Selective modulation of P-glycoprotein activity by steroidal saponines from Paris polyphylla

Bio-guided fractionation of the roots of Paris polyphylla (Trilliaceae), based on inhibition of P-glycoprotein-mediated daunorubicin efflux in K562/R7 cell line, led to isolation and identification of the three saponins 3-O-Rha(1 → 2)[Ara(1 → 4)]Glc-pennogenine, gracillin and polyphyllin D, and the two ecdysteroids 20-hydroxyecdysone and pinnatasterone. These compounds were tested for multidrug reversion on P-glycoprotein (ABCB1) with both drug-selected and transfected cell lines, and also on Breast Cancer Resistance Protein (BCRP/ABCG2). By contrast to a weak efficiency on BCRP, the three saponins displayed significant effects as inhibitors of P-glycoprotein-mediated drug efflux

Sesquiterpenes from aerial parts of Ferula vesceritensis

From the dichloromethane extract of aerial parts of Ferula vesceritensis (Apiaceae), 11 sesquiterpene derivatives were isolated. Among them five were compounds designated as 10-hydroxylancerodiol-6-anisate, 2,10-diacetyl-8-hydroxyferutriol-6-anisate, 10-hydroxylancerodiol-6-benzoate, vesceritenone and epoxy-vesceritenol. The six known compounds were identified as feselol, farnesiferol A, lapidol, 2-acetyl-jaeschkeanadiol-6-anisate, lasidiol-10-anisate and 10-oxo-jaesckeanadiol-6-anisate. All the structures were determined by extensive spectroscopic studies including 1D and 2D NMR experiments and mass spectroscopy analysis. Two of the compounds, the sesquiterpene coumarins farnesiferol A and feselol, bound to the model recombinant nucleotide-binding site of an MDR-like efflux pump from the enteropathogenic protozoan Cryptosporidium parvum

Cytotoxic and Antiplasmodial Xanthones from Pentadesma butyracea

Four new xanthones, butyraxanthones A-D (1-4), were isolated from the stem bark of Pentadesma butyracea, together with six known xanthones (5-10) and a triterpenoid (lupeol). The structures of 1-4 were established by spectroscopic methods. Compounds 1-10 were tested in vitro for antiplasmodial activity against a Plasmodium falciparum chloroquine-resistant strain and for cytotoxicity against a human breast cancer cell line (MCF-7). Nearly all of these xanthones exhibited good antiplasmodial activity, and some of them also demonstrated potent cytotoxicity

Antiplasmodial and cytotoxic activities of flavonoids and arylbenzofuran derivatives from Morus mesozygia

Morus mesozygia Stapf (Moraceae) is a plant found in many regions and used in treating many diseases including malaria and fever. Fractionation of the methanolic extract of its stem bark, using various chromatographic methods has led to the isolation and identification of 3 flavonoids: artocarpesin, artochamin C and kushenol E. And 4 arylbenzofuran derivatives: moracin M, moracin C, moracin L and mulberofuran F. The methanolic extract and the seven isolated compounds were tested for antiplasmodial activity against the chloroquine-resistant FcB1 Plasmodium falciparum strain and cytotoxicity on MCF-7 human breast cancer cells. Relating to the antiplasmodial activity, it was found that all compounds were active against the FcB1 strain of Plasmodium with artocarpesin, koushenol E and mulberrofuran F showing particular potency (with the median inhibitory concentrations IC50 = 2.5-2.6 μg/ml). Cytotoxicity tests performed on MCF-7 cells revealed all the IC50 varying from <1.0 to 5.0 ± 0.6 μg/mL. A structure – activity relationship is discussed

Breast cancer resistance protein (BCRP/ABCG2): New inhibitors and QSAR studies by a 3D linear solvation energy approach

A series of compounds derived from naturally occurring flavonoids and synthetic analogs have been evaluated on cell lines overexpressing the wild-type breast cancer resistance protein (BCRP/ABCG2) half-transporter. Human ABCG2-transfected cells were used for screening their inhibitory activity. Five new natural compounds obtained from Morus mesozygia Stapf and one synthetic chromone, comprising a flavonoidic scaffold, were also evaluated. Based on the results obtained with a total of 34 compounds, a 3D linear solvation energy QSAR was investigated by VolSurf descriptors of molecular-interaction fields (MIFs) related to hydrophobic-interaction forces, polarisability and hydrogen-bonding capacity. Accuracy of the constructed 3D-QSAR model was attested by a correlation coefficient r2 of 0.77. Shape parameters and hydrophobicity were revealed to be major physicochemical parameters responsible for the inhibition activity of flavonoid derivatives and synthetic analogs towards ABCG2, whereas hydrogen-bond donor capacity appeared highly unfavorable

Antitumor activity and distribution of pyrroloiminoquinones in the sponge genus Zyzzya

A detailed analysis of four different collections of the sponge genus Zyzzya yielded nine pyrroloiminoquinones of the makaluvamine, batzelline, and isobatzelline/damirone classes. Dereplication analyses of additional Zyzzya extracts did not disclose more potent or additional new compounds. Comparative testing of these compounds in the National Cancer Institute's 60 cell line human tumor screen revealed varying levels of potency and differential cytotoxicity, apparently related to the unsaturation levels in and substitution patterns on the core ring system. Further studies on the topoisomerase II-mediated DNA cleavage were conducted. Reductive activation of the pyrroloiminoquinones led to DNA damage in vitro, which correlated with half wave potentials and reversibility parameters. DNA damage could be abrogated by ascorbate. Fluorescence displacement was used to measure intercalation with DNA; intercalation efficiency did not correlate with DNA-damaging proficiency. Makaluvamine H (5) emerged as the most potent and differential of our isolates, roughly comparable to makaluvamines C (in vitro) and I (in vivo). 3,7-Dimethyl guanine was isolated from one of the Zyzzya collections and from the sponge Latrunculia purpurea. (c) 2005 Elsevier Ltd. All rights reserved