Activation of sulfonate ester based matrix metalloproteinase proinhibitors by hydrogen peroxide.
Activation of sulfonate ester based matrix metalloproteinase proinhibitors by hydrogen peroxide.
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DOI：
10.1007/s00775-010-0727-x
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发表时间：
2011-02
影响因子：
3
通讯作者：
Cohen, Seth M.
中科院分区：
文献类型：
--
作者：
Daniel, Kevin B.;Jourden, Jody L. Major;Negoescu, Kimberly E.;Cohen, Seth M.
本研究详细介绍了在活性氧（ROS）存在下激活的基质金属蛋白酶抑制剂前体药物（proMMPi）的开发。传统的基质金属蛋白酶抑制剂（MMPi）利用锌结合基团（ZBG）与基质金属蛋白酶（MMPs）的催化锌（II）离子螯合来抑制其活性。为了制造对ros敏感的前药，我们使用磺酸酯作为ZBG的保护基团来阻断它们的金属结合能力。令人惊讶的是，只有当ZBG含有n -氧化物给体原子片段时，这些磺酸酯才会被H2O2切割。基于这些可触发ros的体系合成了全长MMPi的磺酸酯衍生物。结果表明，具有磺酸酯保护基团的proMMPi在H2O2的作用下具有较高的裂解率，从而释放出活性MMPi。体外MMP抑制研究证实，添加H2O2后，proMMPi的抑制活性显著增加，表明使用磺酸酯作为ros激活前药的可切割触发器。
This study details the development of matrix metalloproteinase inhibitor prodrugs (proMMPi) that are activated in the presence of reactive-oxygen species (ROS). Conventional matrix metalloproteinase inhibitors (MMPi) utilize a zinc-binding group (ZBG) that chelates to the catalytic zinc(II) ion of matrix metalloproteinases (MMPs) to inhibit their activity. To create ROS-sensitive prodrugs, sulfonate esters were used as a protecting group for the ZBG to block their metal binding ability. Surprisingly, these sulfonate esters were found to be cleaved by H2O2 only when the ZBG contained an N-oxide donor atom moiety. Sulfonate ester derivatives of full-length MMPi based on these ROS-triggerable systems were synthesized. It was found that proMMPi with sulfonate ester protecting groups showed relatively high rates of cleavage in the presence of H2O2 to release the active MMPi. In vitro MMP inhibition studies confirmed a significant increase in inhibitory activity of proMMPi upon addition of H2O2, demonstrating the use of sulfonate esters to act as cleavable triggers for ROS-activated prodrugs.
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