Click and Release: A Chemical Strategy toward Developing Gasotransmitter Prodrugs by Using an Intramolecular Diels-Alder Reaction
Click and Release: A Chemical Strategy toward Developing Gasotransmitter Prodrugs by Using an Intramolecular Diels-Alder Reaction
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DOI：
10.1002/anie.201608732
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发表时间：
2016-12-19
影响因子：
16.6
通讯作者：
Wang, Binghe
中科院分区：
文献类型：
--
作者：
Ji, Xingyue;Zhou, Cheng;Wang, Binghe
前药策略已被证明是解决递送问题的非常有效的方式。前药开发中的许多化学过程依赖于掩蔽适当官能团的能力，这些官能团可以在适当条件下去除。然而，开发气体递质的有机前药代表了独特的挑战。对于一氧化碳尤其如此，其对于生物可逆性衍生化不具有容易的处理。通过利用分子内Diels-Alder反应，我们已经开发了一种前药策略，用于制备在合成和储存过程中稳定的有机CO前药，并且在接近生理条件下以可调的释放速率容易地释放CO。已经使用细胞培养抗炎测定和结肠炎动物模型研究了CO前药系统在递送足够量的CO以用于可能的治疗应用中的有效性。这些研究充分证明了概念的验证，并为进一步开发有机CO前药的药物化学工作奠定了坚实的基础。
Prodrug strategies have been proven to be a very effective way of addressing delivery problems. Much of the chemistry in prodrug development relies on the ability to mask an appropriate functional group, which can be removed under appropriate conditions. However, developing organic prodrugs of gasotransmitters represent unique challenges. This is especially true with carbon monoxide, which does not have an easy handle for bioreversible derivatization. By taking advantage of an intramolecular Diels-Alder reaction, we have developed a prodrug strategy for preparations of organic CO prodrugs that are stable during synthesis and storage, and yet readily release CO with tunable release rates under near physiological conditions. The effectiveness of the CO prodrug system in delivering a sufficient quantity of CO for possible therapeutic applications has been studied using a cell culture anti-inflammatory assay and a colitis animal model. These studies fully demonstrate the proof of concept, and lay a strong foundation for further medicinal chemistry work in developing organic CO prodrugs.