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Unequivocal determination of caulamidines A and B: application and validation of new tools in the structure elucidation tool box
Chemical Science ( IF 7.6 ) Pub Date : 2017-11-06 00:00:00 , DOI: 10.1039/c7sc01996c Dennis J. Milanowski 1, 2, 3, 4, 5 , Naoya Oku 1, 2, 3, 4, 5 , Laura K. Cartner 1, 2, 3, 4, 5 , Heidi R. Bokesch 1, 2, 3, 4, 5 , R. Thomas Williamson 5, 6, 7, 8 , Josep Saurí 5, 6, 7, 8 , Yizhou Liu 5, 6, 7, 8 , Kirill A. Blinov 5, 9, 10, 11 , Yuanqing Ding 12, 13, 14, 15, 16 , Xing-Cong Li 12, 13, 14, 15, 16 , Daneel Ferreira 12, 13, 14, 15, 16 , Larry A. Walker 12, 13, 14, 15, 16 , Shabana Khan 12, 13, 14, 15, 16 , Michael T. Davies-Coleman 17, 18, 19, 20 , James A. Kelley 2, 3, 4, 5, 21 , James B. McMahon 1, 2, 3, 4, 5 , Gary E. Martin 5, 6, 7, 8 , Kirk R. Gustafson 1, 2, 3, 4, 5
Chemical Science ( IF 7.6 ) Pub Date : 2017-11-06 00:00:00 , DOI: 10.1039/c7sc01996c Dennis J. Milanowski 1, 2, 3, 4, 5 , Naoya Oku 1, 2, 3, 4, 5 , Laura K. Cartner 1, 2, 3, 4, 5 , Heidi R. Bokesch 1, 2, 3, 4, 5 , R. Thomas Williamson 5, 6, 7, 8 , Josep Saurí 5, 6, 7, 8 , Yizhou Liu 5, 6, 7, 8 , Kirill A. Blinov 5, 9, 10, 11 , Yuanqing Ding 12, 13, 14, 15, 16 , Xing-Cong Li 12, 13, 14, 15, 16 , Daneel Ferreira 12, 13, 14, 15, 16 , Larry A. Walker 12, 13, 14, 15, 16 , Shabana Khan 12, 13, 14, 15, 16 , Michael T. Davies-Coleman 17, 18, 19, 20 , James A. Kelley 2, 3, 4, 5, 21 , James B. McMahon 1, 2, 3, 4, 5 , Gary E. Martin 5, 6, 7, 8 , Kirk R. Gustafson 1, 2, 3, 4, 5
Affiliation
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Ambiguities and errors in the structural assignment of organic molecules hinder both drug discovery and total synthesis efforts. Newly described NMR experimental approaches can provide valuable structural details and a complementary means of structure verification. The caulamidines are trihalogenated alkaloids from a marine bryozoan with an unprecedented structural scaffold. Their unique carbon and nitrogen framework was deduced by conventional NMR methods supplemented by new experiments that define 2-bond heteronuclear connectivities, reveal very long-range connectivity data, or visualize the 35,37Cl isotopic effect on chlorinated carbons. Computer-assisted structural elucidation (CASE) analysis of the spectroscopic data for caulamidine A provided only one viable structural alternative. Anisotropic NMR parameters, specifically residual dipolar coupling and residual chemical shift anisotropy data, were measured for caulamidine A and compared to DFT-calculated values for the proposed structure, the CASE-derived alternative structure, and two energetically feasible stereoisomers. Anisotropy-based NMR experiments provide a global, orthogonal means to verify complex structures free from investigator bias. The anisotropic NMR data were fully consistent with the assigned structure and configuration of caulamidine A. Caulamidine B has the same heterocyclic scaffold as A but a different composition and pattern of halogen substitution. Caulamidines A and B inhibited both wild-type and drug-resistant strains of the malaria parasite Plasmodium falciparum at low micromolar concentrations, yet were nontoxic to human cells.
中文翻译：
明确确定花椰菜苷A和B：结构鉴定工具箱中新工具的应用和验证
有机分子结构分配中的歧义和错误会阻碍药物发现和总合成工作。最新描述的NMR实验方法可以提供有价值的结构细节和结构验证的补充手段。花椰菜苷是来自海洋苔藓动物的三卤代生物碱，具有空前的结构支架。它们的独特碳和氮骨架是通过常规NMR方法推导出来的，并辅之以定义2键异核连通性，揭示非常长距离的连通性数据或可视化35,37Cl同位素对氯化碳的影响。计算机辅助的结构解析（CASE）分析可乐敏A的光谱数据仅提供了一种可行的结构选择。测量了Caulamidine A的各向异性NMR参数，特别是残留的偶极偶合和残留的化学位移各向异性数据，并将其与DFT计算得出的结构，CASE衍生的替代结构和两种在能量上可行的立体异构体的DFT计算值进行了比较。基于各向异性的NMR实验提供了一种全局的，正交的方法来验证没有研究者偏倚的复杂结构。各向异性NMR数据与高岭土A的指定结构和构型完全一致。枯草嘧啶B具有与A相同的杂环骨架，但卤素取代基的组成和图案不同。低摩尔浓度的恶性疟原虫，对人细胞无毒。
更新日期：2017-11-14
中文翻译：
明确确定花椰菜苷A和B：结构鉴定工具箱中新工具的应用和验证
有机分子结构分配中的歧义和错误会阻碍药物发现和总合成工作。最新描述的NMR实验方法可以提供有价值的结构细节和结构验证的补充手段。花椰菜苷是来自海洋苔藓动物的三卤代生物碱，具有空前的结构支架。它们的独特碳和氮骨架是通过常规NMR方法推导出来的，并辅之以定义2键异核连通性，揭示非常长距离的连通性数据或可视化35,37Cl同位素对氯化碳的影响。计算机辅助的结构解析（CASE）分析可乐敏A的光谱数据仅提供了一种可行的结构选择。测量了Caulamidine A的各向异性NMR参数，特别是残留的偶极偶合和残留的化学位移各向异性数据，并将其与DFT计算得出的结构，CASE衍生的替代结构和两种在能量上可行的立体异构体的DFT计算值进行了比较。基于各向异性的NMR实验提供了一种全局的，正交的方法来验证没有研究者偏倚的复杂结构。各向异性NMR数据与高岭土A的指定结构和构型完全一致。枯草嘧啶B具有与A相同的杂环骨架，但卤素取代基的组成和图案不同。低摩尔浓度的恶性疟原虫，对人细胞无毒。
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