) and 320 mg (p = 0.049) showed significant reductions in their ASBP. Group 320 mg showed a significant 9.2% improvement in TAS. CONCLUSION: TRE at doses up to 320 mg daily were well tolerated. Treatment significantly increased alpha, delta, and gamma tocotrienol concentrations but did not significantly affect arterial compliance, plasma TAS, serum TC or LDL-C levels in normal subjects.

A functional platelet fibrinogen receptor with a deletion in the cysteine-rich repeat region of the beta(3) integrin: the Oe(a) alloantigen in neonatal alloimmune thrombocytopenia.

This report describes a new low-frequency alloantigen, Oe(a), responsible for a case of neonatal alloimmune thrombocytopenia (NAIT). In a population study none of 600 unrelated blood donors was an Oe(a) carrier. By immunochemical studies the Oe(a) antigen could be assigned to platelet glycoprotein (GP) IIIa. Sequencing of GPIIIa complementary DNA from an Oe(a) (+) individual showed deletion of a lysine residue at position 611 (DeltaLys(611)). Analysis of 20 Oe(a) (-) and 3 Oe(a) (+) individuals showed that the DeltaLys(611) form of GPIIIa was related to the phenotype. Anti-Oe(a) reacted with the DeltaLys(611), but not with the wild-type isoforms on stable transfectants expressing GPIIIa, indicating that DeltaLys(611) directly induces the expression of Oe(a) epitopes. Under nonreducing conditions the Pro(33)DeltaLys(611) variant migrated with a slightly decreased molecular weight compared to the Pro(33)Lys(611) isoform suggesting that DeltaLys(611) has an influence on the disulfide bonds of GPIIIa. The Pro(33)DeltaLys(611) GPIIIa could undergo conformational changes and bind to fibrinogen in a similar manner as the Pro(33)Lys(611) isoform. No difference was found in the tyrosine phosphorylation of pp125(FAK), suggesting that DeltaLys(611) has no effect on integrin function. In contrast to all other low-frequency antigens, the DeltaLys(611) isoform was associated with the HPA-1b, but not with the high frequency HPA-1a allele. Comparison with GPIIIa DNA from nonhuman primates indicated that the HPA-1a allele represents the ancestral form of GPIIIa. It can be assumed that the Oe(a) form did arise as a result of a mutational event from an already mutated GPIIIa allele.