结构修饰调节谷胱甘肽激活的芳基偶氮二氮烯醇前药的稳定性。
Structural modifications modulate stability of glutathione-activated arylated diazeniumdiolate prodrugs.
机构信息
Drug Design Section, Chemical Biology Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
出版信息
Bioorg Med Chem. 2012 May 1;20(9):3094-9. doi: 10.1016/j.bmc.2012.02.045. Epub 2012 Mar 9.
Abstract
JS-K, a diazeniumdiolate-based nitric oxide (NO)-releasing prodrug, is currently in late pre-clinical development as an anti-cancer drug candidate. This prodrug was designed to be activated by glutathione (GSH) to release NO. To increase the potency of JS-K, we are investigating the effect of slowing the reaction of the prodrugs with GSH. Herein, we report the effect of replacement of nitro group(s) by other electron-withdrawing group(s) in JS-K and its homo-piperazine analogues on GSH activation and the drugs' biological activity. We show that nitro-to-cyano substitution increases the half-life of the prodrug in the presence of GSH without compromising the compound's in vivo antitumor activity.
摘要
JS-K 是一种基于重氮二酮的一氧化氮（NO）释放前药，目前处于晚期临床前开发阶段，作为一种抗癌药物候选物。该前药旨在通过谷胱甘肽 (GSH) 激活以释放 NO。为了提高 JS-K 的效力，我们正在研究减缓前药与 GSH 反应的效果。在此，我们报告了在 JS-K 及其同哌嗪类似物中将硝基（s）替换为其他吸电子基团对 GSH 激活和药物生物活性的影响。我们表明，硝基到氰基的取代在 GSH 存在的情况下增加了前药的半衰期，而不影响化合物的体内抗肿瘤活性。
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