Department of Biochemistry, Bose Institute , P-1/12 CIT Scheme VIIM, Kolkata 700054, India.
Biochemistry. 2013 Oct 22;52(42):7449-60. doi: 10.1021/bi400734e. Epub 2013 Oct 10.
Curcumin has shown promising therapeutic utilities for many diseases, including cancer; however, its clinical application is severely limited because of its poor stability under physiological conditions. Here we find that curcumin also loses its activity instantaneously in a reducing environment. Curcumin can exist in solution as a tautomeric mixture of keto and enol forms, and the enol form was found to be responsible for the rapid degradation of the compound. To increase the stability of curcumin, several analogues were synthesized in which the diketone moiety of curcumin was replaced by isoxazole (compound 2) and pyrazole (compound 3) groups. Isoxazole and pyrazole curcumins were found to be extremely stable at physiological pH, in addition to reducing atmosphere, and they can kill cancer cells under serum-depleted condition. Using molecular modeling, we found that both compounds 2 and 3 could dock to the same site of tubulin as the parent molecule, curcumin. Interestingly, compounds 2 and 3 also show better free radical scavenging activity than curcumin. Altogether, these results strongly suggest that compounds 2 and 3 could be good replacements for curcumin in future drug development.
姜黄素在许多疾病（包括癌症）的治疗中有很大的应用潜力；然而，由于其在生理条件下的稳定性差，其临床应用受到严重限制。在这里，我们发现姜黄素在还原环境中也会立即失去活性。姜黄素在溶液中可以以酮式和烯醇式的互变异构混合物形式存在，而烯醇式被发现是导致化合物快速降解的原因。为了提高姜黄素的稳定性，我们合成了几种类似物，其中姜黄素的二酮部分被异噁唑（化合物 2）和吡唑（化合物 3）基团取代。异噁唑和吡唑姜黄素在生理 pH 值以及还原气氛下都非常稳定，并且可以在血清耗尽的条件下杀死癌细胞。通过分子建模，我们发现化合物 2 和 3 都可以与亲代分子姜黄素结合到微管蛋白的相同部位。有趣的是，化合物 2 和 3 的自由基清除活性也比姜黄素好。总的来说，这些结果强烈表明，化合物 2 和 3 可能是未来药物开发中替代姜黄素的良好选择。
