Search

A series of styrylpyrazoles, styrylisoxazoles, and styrylisothiazoles were prepared and found to be dual inhibitors of 5-lipoxygenase and cyclooxygenase in rat basophilic leukemia cells. Compounds from this series also were found to inhibit the in vivo production of LTB4 when dosed orally in rats. Among these compounds, di-tert-butylphenols 19 and 33 exhibit oral activity in various models of inflammation and, most importantly, are devoid of ulcerogenic potential.

The structure of the gene encoding human hexabrachion (tenascin) has been determined from overlapping clones isolated from a human genomic bacteriophage library. The genomic inserts were characterized by restriction mapping, Southern blot analysis, PCR, and DNA sequencing. The coding region of the hexabrachion gene spans approximately 80 kilobases of DNA and consists of 27 exons separated by 26 introns. The exon-intron structure supports a hypothesis based on the cDNA sequence that the hexabrachion gene is an assembly of DNA modules that are also found elsewhere in the genome. Single exons may encode a module, a portion of a module, or a group of modules. The 15 type III units similar to those found in fibronectin are each encoded either by a single exon or by two exons interrupted by an intron. All type III units known to be spliced out of the smaller forms of the protein are encoded by one exon. The fibrinogen-like domain of 210 amino acids is encoded by five exons. The 14.5 epidermal growth factor-like repeats are all encoded by a single exon.

A series of styrylpyrazoles, styrylisoxazoles, and styrylisothiazoles were prepared and found to be dual inhibitors of 5-lipoxygenase and cyclooxygenase in rat basophilic leukemia cells. Compounds from this series also were found to inhibit the in vivo production of LTB4 when dosed orally in rats. Among these compounds, di-tert-butylphenols 19 and 33 exhibit oral activity in various models of inflammation and, most importantly, are devoid of ulcerogenic potential.

We have cloned and sequenced two cDNA molecules that code for parts of two forms of human hexabrachion. The smaller clone has a sequence that corresponds to the previously published sequence of a cDNA clone coding for a part of chicken hexabrachion [Jones, F. S., Burgoon, M. P., Hoffman, S., Crossin, K. L., Cunningham, B. A. & Edelman, G. M. (1988) Proc. Natl. Acad. Sci. USA 85, 2186-2190]. It has eight consecutive domains similar to the type III homology units from fibronectin, several epidermal growth factor repeats, and a domain similar to the beta and gamma chains of fibrinogen. The larger clone has 5' and 3' ends that are identical to the smaller clone but also has an alternatively spliced 1.9-kilobase internal segment. The unique segment contains remarkable repeats of potential glycosylation sites and an additional seven type III homology units.

Diels-Alder reaction of 3-chloro-1-methoxy-1,3-butadiene ( 1 ) with 2,3-dimethoxy-2,5-cyclohexadiene-1,4-dione (2) provides a facile and convergent synthesis of the β-halogenated polysubstituted naphthalene 5-lipoxygenase inhibitor RS-43179.

Diels-Alder reaction of 3-chloro-1-methoxy-1,3-butadiene ( 1 ) with 2,3-dimethoxy-2,5-cyclohexadiene-1,4-dione (2) provides a facile and convergent synthesis of the β-halogenated polysubstituted naphthalene 5-lipoxygenase inhibitor RS-43179.

The stimulation of hexose monophosphate shunt (HMS) activity in rabbit lens has been investigated during exposure to t-butyl hydroperoxide (TBHP), an oxidant for glutathione (GHS). Exposure of lenses to 1·0 m m -TBHP produced maximum stimulation of HMS activity as measured by the oxidation of 14C-labeled glucose, labeled in either the C-1, C-2 or C-6 position. A significant increase in the oxidation of both C-1 and C-2 labeled glucose was observed. Removal of TBHP from the medium resulted in a rapid decrease in the rate of oxidation. The maximum rate of liberation of CO2 from the HMS pathway was estimated to be 0·75 μmol/g wet wt/hr, which was 7·7 times the control value. The generation of NADPH at maximum stimulation was estimated to be 1·5 μmol/g wet wt/hr which corresponded to a complete turnover of NADP+ to NADPH in the lens every 48 sec. This rate of generation of NADPH was sufficient to result in a reduction of oxidized glutathione (GSSG) at the rate of 26% of total glutathione in the lens per hour. Exposure of lenses to 0·10 m m -TBHP stimulated shunt activity by three times the control. However, under these conditions only minimal accumulation of GSSG was detected in the lens and no effect was observed on the uptake or efflux of 86Rb. Higher levels of TBHP resulted in a significant accumulation of GSSG in the lens and impaired cation transport. The distribution of the activity of the HMS pathway was determined in homogenates of various regions of rabbit lens. It was found that 65% of the total activity was present in the equatorial cortex, which made up 45% of the total weight. The results indicate that a direct link exists between the rate of formation of GSSG in the lens and the stimulation of HMS activity. In addition, the findings exemplify the ability of the lens to protect itself against oxidative damage through an interrelationship of the shunt, glutathione peroxidase, GSH, NADPH and glutathione reductase.