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Manipulation of Glutathione-Mediated Degradation of Thiol–Maleimide Conjugates
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-10-04 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00546 Haocheng Wu , Paige J. LeValley , Tianzhi Luo , April M. Kloxin , Kristi L. Kiick 1
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-10-04 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00546 Haocheng Wu , Paige J. LeValley , Tianzhi Luo , April M. Kloxin , Kristi L. Kiick 1
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The retro Michael-type addition and thiol exchange of thioether succinimide click linkages in response to thiol-containing environments offers a novel strategy for the design of glutathione-sensitive degradable hydrogels for controlled drug delivery. Here we characterize the kinetics and extent of the retro Michael-type addition and thiol exchange with changes in both the pKa of the thiols and the identity of N-substituents of maleimides. A series of N-substituted thioether succinimides were prepared through typical Michael-type addition. Model studies (1H NMR, HPLC) of 4-mercaptophenylacetic acid (MPA, pKa 6.6) conjugated to N-ethyl maleimide (NEM), N-phenyl maleimide (NPM), or N-aminoethyl maleimide (NAEM) and then incubated with glutathione showed half-lives of conversion from 3.1 to 18 h, with extents of conversion from approximately 12% to 90%. The variations in the rates of exchange and hydrolytic ring opening appear to be mediated by resonance effects, electron-withdrawing capacity of the N-substituted moiety, as well as the potential for intramolecular catalytic hydrogen bonding of amine substituents with water (particularly in the case of ring opening). Further model studies of 4-mercaptohydrocinnamic acid (MPP, pKa 7.0) and N-acetyl-l-cysteine (NAC, pKa 9.5) conjugated to selected N-substituted maleimides and then incubated with glutathione showed half-lives of conversion from 3.6 to 258 h, with extents of conversion from approximately 1% to 90%. A higher pKa of the thiol decreased the rate of the exchange reaction and limited the impact of other electronic effects of N-substituents on the extents of conversion. Additional factors affecting the conversion kinetics were studied on NEM conjugates. The kinetics of the retro Michael-type addition and exchange reaction were not hindered by thiol traps of lower pKa, but were retarded in conditions of lower pH. These studies shed light into details of thiol and maleimide design that could be used to tune the rates of degradation of drug and polymer conjugates for a variety of applications.
中文翻译：
谷胱甘肽介导的巯基-马来酰亚胺偶联物的降解。
响应于含硫醇的环境，硫醚琥珀酰亚胺点击键的复古迈克尔型加成和硫醇交换为设计可控药物递送的谷胱甘肽敏感的可降解水凝胶提供了一种新颖的策略。在这里我们表征了动力学和逆向迈克尔型加成和硫醇交换程度与硫醇的p K a和马来酰亚胺的N-取代基的身份的变化。通过典型的迈克尔型加成制备了一系列的N-取代的硫醚琥珀酰亚胺。结合到N-乙基马来酰亚胺（NEM），N-苯基马来酰亚胺（NPM）上的4-巯基苯乙酸（MPA，p K a 6.6）的模型研究（1 H NMR，HPLC）或N-氨乙基马来酰亚胺（NAEM），然后与谷胱甘肽一起孵育，显示半衰期为3.1到18 h，转化率约为12％到90％。交换速率和水解开环速率的变化似乎是由共振效应，N-取代的部分的吸电子能力以及胺取代基与水的分子内催化氢键合的电势引起的（尤其是在这种情况下）开环）。4-巯基肉桂酸（MPP，p K a 7.0）和N-乙酰基-1-半胱氨酸（NAC，p K a的进一步模型研究9.5）与选定的N-取代的马来酰亚胺偶联，然后与谷胱甘肽一起孵育，显示半衰期为3.6至258小时，转化率约为1％至90％。较高的硫醇的p K a降低了交换反应的速率，并限制了N-取代基的其他电子效应对转化程度的影响。在NEM共轭物上研究了影响转化动力学的其他因素。较低的p K a的硫醇阱不会阻碍麦克尔型加成和交换反应的动力学。，但在较低pH的条件下被阻滞。这些研究揭示了硫醇和马来酰亚胺设计的细节，这些细节可用于调整药物和聚合物共轭物的降解速度，以用于各种应用。
更新日期：2018-10-04
中文翻译：
谷胱甘肽介导的巯基-马来酰亚胺偶联物的降解。
响应于含硫醇的环境，硫醚琥珀酰亚胺点击键的复古迈克尔型加成和硫醇交换为设计可控药物递送的谷胱甘肽敏感的可降解水凝胶提供了一种新颖的策略。在这里我们表征了动力学和逆向迈克尔型加成和硫醇交换程度与硫醇的p K a和马来酰亚胺的N-取代基的身份的变化。通过典型的迈克尔型加成制备了一系列的N-取代的硫醚琥珀酰亚胺。结合到N-乙基马来酰亚胺（NEM），N-苯基马来酰亚胺（NPM）上的4-巯基苯乙酸（MPA，p K a 6.6）的模型研究（1 H NMR，HPLC）或N-氨乙基马来酰亚胺（NAEM），然后与谷胱甘肽一起孵育，显示半衰期为3.1到18 h，转化率约为12％到90％。交换速率和水解开环速率的变化似乎是由共振效应，N-取代的部分的吸电子能力以及胺取代基与水的分子内催化氢键合的电势引起的（尤其是在这种情况下）开环）。4-巯基肉桂酸（MPP，p K a 7.0）和N-乙酰基-1-半胱氨酸（NAC，p K a的进一步模型研究9.5）与选定的N-取代的马来酰亚胺偶联，然后与谷胱甘肽一起孵育，显示半衰期为3.6至258小时，转化率约为1％至90％。较高的硫醇的p K a降低了交换反应的速率，并限制了N-取代基的其他电子效应对转化程度的影响。在NEM共轭物上研究了影响转化动力学的其他因素。较低的p K a的硫醇阱不会阻碍麦克尔型加成和交换反应的动力学。，但在较低pH的条件下被阻滞。这些研究揭示了硫醇和马来酰亚胺设计的细节，这些细节可用于调整药物和聚合物共轭物的降解速度，以用于各种应用。
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