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首页> 外文期刊>Journal of Physical Organic Chemistry >Molecular recognition and physicochemical properties in the discovery of selective antibacterial minor groove binders
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Molecular recognition and physicochemical properties in the discovery of selective antibacterial minor groove binders

机译：选择性抗菌小沟粘合剂的发现中的分子识别和理化性质

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摘要

The polyamide minor groove binders (MGBs), distamycin and netropsin, have been known for many years to have significant biological activities but high toxicity. Strategies are described for the development of more selective MGBs taking advantage of hydrophobic interactions with the minor groove of DNA. The introduction of branched alkyl side chain substituents, planar aromatic head groups and alkene isosteres of the amides have all been investigated. MGBs designed using these strategies and built from heterocyclic and aromatic amino acids with the ability to recognise short sequences of DNA have been found to be potent and selective antibacterial agents. Detailed structural and strength of binding investigations (NMR, capillary electrophoresis (CE), DNA footprinting, melting temperature measurement, ITC) show that their activity depends primarily upon molecular recognition in terms of both molecular shape and specific hydrogen bonding. However the lack of toxicity depends upon their basic tail group structure, the pK(a) of which has a major influence on access to bacterial and mammalian cells. Lead compounds are active in vivo at doses competitive with recently introduced antibacterial drugs.
机译：多年来，人们已经知道聚酰胺小沟粘合剂（MGB），双霉素和Netropsin具有显着的生物学活性，但毒性很高。描述了利用与DNA小沟的疏水性相互作用开发更具选择性的MGB的策略。已经研究了酰胺的支链烷基侧链取代基，平面芳族头部基团和烯烃等位异构体的引入。使用这些策略设计并由具有识别DNA短序列能力的杂环和芳香族氨基酸构建的MGB被发现是有效的选择性抗菌剂。结合研究的详细结构和强度（NMR，毛细管电泳（CE），DNA足迹，熔融温度测量，ITC）表明，它们的活性主要取决于分子识别，无论是分子形状还是特定的氢键。然而，毒性的缺乏取决于它们的基本尾基结构，其pK（a）对细菌和哺乳动物细胞的获取有重大影响。铅化合物在体内具有与最近推出的抗菌药物竞争的剂量。

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