宝石二氟化对模型大环系统构象和性质的影响

IF 7.6 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Laurent Knerr, Thomas Cogswell, Marie. Ahlqvist, Richard James Lewis, Anneli Nordqvist, Christian Sköld
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引用次数: 0

摘要

对候选药物进行构象控制以提高药效和 ADME 特性是一个持续的研究领域。与非环化小分子相比,大环往往具有更高的刚性,因此是进行构象控制的完美平台。本研究将二氟烷氧基苯基分子作为改变大环构象的工具进行研究。从构象偏好和相关 ADME 特性的角度对含氟和不含氟的大环配对进行了比较。结果发现,合成的大环具有相似的主要构象,在大环骨架中呈现反式酰胺。不过,对于含氟大环来说,主要的反式酰胺构象与顺式酰胺次要构象处于平衡状态,通过 1H NMR 可以看出,反式/顺式的比例为 4:1。次要氟化异构体的构象拟合表明,二氟烷氧基系统的平面外偏好促使大环骨架中的酰胺采用顺式构象。与非氟化大环相比,氟化大环的代谢稳定性大大降低,据推测这是反式酰胺相互转化为顺式酰胺的结果,顺式酰胺可能更容易被代谢掉。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The Effect of gem-Difluorination on the Conformation and Properties of a Model Macrocyclic System
Conformational control of drug candidates to engineer improved potency and ADME properties is an ongoing area of research. Macrocyclic rings tend to offer a greater degree of rigidity than non-cyclised small molecules, and, as a result they are perfect platforms to instil conformational controls. In this study, the difluoroalkoxyphenyl moiety is examined as a tool to alter the conformation of macrocycles. A fluorinated and non-fluorinated macrocyclic matched pair is compared in terms of conformation preferences and related ADME properties. The synthesised macrocycles are found to give similar major conformations exhibiting a trans amide in the macrocyclic backbone. However, for the fluorinated macrocycle, the major trans amide conformation is in equilibrium with a cis amide minor conformation, seen by 1H NMR in a 4:1 ratio of trans/cis. The conformational fits for the minor fluorinated isomer demonstrate the out of plane preference of the difluoroalkoxy system encouraging the amide within the macrocycle backbone to adopt a cis conformation. A dramatic reduction in metabolic stability was found for the fluorinated macrocycle compared to the non-fluorinated and is postulated to be a result of the interconversion of trans amide to the cis amide, which may be more readily metabolised.
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来源期刊
Chemical Science
Chemical Science CHEMISTRY, MULTIDISCIPLINARY-
CiteScore
14.40
自引率
4.80%
发文量
1352
审稿时长
2.1 months
期刊介绍: Chemical Science is a journal that encompasses various disciplines within the chemical sciences. Its scope includes publishing ground-breaking research with significant implications for its respective field, as well as appealing to a wider audience in related areas. To be considered for publication, articles must showcase innovative and original advances in their field of study and be presented in a manner that is understandable to scientists from diverse backgrounds. However, the journal generally does not publish highly specialized research.
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