Antiplasmodial Activities of Homogentisic Acid Derivative Protein Kinase Inhibitors Isolated from a Vanuatu Marine Sponge Pseudoceratina sp.

As part of our search for new antimalarial drugs in South Pacific marine sponges, we have looked for inhibitors of Pfnek-1, a specific protein kinase of Plasmodium falciparum. On the basis of promising activity in a preliminary screening, the ethanolic crude extract of a new species of Pseudoceratina collected in Vanuatu was selected for further investigation. A bioassay-guided fractionation led to the isolation of a derivative of homogentisic acid [methyl (2,4-dibromo-3,6-dihydroxyphenyl)acetate, 4a] which inhibited Pfnek-1 with an IC50 around 1.8 μM. This product was moderately active in vitro against a FcB1 P. falciparum strain (IC50 = 12 μM). From the same sponge, we isolated three known compounds [11,19-dideoxyfistularin-3 (1), 11-deoxyfistularin-3 (2) and dibromo-verongiaquinol (3)] which were inactive against Pfnek-1. Synthesis and biological evaluation of some derivatives of 4a are reported

Isolation and structure elucidation of cytotoxic agents from the higher plant Psorospermum febrifugum

Activity-directed fractionation of the ethanolic extract of Psorospermum febrifugum has led to a number of significantly active fractions devoid of psorospermin. Chemical study of these fractions has led to the isolation of a series of novel active xanthone analogs of the parent compound. Repetitive fractionation and chromatography, guided by in vitro 9PS cytotoxic activity and in vitro 3PS antitumor activity, has led to the isolation of twelve novel xanthones. Six compounds exhibited significant cytotoxic activity while two other compounds showed borderline cytotoxic activity against PS cells in culture. One compound was found to exhibit both significant cytotoxic and antitumor activity. Analysis using UV, IR, MS, PMR and CMR spectroscopy allowed the structural elucidation of these twelve compounds which were found to belong to two groups of xanthonoids. Eight of the isolated compounds were found to be of the furanoxanthone type while the other four belong to the rare xanthonolignoid class. The difference in structure among the furanoxanthones is in either the substitution pattern on the C-1 and C-5 carbons of the xanthone nucleus or at the C-4\sp\prime and C-5\sp\prime carbons of the side chain part of the molecule. 5\sp\primeHydroxypsorospermin was isolated from one of the fractions that exhibited in vivo antitumor activity. This compound was found to have both in vitro cytotoxic and in vivo antitumor activity (9PS, 7 $\times$ 10\sp{\rm -5} g/ml; 3PS, 136/16 (T/C %/dose mg/kg)). Compounds 4\sp\prime-ethoxy-3\sp\prime, 4\sp\prime-deoxypsorospermin-3\sp\prime-ol, 4\sp\prime-chloro-5-0-methyl-3\sp\prime, 4\sp\primedeoxypsorospermin-3\sp\prime, 5\sp\prime-diol, 4\sp\prime-methoxy-3\sp\prime, 4\sp\prime-deoxypsorospermin-3\sp\prime-ol and 3\sp\prime, 4\sp\prime-deoxypsorospermin-3\sp\prime, 4\sp\prime, 5\sp\prime-triol were found to exhibit significant activity against PS cells in culture with an ED\sb{\rm 50} of 2 $\times$ 10\sp{\rm -4}, \u3c\u3c10\sp{-5}, 1 $\times$ 10\sp{\rm -2}, 2 $\times$ 10\sp{\rm -4} and 3 $\times$ 10\sp\circ g/ml respectively. Isocadensin D, isocadensin D monoacetate, 6-hydroxy-8-methoxycadensin D and 8-methoxycadensin D were isolated as new members of the xanthonolignoid class. Aged alkaloidal extracts of Cephalotaxus harringtonia were analyzed by mass spectrometry. Cephalotaxinamide was isolated as the main component of the neutral fraction of the alkaloidal residue. Cephalotaxine and desmethylcephalotaxinone were isolated as the major components of the alkaloidal mixture obtained by fractionation of the aged alcoholic extracts of C. harringtonia roots

Alkaloids and flavone acyl glycosides from Acanthus arboreus

Phytochemical study of Acanthus arboreus resulted in the isolation of three novel alkaloids: 6-hydroxy-benzoxazolinone, 4-hydroxyacanthamine and acanthaminoside. In addition, a new acyl flavonoid apigenin-7-O-beta-D-(6"-trans-p -coumaroyl)-3"-O-acetyl glucopyranoside was also isolated. The known compounds were identified as apigenin, apigenin-7- O-beta-D-(6"-trans-p-coumaroyl) -glucoside, vanillic acid, lupeol, stigmasterol and sitosterol glucoside. The structures were determined by physical, chemical and spectral techniques

Bioactive metabolites from the sponge Suberea sp.

Two new brominated compounds, subereaphenol K (2) and 2-(3,5-dibromo-1-ethoxy-4-oxocyclohexa-2,5-dien-1-yl)acetamide (3), together with subereaphenol B (methyl 2-(2,4-dibromo-3,6-dihydroxyphenyl)acetate; 1) with a revised structure, and five dibromotyrosine-derived metabolites, 4–8, were isolated from the sponge Suberea sp. and characterized by 1D- and 2D-NMR spectroscopic and HR-MS spectrometric data. Compounds 1, 2, 6, and 8 exhibited various weak or moderate bioactivities, including antimicrobial and cytotoxic activities. Furthermore, compounds 1 and 2 inhibited human recombinant phosphodiesterase 4 (PDE4) with IC50 values of 2 μM, whereas compounds 6 and 8 were less active

Approach to the discovery of novel, selective inhibitors of p56lck tyrosine kinase: Identification of non-hydroxylated chromones as p56lck inhibitors

The protein tyrosine kinase p56(lck), which is expressed predominantly in lymphocytes, plays a critical role in optimal T cell activation through the T cell antigen receptor. An approach is presented for the discovery of selective p56(lck) inhibitors, which are potential immunosuppressants. A non-radioactive assay for p56(lck) tyrosine kinase activity has been developed and adapted for high volume screening. This assay does not require purified enzyme. p56(lck) in the plasma membranes of a human T cell line is purified in situ by immobilization onto the wells of a microtiter plate using an antibody specific for p56(lck). Following the kinase reaction in the presence of test compound, autophosphorylated p56(lck) is detected with a biotinylated monoclonal antibody to phosphotyrosine. Using the approach described in this report, three simple chromones have been identified that inhibit p56(lck) autophosphorylation with low micromolar potencies and exhibit some selectivity fdr p56(lck) over the serine/threonine and other tyrosine kinases tested. These compounds constitute a novel group of p56(lck) tyrosine kinase inhibitors. (C) 1995 Wiley-Liss, Inc