Three new imidazole alkaloids, leucettamines A [1] and B [2] and leucettamidine [31, have been isolated from the Palauan sponge Leucetta microraphis. Their structures were established on the basis of extensive spectral analyses. Leucettamine A showed potent leukotriene B4 receptor binding activity (K¡ =1.3 µ ), while leucettamine B was essentially inactive (K¡ = 100 µ ) and leucettamidine showed significant activity (K¡ = 5.3 µ ). With leucettamine A identified as a pure LTB4 receptor antagonist, a new structure lead is presented to inflammation therapy.

The recruitment of inflammatory cells into sites of inflammation is a normal physiological response designed to fight infection, remove damaged cells, and stimulate healing. However, the excessive recruitment of such cells often exacerbates tissue damage, slows healing, and in some cases leads to host death. Therefore, inhibition of inflammatory cell recruitment may be an appropriate therapeutic strategy in a number of inflammatory diseases, such as asthma, reperfusion injury, arthritis, and inflammatory bowel disease.Chemokines are a superfamily of approximately 30 distinct small secreted proteins, and additional members continue to be identified (1, 2). They are classified into two major groups, CXC and CC, based on the position of the first two of their four invariant cysteines (3). The actions of chemokines are mediated via interactions with 7-TM 1 G protein-coupled receptors on the surface of immune and inflammatory cells. To date, 18 unique chemokine receptors, including 11 CC chemokine receptors, have been cloned (4, 5).The properties of the chemokines suggest that they are essential for leukocyte trafficking and inflammatory processes and thus are important components in a number of disease states (6, 7). Eosinophils are proinflammatory granulocytes that play a major role in allergic diseases, such as bronchial asthma (8), allergic rhinitis (9), atopic dermatitis (10), and eosinophilic gastroenteritis (11). Upon activation, eosinophils release lipid mediators, cytotoxic proteins, oxygen metabolites, and cytokines, all of which have the potential to produce pathophysiology. Recent studies have clearly demonstrated the presence of eosinophils or eosinophil-specific products in inflamed lung biopsy tissues in human asthma (10).Although the molecular mechanism responsible for the selective infiltration of eosinophils into inflamed tissue has not been elucidated, recently the CC chemokine eotaxin was identified in guinea pig lung following antigen challenge in sensitized guinea pigs (12, 13). Furthermore, neutralizing antibodies to eotaxin in a mouse model of allergy demonstrated inhibition of eosinophil recruitment when administered before the antigen challenge (14). Five CCR3 ligands have been shown to induce eosinophil transendothelial migration using human umbilical vein endothelial cells. This migration is inhibited by pretreatment with anti-CCR3. In addition, a human lung epithelial cell line (BEAS-2B), stimulated with proinflammatory cytokines, has been shown to produce eotaxin and 16). In humans, biopsies obtained from asthmatic lung have shown increased levels of CCR3 and its ligands, eotaxin, eotaxin-2, RANTES, and MCP-4, both at the mRNA and pro-* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.§ To whom correspondence should be addressed: Dept. of Immunology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Rd., King of ...

No abstract

No abstract

No abstract

No abstract

The oxoaporphine alkaloids oxophoebine [1] and liriodenine [2] have been isolated from Xylopia aethiopica (Annonaceae). Both showed selective toxicity against DNA repair and recombination deficient mutants of the yeast Saccharomyces cerevisae. Three related but inactive compounds, oxoglaucine [3], O-methylmoschatoline [4], and lysicamine [5], were also isolated from this plant. Selective toxicity was also observed for 10-methoxyliriodenine (lauterine) [6] and 10-hydroxyliriodenine [7], two oxoaporphine alkaloids isolated from Miliusa cf. banacea (Annonaceae). The structure of 10-hydroxyliriodenine [7], a novel oxoaporphine, was determined by spectroscopic methods and chemical conversion to compound 6. The role of the bioactive oxoaporphine alkaloids as DNA topoisomerase inhibitors is discussed.

A new antibacterial antibiotic complex, aridicin, was produced by a new genus, Kibdelosporangiun: aridum (SK&F-AAD-216).The individual factors, aridicins A, B and C, were isolated from the fermentation broth by an Amberlite XAD-7 resin extraction and purified by preparative reversed phase HPLC. The aridicins were found to be novel members of the glycopeptide class of antibiotics as exemplified by ristocetin and vancomycin, based on chemical and spectroscopic data, their molecular weights as determined by FAB mass spectrometry (1,786, 1,800 and 1,814), the detection of actinoidinic acid in their acid hydrolysates, and detailed TLC and HPLC comparisons with representative members of this class.The aridicins are a new complex of cell-wall active antibiotics produced by fermentation of a new genus Kibdelosporangium ariduin (SK&F-AAD-216, ATCC 39323), isolated from a soil sample collected near Pima, Arizona1). The antibiotic complex was isolated from fermentation broth by acid precipitation and chromatography on Amberlite XAD-7. The individual components were separated and purified by preparative reversed phase high performance liquid chromatography (HPLC). Chemical characterization of the components indicated that they were novel glycopeptide antibiotics2) related to vancomycin3,4), ristocetin5,6), avoparcin7) and teicoplanin8). In this report the isolation and characterization of aridicins A, B and C are reported. Isolation and PurificationThe antibiotic complex was isolated from the fermentation broth as outlined in Scheme 1. Precipitation at pH 3 and redissolution at pH 7 provided a 10-fold volume reduction with high recovery in the preliminary isolation step. This solution was passed through an Amberlite XAD-7 column and eluted with 60 % acetonitrile -water to yield a crude extract after concentration in vacuo. The overall recovery from broth after these two steps was in excess of 80 % with an accompanying volume reduction of 100-fold. Further purification was effected by preparative reversed phase HPLC. The frequently reported multistep schemes for the purification of polar, water soluble fermentation products often yield products in low recovery and, being limited in capacity, are difficult to scale-up. However, reversed phase HPLC, a useful analytical tool for monitoring antibiotic production, isolation and purification, also has great potential as a preparative tool for isolating and purifying the sesame products, often in one step9,10,11). An analytical HPLC chromatogram of the crude extract is shown in Fig. 1, with the major components indicated by peaks A, B and C. This separation was readily scaled-up to preparative level (Fig. 2) on Whatman Partisil Prep 40 ODS-3 packing (37' 60 Jim) I Present Address: SeaPharm ,