Bioorthogonal Cycloadditions: Computational Analysis with the Distortion/Interaction Model and Predictions of Reactivities.
Bioorthogonal Cycloadditions: Computational Analysis with the Distortion/Interaction Model and Predictions of Reactivities.
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DOI：
10.1021/acs.accounts.7b00265
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发表时间：
2017-09-19
影响因子：
18.3
通讯作者：
Houk KN
中科院分区：
文献类型：
--
作者：
Liu F;Liang Y;Houk KN
生物正交化学对体内生物过程的研究产生了重大影响。可以通过使用不与细胞成分发生反应且不干扰活细胞代谢过程的探针和报告基因来追踪感兴趣的生物分子。人们投入了大量的时间和精力来通过实验筛选潜在的生物正交试剂。本帐户描述了我们的小组如何对反应性和相互正交性进行计算筛选。我们与实验学家的合作导致了新的、有用的反应的发展。过去几年，文献中报道了数十种生物正交环加成，但随着跟踪多个目标的兴趣的兴起，我们的计算筛选对于发现新的相互正交生物正交环加成对变得越来越重要。已探索了应变烯烃和炔烃与常见 1,3-偶极子（例如叠氮化物）以及介离子悉尼酮和其他新型 1,3-偶极子的反应性。描述了用于生物正交狄尔斯-阿尔德环加成反应的“逆电子需求”二烯（例如三嗪和四嗪）的研究。我们开发的彩色图形提供了一个快照，显示反应对于细胞应用来说是否足够快（绿色），对于标记是否有足够的反应性（黄色），或者仅对合成有用或根本不发生（红色）。每个框的颜色提供了速率的即时视图，而条形图则提供了控制反应性因素的分析。该分析使用我们小组和荷兰 F. Matthias Bickelhaupt 小组独立开发的环加成反应性的扭曲/相互作用或活化应变模型。该模型根据将反应物扭曲为过渡态几何形状所需的能量来分析活化势垒。这种能量称为畸变能或活化应变，构成活化能的主要组成部分。两种反应物末端之间的强键合相互作用，我们称之为相互作用能，克服了畸变能并导致产物中形成新的键。本报告描述了我们如何使用畸变/相互作用模型分析和预测生物正交环加成反应性，以及我们的实验合作者如何利用这些见解来创建新的生物正交环加成。我们使用的图形记录并预测了哪些环加成组合将在生物正交化学中有用以及哪些反应对是相互正交的。例如，5-苯基-1,2,4-三嗪和硫代环庚炔的快速反应不会干扰3,6-二苯基-1,2,4,5-四嗪和环丙烯的另一个快速反应。不会发生交叉反应，因为这些反应非常缓慢。
Bioorthogonal chemistry has had a major impact on the study of biological processes in vivo. Biomolecules of interest can be tracked by using probes and reporters that do not react with cellular components and do not interfere with metabolic processes in living cells. Much time and effort has been devoted to the screening of potential bioorthogonal reagents experimentally. This Account describes how our groups have performed computational screening of reactivity and mutual orthogonality. Our collaborations with experimentalists have led to the development of new and useful reactions. Dozens of bioorthogonal cycloadditions have been reported in the literature in the past few years, but as interest in tracking multiple targets arises, our computational screening has gained importance for the discovery of new mutually orthogonal bioorthogonal cycloaddition pairs. The reactivities of strained alkenes and alkynes with common 1,3-dipoles such as azides, along with mesoionic sydnones and other novel 1,3-dipoles, have been explored. Studies of “inverse-electron-demand” dienes such as triazines and tetrazines that have been used in bioorthogonal Diels–Alder cycloadditions are described. The color graphics we have developed give a snapshot of whether reactions are fast enough for cellular applications (green), adequately reactive for labeling (yellow), or only useful for synthesis or do not occur at all (red). The colors of each box give an instant view of rates, while bar graphs provide an analysis of the factors that control reactivity. This analysis uses the distortion/interaction or activation strain model of cycloaddition reactivity developed independently by our group and that of F. Matthias Bickelhaupt in The Netherlands. The model analyzes activation barriers in terms of the energy required to distort the reactants to the transition state geometry. This energy, called the distortion energy or activation strain, constitutes the major component of the activation energy. The strong bonding interaction between the termini of the two reactants, which we call the interaction energy, overcomes the distortion energy and leads to the new bonds in the products. This Account describes how we have analyzed and predicted bioorthogonal cycloaddition reactivity using the distortion/interaction model and how our experimental collaborators have employed these insights to create new bioorthogonal cycloadditions. The graphics we use document and predict which combinations of cycloadditions will be useful in bioorthogonal chemistry and which pairs of reactions are mutually orthogonal. For example, the fast reaction of 5-phenyl-1,2,4-triazine and a thiacycloheptyne will not interfere with the other fast reaction of 3,6-diphenyl-1,2,4,5-tetrazine and a cyclopropene. No cross reactions will occur, as these are very slow reactions.
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影响因子：
15
作者：
Blackman, Melissa L.;Royzen, Maksim;Fox, Joseph M.
通讯作者：
Fox, Joseph M.
影响因子：
5.2
作者：
Ess, Daniel H.;Jones, Gavin O.;Houk, K. N.
通讯作者：
Houk, K. N.
影响因子：
3.2
作者：
Cole, Christian M.;Yang, Jun;Seckute, Jolita;Devaraj, Neal K.
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DOI：
10.1073/pnas.0707090104
发表时间：
2007-10-23
影响因子：
11.1
作者：
Baskin, Jeremy M.;Prescher, Jennifer A.;Bertozzi, Carolyn R.
通讯作者：
Bertozzi, Carolyn R.
影响因子：
2.9
作者：
Barone, V;Cossi, M
通讯作者：
Cossi, M