Inhibition of glycosidases by Astragalus lusitanicus and correlation with toxicity.

This study determined whether Astragalus lusitanicus inhibits glycosidase enzymes other than alpha-mannosidase. Plasma collected from lambs given fresh A lusitanicus inhibited beta-glucosidase and beta-galactosidase, indicating the presence of inhibitors in their blood. The residual activity of these enzymes was also modified in tissues of dead animals. beta-glucosidase activity was reduced in liver and kidney specimens with pronounced effects in tissues of animal that presented with prominent clinical signs of poisoning; beta-galactosidase activity was decreased by 88.5 to 95% in kidney, while that of liver remained unchanged. Fractions of the plant butanol extract inhibited the gycosidase enzymes. Chemical analysis revealed the presence of hypaphorin in the extract of A lusitanicus. As a tryptophan derivative, this alkaloid may play a role in the toxicity of this legume.

Redox regulation of tumor cell toxicity by flavones from Lethedon tannaensis.

The purpose of the present work has been to seek a correlation of potential predictive value, demonstrating redox control of cytotoxicity toward human nasopharynx carcinoma (KB) cells by seven 5-hydroxy-7-methoxyflavones, together with two glycoside derivatives, all extracted from Lethedon tannaensis. In this approach, redox control is characterized by a physicochemical parameter expressing quantitatively the relative electron-donating power of the flavones, this parameter being the second order rate constant, kdelta, for quenching of singlet oxygen O2 (1deltag). This rate constant kdelta is usually related to the ability of a given molecule D to donate an electron and, thus, with the reduction potential E of the couple (D*+/D). Our results show that the flavone toxicity is linearly correlated with ease of oxidation: the higher the rate constant of reaction with singlet oxygen, the easier the oxidation, the less positive or more negative the reduction potential ((D*+/D), the higher the cytotoxicity. The results suggest new screening strategies to identify and improve potential antitumor drugs.

Five new flavone 5-O-glycosides from Lethedon tannaensis: lethedosides and lethediosides.

Five new 7-methoxy-flavone 5-O-glycosides were isolated from a cytotoxic MeOH extract of Lethedon tannaensis, and the structures were elucidated by 2D NMR spectral analysis and by chemical methods. Lethedosides A (1), B (2), and C (3) were 5-O-glucosides of 7,3', 4'-tri-O-methylluteolin, 7,3',4',5'-tetra-O-methyltricetin, and 7,3', 4'-tri-O-methytricetin, respectively; lethediosides A (4) and B (5) and a known compound 6 were 5-O-xylosylglucosides of 7,3', 4'-tri-O-methylluteolin, 7,3',4',5'-tetra-O-methyltricetin, and 7, 4'-di-O-methylapigenin, respectively. These flavonoids were either inactive or weakly active against KB tumor cells, in contrast to previously isolated flavones from the same plant.

DNA topoisomerase I inhibitors: cytotoxic flavones from Lethedon tannaensis.

From ethyl acetate and methanolic extracts of Lethedon tannaensis leaves, which were cytotoxic against murine leukemia (P-388) and human nasopharynx carcinoma (KB) cells, one new and six known 5-hydroxy-7-methoxyflavones variously substituted on the B ring were isolated and their structures determined by spectral analysis. Compounds active against KB cells were velutin (4) (IC50 4.8 microM), 7,3',5'-tri-O-methyltricetin (2) (IC50 22.2 microM), genkwanin (6) (IC50 30.6 microM), and the novel compound, 7,3',4'-tri-O-methyltricetin, named lethedocin (1) (IC50 47.6 microM). These flavones required the presence of hydroxyl groups at C-5 and C-4' and methoxyl groups at C-7 and C-3' for inhibition of calf thymus DNA topoisomerase I activity.

Bisbenzylisoquinolines as modulators of chloroquine resistance in Plasmodium falciparum and multidrug resistance in tumor cells.

Ten naturally occurring bisbenzylisoquinolines (BBIQ) and two dihydro derivatives belonging to five BBIQ subgroups were evaluated in vitro for their ability to inhibit Plasmodium falciparum growth and, in drug combination, to reverse the resistance to chloroquine of strain FcB1. The same alkaloids were also assessed in vitro for their potentiating activity against vinblastine with the multidrug-resistant clone CCRF-CEM/VLB, established from lymphoblastic acute leukemia. Three of the BBIQ tested had 50% inhibitory concentrations of less than 1 microM. The most potent antimalarial agent was cocsoline (50% inhibitory concentration, 0.22 microM). Regarding the chloroquine-potentiating effect, fangchinoline exhibited the highest biological activity whereas the remaining compounds displayed either antagonistic or slight synergistic effects. Against the multidrug-resistant cancer cell line, fangchinoline was also by far the most active compound. Although there were clear differences between the activities of tested alkaloids, no relevant structure-activity relationship could be established. Nevertheless, fangchinoline appears to be a new biochemical tool able to help in the comprehension of the mechanism of both chloroquine resistance in P. falciparum and multidrug resistance in tumor cells.

Patuletin acetylrhamnosides from Kalanchoe brasiliensis as inhibitors of human lymphocyte proliferative activity.

The fractionation of the juice of fresh stems and leaves of Kalanchoe brasiliensis was monitored by an assay measuring lymphocyte proliferative activity and allowed the isolation and identification of seven patuletin rhamnoside derivatives [1-7]. Three of them are novel, namely, patuletin 3-O-(4"-O-acetyl-alpha-L-rhamnopyranosyl)-7-O-(2'"-O-acetyl- alpha-L-rhamnopyranoside) [1], patuletin 3-O-alpha-L-rhamnopyranosyl-7-O-(2'"-O-acetyl-alpha-L- rhamnopyranoside) [3], and patuletin 3-O-(4"-O-acetyl-alpha-L-rhamnopyranosyl)-7-O- rhamnopyranoside [4], and four are known [2, 5-7]. Their structures were determined by the analysis of 1H-1H and 1H-13C COSY nmr, ci, and fab mass spectra.

Cinnamrutinoses A and B, glycosides of Populus tremula.

The cinnamylrutinosides, cinnamrutinoses A and B, were isolated along with known phenolic glucosides, from the stem bark of Populus tremula infected with the pathogenic fungus Hypoxylon mammatum. The structures were determined from spectroscopic and chemical evidence.

[Annomonysvin: a new cytotoxic gamma-lactone-monotetrahydrofuranyl acetogenin from Annona montana]. / Annomontacine: une nouvelle acétogénine gamma-lactone-monotetrahydrofurannique cytotoxique de l'Annona montana.

The structure of annomontacin [I], a novel monotetrayhydrofuran fatty acid gamma-lactone (acetogenin) isolated from the seeds of Amnona montana, was determined by spectral analysis. The cytotoxicities in vitro of annomontacin [I], annonacinone [2], and annonacin were measured against murine leukemia L1210, human breast adenocarcinoma MDA-MB231, and human breast carcinoma MCF7 cell lines and compared with adriamycin.

[Alkaloids from annonaceae.]. / Alcaloïdes des Annonacées.

From diverse parts of POLYALTHIA NITIDISSIMA, thirteen isoquinoline alkaloids have been isolated and identified. They belong to the structural types of benzylisoquinolines, aporphinoids, protoberberines and mainly bisbenzylisoquinolines. Four of these dimers, namely N,N'-dimethyllindoldhamine, isodaurisoline, 7-O-methyllindoldhamine and 7'-O-methyllindoldhamine, are new natural products.