Boron Mimetics: 1,2-Dihydro-1,2-azaborines Bind inside a Nonpolar Cavity of T4 Lysozyme
Boron Mimetics: 1,2-Dihydro-1,2-azaborines Bind inside a Nonpolar Cavity of T4 Lysozyme
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DOI：
10.1002/anie.200903390
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发表时间：
2009-01-01
影响因子：
16.6
通讯作者：
Liu, Shih-Yuan
中科院分区：
文献类型：
--
作者：
Liu, Lijun;Marwitz, Adam J. V.;Liu, Shih-Yuan
与元素周期表中的碳、氮和氧相比，硼元素在生物医学应用中没有受到太多关注。可以说，这可能是由于硼在自然界生命进化中的明显“微不足道”。[1，2]然而，硼具有有用的元素和化学特征，包括核自旋、中子俘获的大截面和刘易斯酸性。如果硼可以被整合到生物相关分子中[3]，它可能会通过用作标记物[4]，作为新的药效团[5]或用于癌症治疗而有益于生物医学研究。[6]我们感兴趣的是合成方法，将允许硼纳入这些分子[7]，其结构的干扰最小。1，2-二氢-1，2-氮杂硼杂环（缩写为1，2-azaborines）作为一种独特的结构平台来实现这一目标，因为它们与芳烃（在活生物体和药物中普遍存在的基序）的同构关系。此外，已证明芳烃与阳离子和其他芳烃通过阳离子-π [8]和π-π [9]相互作用形成的键合在生物系统中至关重要。因此，芳烃在生物医学研究中的广泛用途和根本重要性与硼的独特元素/化学特征相结合，以及通过CC/BN电子等排性扩大芳烃结构多样性的潜力[10]使得1，2-氮杂硼杂环成为生物医学研究的有吸引力的目标Dewar和白色在20世纪60年代开创了单环和环稠合的多环1，2-氮杂硼杂环衍生物的化学。[11]自2000年以来，Ashe [12] Piers [13]和Paetzold [14]的贡献进一步推进了新型BN杂环的制备，并引发了对这些化合物的化学和性质的新兴趣。[15]我们最近开发了合成方法，扩大了可获得的1，2-氮杂硼杂环的范围[16]，并能够制备该杂环家族的长期寻求的母体化合物。[17]我们还通过X射线晶体学研究表明，1，2-氮杂硼具有与芳香性一致的离域结构。[18]虽然1，2-氮杂硼杂环的多功能合成工具箱的开发已经得到改进，但它们在生物学背景下的研究仍然是难以捉摸的。在这次交流中，我们提供了第一个实验证据的1，2-氮杂硼与生物系统的相互作用。具体地，我们描述了N-Et-1，2-氮杂硼杂和母体1，2-氮杂硼杂（以下分别为EtAzB和HAzB）通过单晶X射线晶体学在T4溶菌酶的工程化非极性腔内的结合。
The element boron has not received much attention in biomedical applications compared to its periodic table neighbors carbon, nitrogen and oxygen. Arguably, this might be due to the apparent “insignificance” of boron in Nature’s evolution of life.[1, 2] Boron has however useful elemental and chemical features that include nuclear spin, large cross section for neutron capture, and Lewis acidity. If boron could be incorporated into biologically relevant molecules [3] it might benefit biomedical research by being used as a marker,[4] as a new pharmacophore,[5] or in cancer therapy.[6] We are interested in synthetic approaches that will allow the incorporation of boron into such molecules [7] with minimal perturbation of their structures. 1, 2-Dihydro-1, 2-azaborines (abbreviated as 1, 2-azaborines) serve as a unique structural platform to accomplish this goal because of their isostructural relationship with arenes, a ubiquitous motif in living organisms and in pharmaceuticals. Furthermore, the bonding of arenes with cations and other arenes through cation-π [8] and π-π [9] interactions have been demonstrated to be vital in biological systems. Thus, the broad utility and fundamental importance of arenes in biomedical research combined with the unique elemental/chemical features of boron, and the potential of expanding the diversity of arene structures through CC/BN isosterism [10] make 1, 2-azaborines attractive targets for biomedical investigation (Scheme 1).Dewar and White pioneered the chemistry of monocyclic and ring-fused polycyclic 1, 2-azaborine derivatives in the 1960s.[11] Since 2000, contributions by Ashe,[12] Piers,[13] and Paetzold,[14] have further advanced the preparation of novel BN heterocycles and sparked a renewed interest in the chemistry and properties of these compounds.[15] We have recently developed synthetic methods that expand the scope of accessible 1, 2-azaborines [16] and enable the preparation of the long sought-after parent compound of this family of heterocycles.[17] We have also shown through X-ray crystallographic studies that 1, 2-azaborines possess delocalized structures consistent with aromaticity.[18] While the development of a versatile synthetic toolbox for 1, 2-azaborines has been improved, their investigation in a biological context has remained elusive. In this communication we provide the first experimental evidence for the interaction of 1, 2-azaborines with a biological system. Specifically, we describe the binding of N-Et-1, 2-azaborine and the parent 1, 2-azaborine (hereafter EtAzB and HAzB, respectively) inside an engineered non-polar cavity of T4 lysozyme via single-crystal X-ray crystallography.