EaStCHEM, School of Chemistry, University of Edinburgh, David Brewster Road, Edinburgh, EH9 3FJ, UK.
Present address: Laboratory of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
Chembiochem. 2019 Apr 1;20(7):872-876. doi: 10.1002/cbic.201800590. Epub 2019 Jan 16.
Traditionally, prodrug activation has been limited to enzymatic triggers or gross physiological aberrations, such as pH, that offer low selectivity and control over dosage. In recent years, the field of prodrug activation chemistry has been transformed by the use of bioorthogonal reactions that can be carried out under biological conditions at sub-millimolar concentrations, with the tetrazine-mediated inverse electron demand Diels-Alder reaction amongst the most recognised. Their high reaction rates, chemoselectivity and excellent biocompatibility make tetrazines ideal small molecules for activating prodrugs. Recently the tetrazine moiety has been used as a prodrug for a pyridazine thus broadening the scope of prodrug systems. This article discusses the concept of using tetrazines as small-molecule activators for prodrugs, and provides an overview of tetrazine-based prodrug systems, with a particular focus on the recently reported prodrug-prodrug activation strategy.
传统上，前药激活仅限于酶触发或明显的生理异常，如 pH 值，这些方法选择性和剂量控制较低。近年来，前药激活化学领域发生了转变，使用了可以在亚毫摩尔浓度下在生物条件下进行的生物正交反应，其中最著名的是四嗪介导的逆电子需求 Diels-Alder 反应。它们的高反应速率、化学选择性和优异的生物相容性使四嗪成为激活前药的理想小分子。最近，四嗪部分已被用作哒嗪的前药，从而拓宽了前药系统的范围。本文讨论了使用四嗪作为小分子激活剂来激活前药的概念，并概述了基于四嗪的前药系统，特别关注最近报道的前药-前药激活策略。
