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    J Org Chem. 2007 Apr 13;72(8):2769-76. Epub 2007 Mar 10.

    A novel lumazine synthase inhibitor derived from oxidation of 1,3,6,8-tetrahydroxy-2,7-naphthyridine to a tetraazaperylenehexaone derivative.

    Zhang Y, Illarionov B, Bacher A, Fischer M, Georg GI, Ye QZ, Vander Velde D, Fanwick PE, Song Y, Cushman M.

    Source

    Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, and The Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.

    Abstract

    Air oxidation of 1,3,6,8-tetrahydroxy-2,7-naphthyridine afforded 2,5,8,11-tetraaza-5,11-dihydro-4,10-dihydroxyperylene-1,3,6,7,9,12-hexaone. X-ray crystallography of the product revealed that it exists in the meso form in the solid state. The mechanism of product formation most likely involves oxidative phenolic coupling and oxidation. The product proved to be a competitive inhibitor of Schizosaccharomyces pombe lumazine synthase with a Ki of 66+/-13 microM in Tris buffer and 22+/-4 microM in phosphate buffer. This is significantly more potent than the reactant (Ki 350+/-76 microM, competitive inhibition), which had previously been identified as a lumazine synthase inhibitor by high-throughput screening. Ab initio calculations indicate that the meso form is slightly less stable than the enantiomeric form, and that the two forms interconvert rapidly at room temperature.

    PMID:
    17348709
    [PubMed - indexed for MEDLINE]
    PMCID:
    PMC2526313
    Free PMC Article

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