Design, synthesis and evaluation of a novel series of spiroketals based on the structure of the antibacterial gyrase inhibitor novobiocin
Design, synthesis and evaluation of a novel series of spiroketals based on the structure of the antibacterial gyrase inhibitor novobiocin
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DOI：
10.1039/a700647k
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发表时间：
1997-09-21
期刊：
影响因子：
--
通讯作者：
Timms, D
中科院分区：
文献类型：
--
作者：
Bell, W;Block, MH;Timms, D
分子建模已经与晶体学和生物学数据结合使用，试图设计模拟香豆素抗生素新生霉素2的结构和活性的化合物。对6，6-螺缩酮系统8-11的四种构象的计算表明，虽然9应该是最低能量，8也应该容易获得并且这种构象与新生霉素的香豆素和糖环很好地重叠，关键的羟基和氨基甲酸酯基团结合到环己烷上，氢键受体结合到芳环上，表明12 a是最初的目标，模型化合物24的晶体结构显示9中所示的构象，因此支持分子建模。然而，新生霉素的晶体结构与促旋酶B的24 kD片段结合，促旋酶B是香豆素抗生素的靶标，表明是内酯羰基而不是Gory基团负责与Arg残基的关键相互作用，因此12 a中的羧基被错置为相应的H-键受体，随后，已经设计了结合额外的带有H-键受体的芳环（如13 a）或杂芳环（如45）以及环己烷环上额外的二甲基的化合物，所述额外的芳环或杂芳环沿着有氢键受体。这些结构的模型令人信服地与结合到24 kD促旋酶B的新生霉素重叠。已经开发了多种合成路线，允许测试这些化合物和潜在的假设。不幸的是，没有一种化合物显示出显著的酶或抗菌活性，我们将其归因于特征的组合，包括缺乏对Noviose甲氧基的替代和不能实现与Arg-76的良好堆积（电荷转移）相互作用。
Molecular modelling has been used in conjunction with crystallographic and biological data in an attempt to design compounds that mimic the structure and activity of the coumarin antibiotic novobiocin 2, Calculations on four conformations of a 6,6-spiroketal system 8-11 suggest that whilst 9 should be the lowest energy, 8 should also be readily accessible and this conformation overlays well with the coumarin and sugar rings of novobiocin, Incorporation of key hydroxy and carbamate groups onto the cyclohexane and a hydrogen bond acceptor onto the aromatic ring suggest 12a as the initial target, The crystal structure of a model compound 24 shows the conformation illustrated in 9 and thus supports the molecular modelling, However, the crystal structure of novobiocin bound to a 24 kD fragment of gyrase B, the target of the coumarin antibiotics, reveals that it is the lactone carbonyl rather than the Gory group which is responsible for a key interaction with an Arg residue and consequently the carboxy group in 12a is misplaced as a corresponding H-bond acceptor, Subsequently, compounds incorporating an extra aromatic (as in 13a) or heteroaromatic ring (as in 45) bearing an H-bond acceptor, along with the extra dimethyl groups on the cyclohexane ring, have been designed. Models of these structures overlay convincingly with novobiocin bound to 24 kD gyrase B, Versatile synthetic routes have been developed allowing these compounds and the underlying hypotheses to be tested, Unfortunately, none of the compounds demonstrates significant enzyme or antibacterial activity, which we attribute to a combination of features, including the lack of a replacement for the noviose methoxy group and the failure to achieve a good stacking (charge transfer) interaction with Arg-76.