Departament de Química Inorgànica i Orgànica (Secció de Química Orgànica) &, Institut de Química Teòrica i Computacional (IQTCUB), Universitat de Barcelona, 08028, Barcelona, Spain.
Department of Theoretical Chemistry, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Amsterdam Center for Multiscale Modeling (ACMM), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV, Amsterdam (The, Netherlands.
Chemistry. 2022 Oct 26;28(60):e202201649. doi: 10.1002/chem.202201649. Epub 2022 Aug 29.
The development of small-molecule covalent inhibitors and probes continuously pushes the rapidly evolving field of chemical biology forward. A key element in these molecular tool compounds is the "electrophilic trap" that allows a covalent linkage with the target enzyme. The reactivity of this entity needs to be well balanced to effectively trap the desired enzyme, while not being attacked by off-target nucleophiles. Here we investigate the intrinsic reactivity of substrates containing a class of widely used electrophilic traps, the three-membered heterocycles with a nitrogen (aziridine), phosphorus (phosphirane), oxygen (epoxide) or sulfur atom (thiirane) as heteroatom. Using quantum chemical approaches, we studied the conformational flexibility and nucleophilic ring opening of a series of model substrates, in which these electrophilic traps are mounted on a cyclohexene scaffold (C H Y with Y=NH, PH, O, S). It was revealed that the activation energy of the ring opening does not necessarily follow the trend that is expected from C-Y leaving-group bond strength, but steeply decreases from Y=NH, to PH, to O, to S. We illustrate that the HOMO -LUMO interaction is an all-important factor for the observed reactivity. In addition, we show that the activation energy of aziridines and phosphiranes can be tuned far below that of the corresponding epoxides and thiiranes by the addition of proper electron-withdrawing ring substituents. Our results provide mechanistic insights to rationally tune the reactivity of this class of popular electrophilic traps and can guide the experimental design of covalent inhibitors and probes for enzymatic activity.
小分子共价抑制剂和探针的发展不断推动着化学生物学这一快速发展的领域前进。在这些分子工具化合物中，一个关键的元素是“亲电陷阱”，它允许与靶酶形成共价键。这种实体的反应性需要很好地平衡，以有效地捕获所需的酶，同时不被非靶标亲核试剂攻击。在这里，我们研究了含有一类广泛使用的亲电陷阱的底物的固有反应性，这些亲电陷阱是含有氮（氮丙啶）、磷（膦烷）、氧（环氧化物）或硫原子（噻吩）的三原子杂环。我们使用量子化学方法研究了一系列模型底物中环的构象灵活性和亲核开环，其中这些亲电陷阱安装在环己烯支架上（C HY，其中 Y=NH、PH、O、S）。结果表明，开环的活化能不一定遵循预期的 C-Y 离去基团键强度的趋势，而是从 Y=NH、PH、O、S 急剧下降。我们说明 HOMO-LUMO 相互作用是观察到的反应性的一个非常重要的因素。此外，我们还表明，通过添加适当的吸电子环取代基，氮丙啶和膦烷的活化能可以远低于相应的环氧化物和噻吩的活化能。我们的结果提供了对这类流行的亲电陷阱反应性进行合理调节的机制见解，并可以指导酶活性的共价抑制剂和探针的实验设计。
