A highly practical RCM approach towards a molecular building kit of spirocyclic reverse turn mimics
A highly practical RCM approach towards a molecular building kit of spirocyclic reverse turn mimics
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DOI：
10.1002/chem.200600432
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发表时间：
2006-08-16
影响因子：
4.3
通讯作者：
Gmeiner, Peter
中科院分区：
文献类型：
--
作者：
Bittermann, Holger;Boeckler, Frank;Gmeiner, Peter
具有特权的分子支架的开发能够有效地模拟反转基序，从而增加结合和选择性，并能够阐明天然多肽的生物活性构象，这引起了人们的极大兴趣。在不同的回转模式中频繁出现的Pro引发了基于Pro的反向回转模拟的设计。作为高效的VI型β转角诱导剂I与饱和螺环内酰胺3有效模拟11β转角的结构杂交，我们开发了一条合成2型不饱和螺环内酰胺的通用路线，将Seebach的自我复制手性方法学与多肽偶联反应和格拉布斯的关环歧化反应相结合。通过这种方法，可以按照统一的途径获得具有6-9个内酰胺环的各种模型多肽。将适当保护的模板引入固相肽合成中，可产生天然神经肽神经降压素的不饱和螺环类似物。光谱研究以及在高水平理论上的密度泛函计算表明，诱导反转的效力与环的大小有显着的相关性。虽然不饱和螺环β-内酰胺12的二级结构与参考的伽马-内酰胺3a非常一致，但不饱和β-内酰胺11是一种非常有效的β-转折诱导剂，甚至优于3b型的β-内酰胺。八元不饱和螺环内酰胺13采用的构象几乎完美地匹配了整个系列中具有最高稳定性的典型类型11β转折的先决条件。相反，九元螺内酰胺14代表具有高构象柔性的支架。
The development of privileged molecular scaffolds efficiently mimicking reverse turn motifs and thus increasing both binding and selectivity and enabling the elucidation of the bioactive conformation of a natural peptide has attracted remarkable interest. The frequent occurrence of proline in various turn patterns initiated the design of proline-based reverse turn mimetics. As a structural hybridization of a highly potent type VI beta-turn inducer I with saturated spirocyclic lactams 3 efficiently mimicking type 11 beta turns, we developed a versatile synthetic route towards unsaturated spirocyclic lactams of type 2, when Seebach's self-reproduction of chirality methodology was combined with a peptide coupling reaction and Grubbs' ring-closing metathesis. By this means, a variety of model peptides with six- up to nine-memembered lactam rings were accessible following a uniform pathway. Introduction of suitably protected templates into solid-phase peptide synthesis gave rise to unsaturated spirocyclic analogues of the naturally occurring neuropeptide neurotensin. Spectroscopic investigations as well as DFT calculations on a high level of theory revealed a remarkable dependence of the reverse-turn inducing potency on the ring size. While the secondary structure of the unsaturated spirocyclic epsilon-lactam 12 closely agrees with the reference gamma-lactam 3a, the unsaturated delta-lactam 11 serves as an extraordinarily potent beta-turn inducer which is even superior to beta-lactams of type 3b. The eight-membered unsaturated spirocyclic lactam 13 adopts a conformation almost ideally matching the prerequisites for a canonical type 11 beta turn with the highest stability of the whole series. In contrast, the nine-membered spirolactam 14 represents a scaffold with a high conformational flexibility.