Tunable degradation of maleimide-thiol adducts in reducing environments.
Tunable degradation of maleimide-thiol adducts in reducing environments.
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DOI：
10.1021/bc200148v
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发表时间：
2011-10-19
影响因子：
4.7
通讯作者：
Kiick, Kristi L.
中科院分区：
文献类型：
--
作者：
Baldwin, Aaron D.;Kiick, Kristi L.
加成化学广泛用于制备生物缀合物，特别是马来酰亚胺-硫醇加合物已被广泛使用。在这里，我们表明，通过硫醇与N-乙基马来酰亚胺（NEM）进行迈克尔型加成形成的琥珀酰亚胺硫醚通常被认为是稳定的，实际上可以在生理pH和温度下在其他硫醇化合物存在的情况下发生逆反应和交换反应，从而提供了一种新的控释策略。与 4-巯基苯乙酸 (MPA)、N-乙酰半胱氨酸或 3-巯基丙酸 (MP) 缀合的 NEM 与谷胱甘肽一起孵育的模型研究（1H NMR、HPLC）显示，MPA 和 N-乙酰半胱氨酸缀合物的转化半衰期为 20-80 小时，转化程度为 20-90%。开环所得的琥珀酰亚胺硫醚以及任何MP加合物均未显示逆反应和交换反应。逆反应的动力学可以通过迈克尔供体的反应性来调节；因此，可以调整马来酰亚胺-硫醇加合物的降解，以在与目前通过二硫化物介导的释放可能不同的时间尺度上控制药物释放或材料降解。这些方法可能会在减少与化疗和亚细胞运输相关的环境中找到控制释放的新利基。
Addition chemistries are widely used in preparing biological conjugates, and in particular, maleimide-thiol adducts have been widely employed. Here we show that the resulting succinimide thioether formed by a Michael type addition of a thiol to N-ethylmaleimide (NEM), generally accepted as stable, can in fact undergo retro and exchange reactions in the presence of other thiol compounds at physiological pH and temperature, offering a novel strategy for controlled release. Model studies (1H NMR, HPLC) of NEM conjugated to 4-mercaptophenylacetic acid (MPA), N-acetylcysteine, or 3-mercaptopropionic acid (MP) incubated with glutathione showed half lives of conversion from 20–80 hrs, with extents of conversion from 20–90% for MPA and N-acetylcysteine conjugates. Ring-opened the resultant succinimide thioether as well as any MP adduct did not show retro and exchange reactions. The kinetics of the retro reactions can be modulated by the Michael donor’s reactivity; therefore the degradation of maleimide-thiol adducts could be tuned for controlled release of drugs or degradation of materials at timescales different than those currently possible via disulfide-mediated release. Such approaches may find a new niche for controlled release in reducing environments relevant in chemotherapy and sub-cellular trafficking.
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影响因子：
4.7
作者：
Schumacher, Felix F.;Nobles, Muriel;Ryan, Chris P.;Smith, Mark E. B.;Tinker, Andrew;Caddick, Stephen;Baker, James R.
通讯作者：
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影响因子：
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作者：
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通讯作者：
Hoffman, A