Zhang Yanlei, Illarionov Boris, Bacher Adelbert, Fischer Markus, Georg Gunda I, Ye Qi-Zhuang, Vander Velde David, Fanwick Phillip E, Song Yunlong, Cushman Mark
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.
J Org Chem. 2007 Apr 13;72(8):2769-76. doi: 10.1021/jo062246d. Epub 2007 Mar 10.
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.
1,3,6,8 - 四羟基 - 2,7 - 萘啶的空气氧化反应生成了2,5,8,11 - 四氮杂 - 5,11 - 二氢 - 4,10 - 二羟基苝 - 1,3,6,7,9,12 - 六酮。产物的X射线晶体学分析表明，它在固态时以内消旋形式存在。产物形成的机制很可能涉及氧化酚偶联和氧化反应。该产物被证明是粟酒裂殖酵母核黄素合酶的竞争性抑制剂，在Tris缓冲液中的Ki为66±13 μM，在磷酸盐缓冲液中的Ki为22±4 μM。这比反应物（Ki 350±76 μM，竞争性抑制）的活性显著更高，反应物之前已通过高通量筛选被鉴定为核黄素合酶抑制剂。从头算计算表明，内消旋形式比对映体形式稍微不稳定，并且这两种形式在室温下会快速相互转化。
