Structural Characterization of Natural and Synthetic Macrocycles Using Charge-Transfer Dissociation Mass Spectrometry
Structural Characterization of Natural and Synthetic Macrocycles Using Charge-Transfer Dissociation Mass Spectrometry
复制标题
使用电荷转移解离质谱法表征天然和合成大环化合物的结构
DOI：
10.1021/jasms.1c00369
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发表时间：
2022
影响因子：
3.2
通讯作者：
Jackson, Glen P.
中科院分区：
文献类型：
--
作者：
Edwards, Halle M.;Sasiene, Zachary J.;Mendis, Praneeth M.;Jackson, Glen P.
随着药物开发商转向大自然来解决耐药性、药物输送和新出现的疾病等问题，对天然产物(NPs)的研究获得了兴趣。虽然纳米粒子提供了一个诱人的新的药理活性化合物的来源，但它们的结构复杂性给分析表征和有机合成带来了挑战。特别值得关注的是环、多环或大环化合物的表征。作为NP发展灵感的内源性化合物的一个例子是钴胺，如维生素B12。外源NPs的一个例子是包括红霉素在内的大环内酯类化合物。这两类大环都具有类似物，但由于它们的循环性质，它们通常抵抗碰撞诱导解离(CID)造成的碎裂。在本工作中，使用电荷转移解离(CTD)，在有或没有补充碰撞活化的情况下，产生不同大环前体的自由基驱动的高能碎裂产物。在CTnoD产物的碰撞激活的帮助下，CTD频繁地裂解大环核心内的两个共价键，以揭示丰富的信息光谱，帮助识别修饰位点和解析结构类似物。在大环碎裂的第三个例子中，CTD使生物样品中的杂质被表征为尼龙-6，6的环状聚合物。在每个例子中，CTD光谱与CID截然不同，并且高度使人想起其他高能碎裂技术，如极端紫外光解离光电离(XUV-DPI)和电子电离诱导解离(EID)。结果表明，CTD-MS是表征天然和合成大环的一种有用的工具。
Research in natural products (NPs) has gained interest as drug developers turn to nature to combat problems with drug resistance, drug delivery, and emerging diseases. Whereas NPs offer a tantalizing source of new pharmacologically active compounds, their structural complexity presents a challenge for analytical characterization and organic synthesis. Of particular concern is the characterization of cyclic-, polycyclic-, or macrocyclic compounds. One example of endogenous compounds as inspiration for NP development are cobalamins, like vitamin B12. An example of exogenous NPs is the class of macrolides that includes erythromycin. Both classes of macrocycles feature analogues with a range of modifications on their macrocyclic cores, but because of their cyclic nature, they are generally resistant to fragmentation by collision-induced dissociation (CID). In the present work, charge-transfer dissociation (CTD) was employed, with or without supplemental collisional activation, to produce radical-driven, high-energy fragmentation products of different macrocyclic precursors. With the assistance of collisional activation of CTnoD products, CTD frequently cleaved two covalent bonds within the macrocycle cores to reveal rich, informative spectra that helped identify sites of modification and resolve structural analogues. In a third example of macrocycle fragmentation, CTD enabled an impurity in a biological sample to be characterized as a cyclic polymer of nylon-6,6. In each example, CTD spectra are starkly different from CID and are highly reminiscent of other high-energy fragmentation techniques like extreme ultraviolet dissociative photoionization (XUV-DPI) and electron ionization-induced dissociation (EID). The results indicate that CTD-MS is a useful tool for the characterization of natural and synthetic macrocycles.