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

Yanlei Zhang, Boris Illarionov, Adelbert Bacher, Markus Fischer, Gunda I. George, Qi Zhuang Ye, David Vander Velde, Phillip E. Fanwick, Yunlong Song, Mark Cushman

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17 Scopus citations

Abstract

(Chemical Equation Presented) 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 μM in Tris buffer and 22 ± 4 μM in phosphate buffer. This is significantly more potent than the reactant (K i 350 ± 76 μM, 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.

Original languageEnglish (US)
Pages (from-to)2769-2776
Number of pages8
JournalJournal of Organic Chemistry
Volume72
Issue number8
DOIs
StatePublished - Apr 13 2007
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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    Zhang, Y., Illarionov, B., Bacher, A., Fischer, M., George, G. I., Ye, Q. Z., Vander Velde, D., Fanwick, P. E., Song, Y., & Cushman, M. (2007). A novel lumazine synthase inhibitor derived from oxidation of 1,3,6,8-tetrahydroxy-2,7-naphthyridine to a tetraazaperylenehexaone derivative. Journal of Organic Chemistry, 72(8), 2769-2776. https://doi.org/10.1021/jo062246d