Stabilizing p-Dithiobenzyl Urethane Linkers without Rate-Limiting Self-Immolation for Traceless Drug Release
Stabilizing p-Dithiobenzyl Urethane Linkers without Rate-Limiting Self-Immolation for Traceless Drug Release
复制标题
稳定对二硫代苄基氨基甲酸酯连接体，无需限速自焚，实现无痕药物释放
DOI：
10.1002/cmdc.201900248
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发表时间：
2019
期刊：
影响因子：
3.4
通讯作者：
Wu Chuanliu
中科院分区：
文献类型：
--
作者：
Zheng Yiwu;Shen Yang;Meng Xiaoting;Wu Yaqi;Zhao Yibing;Wu Chuanliu
利用二硫键的氧化还原敏感性是靶向前药设计中的普遍策略。与脂肪族二硫化物相比，基于对硫代苄基的二硫化物很少用于前药设计，因为它们的固有不稳定性由芳香族硫醇的低pKa引起。在这里，我们研究了硫醇-二硫化物交换反应中空间位阻和低pKa效应之间的相互作用，并发现了一种新的硫醇-二硫化物交换过程，用于对硫代苄基基二硫化物的自分解。我们在α，α-二甲基-取代的双二硫代苄基尿烷连接体（DMTB连接体）中观察到中心离去基团位移效应，这导致二硫键稳定性增加两个数量级以上，其程度显着大于观察到的典型脂肪族二硫键。特别地，DMTB连接体不仅显示出高稳定性，而且由于芳香族硫醇的低pKa而显示出快速的自分解动力学，其可用作靶向试剂和细胞毒性药物之间的通用且稳健的连接，用于靶向前药设计。本发明的DMTB接头的独特且有前景的稳定性特征将可能激发新型靶向前药的开发，以实现药物向细胞中的无痕释放。
Exploiting the redox sensitivity of disulfide bonds is a prevalent strategy in targeted prodrug designs. In contrast to aliphatic disulfides,p‐thiobenzyl‐based disulfides have rarely been used for prodrug designs, given their intrinsic instability caused by the low pKaof aromatic thiols. Here, we examined the interplay between steric hindrance and the low‐pKaeffect on thiol–disulfide exchange reactions and uncovered a new thiol–disulfide exchange process for the self‐immolation ofp‐thiobenzyl‐based disulfides. We observed a central leaving group shifting effect in the α,α‐dimethyl‐substitutedp‐dithiobenzyl urethane linkers (DMTB linkers), which leads to increased disulfide stability by more than two orders of magnitude, an extent that is significantly greater than that observed with typical aliphatic disulfides. In particular, the DMTB linkers display not only high stability, but also rapid self‐immolation kinetics due to the low pKaof the aromatic thiol, which can be used as a general and robust linkage between targeting reagents and cytotoxic drugs for targeted prodrug designs. The unique and promising stability characteristics of the present DMTB linker will likely inspire the development of novel targeted prodrugs to achieve traceless release of drugs into cells.