Carbazole formulations for the treatment of psoriasis and angiogenesis
a technology of angiogenesis and cyclosporine, which is applied in the direction of biocide, drug composition, immunodeficiency, etc., can solve the problems of affecting the treatment effect, affecting the development of effective preventive and treatment methods, and affecting the effect of cyclosporine us
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example 1
Identification of Active Ingredient in Coal Tar
[0059] Liquid extract of coal tar was concentrated under vacuum to get crude extract (20.0 mg). This extract was applied on a Sephadex LH 20 (3.0×100 cm) column and eluted with MeOH. The elution was monitored by TLC and similar fractions are combined to get 11 fractions. This fraction was assayed for inhibition of SVR cell viability (Arbiser et al. (1999) J. Am. Acad. Dermatol. 40, 925-929; and Bai et al. (2003) J. Biol. Chem. 278, 35501-35507). One fraction was found to have activity, and induce a characteristic morphologic change in SVR cells. These changes are similar to what is observed when SVR cells are treated with an EGFR tyrosine kinase inhibitor.
[0060] Fraction 5 (0.5 mg) and fraction 6 (1.2 mg) tested positive in the bioassay. TLC comparison of these two fractions revealed the presence of one common UV-active component in both fractions that produced a blue char upon spraying with H2SO4. Fraction 6 (1.2 mg) was subjected to...
example 2
Identification of Active Carbazole Derivatives by Inhibition of Endothelial Proliferation
[0061] Coal tar fractions were tested for their ability to inhibit the proliferation of SVR cells, an established angiogenic bioassay. One fraction was found to have activity, and induce a characteristic morphologic change in SVR cells.
[0062] Since carbazole is known to be metabolized by mammals through hydroxylation, hydroxylated and oxidized derivatives of carbazole, including 2,3, and 4 hydroxylated carbazoles, were also tested for their anti-proliferative activity using SVR cells as previously described (Arbiser et al. (1999) Supra; and Bai et al. (2003) Supra). As shown in FIG. 1, carbazole itself had mild antiproliferative activity, while 2-, 3- and 4-hydroxy carbazole had more potent antiproliferative activity. These findings suggest that carbazole and its derivatives have antiangiogenic and antisignalling activities.
example 3
Drosophila Assay
[0063] The epidermal growth factor receptor pathway controls cell fate throughout phylogeny. Binding of secreted ligands to EGFR on the cell surface initiates a cascade of events that ultimately invokes transcriptional changes in the nucleus. Ligand / receptor interactions are of critical importance during Drosophila eye development, as recruitment and differentiation of almost all photoreceptors are dependent on high levels of activation of the EGFR pathway. Binding of activating ligand to EGFR results in a cascade of membranous and cytoplasmic phosphorylation events.
[0064] In order to test whether carbazole and its derivatives affect EGFR, the compounds were tested using a novel EGFR assay that is amenable to high throughput screening. Drosophila melanogaster that possess an active EGFR have a distinct eye phenotype, and treatment of mutant Drosophila with carbazole and 4-hydroxycarbazole resulted in correction of the phenotypic defect. Carbazole and 4-hydroxycarba...
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