The crystal structures of porcine and human aldehyde reductase, an enzyme implicated in complications of diabetes, have been determined by X-ray diffraction methods. The crystallographic R factor for the refined porcine aldehyde reductase model is 0.19 at 2.8 A resolution. There are two molecules in the asymmetric unit related by a local non-crystallographic twofold axis. The human aldehyde reductase model has been refined to an R factor of 0.21 at 2.48 A resolution. The amino-acid sequence of porcine aldehyde reductase revealed a remarkable homology with human aldehyde reductase. The coenzyme-binding site residues are conserved and adopt similar conformations in human and porcine aldehyde reductase apo-enzymes. The tertiary structures of aldhyde reductase and aldose reductase are similar and consist of a fl/a-barrel, with the coenzyme-binding site located at the carboxyterminus end of the strands of the barrel. The crystal structure of porcine and human aldehyde reductase should allow in vitro mutagenesis to elucidate the mechanism of action for this enzyme and facilitate the effective design of specific inhibitors.
A series of 8-substituted pyrido[2,1-]quinazoline-2-carboxylic acids was prepared by the nickel carbonyl mediated carboxylation of the corresponding bromides. The activities of these compounds in the rat PCA test are comparable to those of the corresponding 2-substituted pyrido[2,1-b]quinazoline-8-carboxylic acids.
A series of substituted (E)-3-(4-oxo-4H-quinazolin-3-yl)-2-propenoic acids was prepared and evaluated in the rat passive cutaneous anaphylaxis (PCA) test for antiallergic activity. Alkoxy, alkylthio, and isopropyl substituents at the 6- or 8-positions provided highly potent compounds. Conversion to the Z isomer, reduction of the side chain double bond, or reduction of the quinazoline ring resulted in substantial loss of activity. Among the analogues that exhibited oral activity in the PCA test, (E)-3-[6-(methylthio)-4-oxo-4H-quinazolin-3-yl]-2-propenoic acid (5i) was the most potent.
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