Residual Complexity Does Impact Organic Chemistry and Drug Discovery: The Case of Rufomyazine and Rufomycin
Residual Complexity Does Impact Organic Chemistry and Drug Discovery: The Case of Rufomyazine and Rufomycin
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DOI：
10.1021/acs.joc.8b00988
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发表时间：
2018-06-15
影响因子：
3.6
通讯作者：
Pauli, Guido F.
中科院分区：
文献类型：
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作者：
Choules, Mary P.;Klein, Larry L.;Pauli, Guido F.
残留复杂性（RC）涉及微妙但关键的结构和生物学特征对药物先导化合物验证的影响，包括与未识别杂质相关的无法解释的影响。由于色谱分离方法的固有缺陷，RC通常困扰药物发现工作。新的二酮哌嗪，rufomyazine（6），和以前已知的抗生素，rufomycin（7），代表了RC的典型病例，（几乎）导致生物活性的错误分配。该案例证明了远低于C-13天然丰度（1.1%）的杂质可能具有高度相关性，并要求使用qNMR和LC-MS对具有>1：1，000的扩展摩尔动态范围的药物先导物进行高级分析表征。分离自放线菌菌株的6最初被发现对结核分枝杆菌具有活性，最低抑制浓度（MIC）为2 μ g/mL，具有高选择性。作为先导验证的一部分，合成了二肽，令人惊讶地发现其无活性。最初观察到的活性最终归因于高度活性的环肽（MIC类似于0.02 μ M）的非常轻微的污染（0.24% [m/m]），随后鉴定为7的类似物。这项研究说明了严重的影响RC可以施加在有机化学和药物发现，什么样的努力是至关重要的，以提高铅的验证和效率，特别是在NP相关的药物发现计划。
Residual complexity (RC) involves the impact of subtle but critical structural and biological features on drug lead validation, including unexplained effects related to unidentified impurities. RC commonly plagues drug discovery efforts due to the inherent imperfections of chromatographic separation methods. The new diketopiperazine, rufomyazine (6), and the previously known antibiotic, rufomycin (7), represent a prototypical case of RC that (almost) resulted in the misassignment of biological activity. The case exemplifies that impurities well below the natural abundance of C-13 (1.1%) can be highly relevant and calls for advanced analytical characterization of drug leads with extended molar dynamic ranges of >1:1,000 using qNMR and LC-MS. Isolated from an actinomycete strain, 6 was originally found to be active against Mycobacterium tuberculosis with a minimum inhibitory concentration (MIC) of 2 mu g/mL and high selectivity. As a part of lead validation, the dipeptide was synthesized and surprisingly found to be inactive. The initially observed activity was eventually attributed to a very minor contamination (0.24% [m/m]) with a highly active cyclic peptide (MIC similar to 0.02 mu M), subsequently identified as an analogue of 7. This study illustrates the serious implications RC can exert on organic chemistry and drug discovery, and what efforts are vital to improve lead validation and efficiency, especially in NP-related drug discovery programs.