School of Natural Sciences (Chemistry), College of Sciences and Engineering, University of Tasmania, Private Bag 75, Hobart, TAS 7001, Australia.
School of Chemistry and Molecular Bioscience, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia.
Molecules. 2023 Feb 8;28(4):1631. doi: 10.3390/molecules28041631.
As part of a project on fused medium-sized ring systems as potential drugs, we have previously demonstrated the usefulness of Density Functional Theory (DFT) to evaluate amine nitrogen-based transannular interactions across the central 10-membered ring in the bioactive dibenzazecine alkaloid, protopine. A range of related hypothetical systems have been investigated, together with transannular interactions involving ring-embedded imino or azo group nitrogens and atoms or groups (Y) across the ring. Electrostatic potential energies mapped onto electron density surfaces in the different ring conformations were evaluated in order to characterise these conformations. Unexpectedly, the presence of sp hybridised nitrogen atoms in the medium-sized rings did not influence the conformations appreciably. The strength and type of the NY interactions are determined primarily by the nature of Y. This is also the case when the substituent on the interacting nitrogen is varied from CH (protopine) to H or OH. With Y = BOH, very strong interactions were observed in protopine analogues, as well as in rings incorporating imino or azo groups. Strong to moderate interactions were observed with Y = CS, CO and SO in all ring systems. Weaker interactions were observed with Y = S, O and weaker ones again with an sp hybridised carbon (Y = CH). The transannular interactions can influence conformational preferencing and shape and change electron distributions at key sites, which theoretically could modify properties of the molecules while providing new or enhanced sites for biological target interactions, such as the H or OH substituent. The prediction of new strong transannular interaction types such as with Y = BOH and CS should be helpful in informing priorities for synthesis and other experimental studies.
作为融合中型环系统作为潜在药物项目的一部分，我们之前已经证明了密度泛函理论 (DFT) 在评估生物活性二苯并氮杂卓生物碱普罗托品中环中心 10 元环中胺氮的跨环相互作用的有用性。研究了一系列相关的假设系统，以及涉及环嵌入亚氨基或偶氮基团氮原子和环上原子或基团 (Y) 的跨环相互作用。为了表征这些构象，评估了不同环构象中电子密度表面上映射的静电势能能。出乎意料的是，中型环中 sp 杂化氮原子的存在并没有显著影响构象。NY 相互作用的强度和类型主要取决于 Y 的性质。当相互作用氮上的取代基从 CH（普罗托品）变为 H 或 OH 时，情况也是如此。当 Y = BOH 时，在普罗托品类似物以及包含亚氨基或偶氮基团的环中观察到非常强的相互作用。在所有环系统中，Y = CS、CO 和 SO 观察到强到中等相互作用。Y = S、O 的相互作用较弱，而 Y = CH（sp 杂化碳）的相互作用更弱。跨环相互作用可以影响构象偏好和形状，并改变关键部位的电子分布，这在理论上可以改变分子的性质，同时为生物靶标相互作用提供新的或增强的位点，例如 H 或 OH 取代基。对新的强跨环相互作用类型（如 Y = BOH 和 CS）的预测应该有助于为合成和其他实验研究确定优先级。
