Department of Chemistry, Howard University, Washington, DC 20059, USA.
Bioorg Med Chem. 2010 Jan 1;18(1):134-41. doi: 10.1016/j.bmc.2009.11.011. Epub 2009 Nov 10.
A series of indazole-dione derivatives were synthesized by the 1,3-dipolar cycloaddition reaction of appropriate substituted benzoquinones or naphthoquinones and N-carboalkoxyamino diazopropane derivatives. These compounds were evaluated for their effects on human carbonyl reductase. Several of the analogs were found to serve as substrates for carbonyl reductase with a wide range of catalytic efficiencies, while four analogs display inhibitory activities with IC(50) values ranging from 3-5 microM. Two of the inhibitors were studied in greater detail and were found to be noncompetitive inhibitors against both NADPH and menadione with K(I) values ranging between 2 and 11 microM. Computational studies suggest that conformation of the compounds may determine whether the indazole-diones bind productively to yield product or nonproductively to inhibit the enzyme.
通过适当取代的苯醌或萘醌与 N-羰烷氧基氨基二嗪丙烷衍生物的 1,3-偶极环加成反应，合成了一系列吲唑二酮衍生物。这些化合物被评估了对人羰基还原酶的影响。一些类似物被发现作为羰基还原酶的底物，具有广泛的催化效率，而四个类似物显示出抑制活性，IC（50）值范围为 3-5μM。两种抑制剂进行了更详细的研究，发现它们是对 NADPH 和 menadione 的非竞争性抑制剂，K（I）值在 2 到 11μM 之间。计算研究表明，化合物的构象可能决定吲唑二酮是与产物结合以产生产物还是与酶非生产性结合以抑制酶。
