No abstract

No abstract

This report describes the first results of a rational hit-finding strategy to design novel small molecule antiinflammatory drugs targeting selectins, a family of three cellular adhesion molecules. Based on recent progress in understanding of molecular interaction between selectins and their natural ligands as well as progress in clinical development of synthetic antagonists like 1 (bimosiamose, TBC1269), this study was initiated to discover small molecule selectin antagonists with improved pharmacological properties. Considering 1 as template structure, a ligand-based approach followed by focused chemical synthesis has been applied to yield novel synthetic small molecules (MWr < 500) with a trihydroxybenzene motif, bearing neither peptidic nor glycosidic components, with nanomolar in vitro activity. Biological evaluation involves two kinds of in vitro assays, a static molecular binding assay, and a dynamic HL-60 cell attachment assay. As compared to controls, the novel compounds showed improved biological in vitro activity both under static and dynamic conditions.

SummaryChronic obstructive pulmonary disease (COPD) is characterized by a dysregulated recruitment of circulating leucocytes into the lung which is associated with the onset and progress of the disease. P-selectin glycoprotein ligand-1 (PSGL-1) is expressed on leucocytes and plays an essential role in primary leucocyte-endothelial cell adhesive contacts. The present study investigated if PSGL-1 is up-regulated on leucocytes of COPD patients. Peripheral blood samples were collected from COPD patients as well as controls (smoking, nonsmoking volunteers) and subjected to analysis of PSGL-1 expression on leucocytes, i.e. neutrophils, eosinophils, monocytes and lymphocytes by flow cytometry. No significant difference was observed between healthy nonsmoking and healthy smoking control subjects. In contrast, PSGL-1 expression was found to be significantly increased on the surface of all four leucocyte populations in COPD patients compared to both control groups. The finding that PSGL-1 surface expression is up-regulated on leucocytes of COPD patients as compared to leucocytes of controls suggests PSGL-1 as a potential target for anti-inflammatory treatment.

Several strains of Rhizobium japonicum have been reported to consist of mixtures of stable derivativess having distinct colony morphologies and physiological characteristics. We isolated derivatives from strains of R. japonicum and systematically compared them with previously isolated derivatives with respect to the utilization of biochemicals, antibiotic sensitivity, and soyben lectin binding. With the exception of a pair of derivatives from 3Ilb110, one of which utilized pyruvate and one of which did not, sibling derivatives had essentially identical biochemical utilization patterns. The sibling derivatives of parental strains 3Ilb110 and 3Ilb140 exhibited marked variation in their sensitivities to several antibiotics, including gentamicin, sul famethoxazole, and tetracycline. Compared with the derivative with small colony morphology, derivatives with large colony morphology were in general more sensitive to these antibiotics. With one exception, the binding of soybean lectin to the derivatives was quantitatively the same as that to the parental strain. The anomaly was 110-Y which, in contrast to its parental strain and sibling derivatives, failed to bind detectable amounts of the lectin. 110-Y, as well as all the other derivatives and parental strains, nodulated Disoy soybean.