Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions.
Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions.
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DOI：
10.1021/acs.jmedchem.6b00788
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发表时间：
2017-02-09
影响因子：
7.3
通讯作者：
Brummond KM
中科院分区：
文献类型：
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作者：
Jackson PA;Widen JC;Harki DA;Brummond KM
虽然迈克尔受体显示出有效和广谱的生物活性，但由于其假定的无差别反应性，它们在药物发现中在很大程度上被忽视。因此，缺乏与具有该部分的天然产物及其类似物的硫醇反应性相关的信息。在最近批准的含丙烯酰胺的药物中，很明显，需要很好地理解异迈克尔加成反应和生理条件下生物硫醇与迈克尔受体的相对反应性，以设计和使用这些化合物作为生物工具和潜在的治疗剂。这种观点提供的信息，将有助于这种理解，如硫醇加成反应，生物活性，以及空间和电子因素，影响迈克尔受体的亲电性和可逆性的动力学。这种观点集中于α，β-不饱和羰基化合物，因为它们在生物活性天然产物中占优势。
Although Michael acceptors display a potent and broad spectrum of bioactivity, they have largely been ignored in drug discovery because of their presumed indiscriminate reactivity. As such, a dearth of information exists relevant to the thiol reactivity of natural products and their analogs possessing this moiety. In the midst of recently approved acrylamide-containing drugs, it is clear that a good understanding of the hetero-Michael addition reaction and the relative reactivities of biological thiols with Michael acceptors under physiological conditions is needed for the design and use of these compounds as biological tools and potential therapeutics. This perspective provides information that will contribute to this understanding, such as kinetics of thiol addition reactions, bioactivities, as well as steric and electronic factors that influence the electrophilicity and reversibility of Michael acceptors. This perspective is focused on α,β-unsaturated carbonyls given their preponderance in bioactive natural products.