The cyclo-β-tetrapeptide (β-HPhe-β-HThr-β-HLys-β-HTrp): synthesis, NMR structure in methanol solution, and affinity for human somatostatin receptors
The cyclo-β-tetrapeptide (β-HPhe-β-HThr-β-HLys-β-HTrp): synthesis, NMR structure in methanol solution, and affinity for human somatostatin receptors
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环-β-四肽 (β-HPhe-β-HThr-β-HLys-β-HTrp)：合成、甲醇溶液中的 NMR 结构以及对人生长抑素受体的亲和力
DOI：
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发表时间：
2000
期刊：
影响因子：
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通讯作者：
D. Hoyer
中科院分区：
文献类型：
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作者：
K. Gademann;M. Ernst;D. Seebach;D. Hoyer
已知的环(β-HALA)4的固态结构被用来模拟环-β-四肽(β-HPhe-β-HThr-β-HLys-β-HTrp)的结构，作为一种潜在的生长抑素模拟物。合成起始于N-保护的天然氨基酸Boc-Phe-OH、Boc-Trp-OH、Boc-Lys(2-Cl-Z)-OH(2-Cl-Z=邻氯苯氧羰基)和Boc-Thr(OBN)-OH(Bn=苄基)，它们都与相应的β-氨基酸衍生物同源。并偶联到Boc-β-HTrp-β-HPhe-β-HThr(OBn)-β-HLys(2-Cl-Z)-OMe.-β-四肽并制备了(N-Me)-β-HTHr-(N-Me)-β-HP类似物。通过五氟苯酯的C-和N-端脱保护和环化得到了INSOL。含有受保护的苏氨酸和赖氨酸侧链的β-四肽。增溶和脱苄只能在LiCl-中进行。四氢呋喃(产率约10%，回收率约55%)。高效液相色谱柱纯化。提供了标题公司的样本，其结构如下所示。通过核磁共振光谱学，与“理论”截然不同。模特。大环16元环之间有一个跨环的氢键，从而形成一个十元和十二元氢键环，前者模仿或实际上可叠加在所谓的β-转角的阿尔法肽上。这四条侧链按计划占据了环上的赤道位置，尽管与最初的相比，它们的几何形状略有不同。环-β-四肽与人生长抑素受体具有微摩尔亲和力。因此，我们首次证明了用一个小的β-肽来模拟一种天然的多肽荷尔蒙是可能的。此外，我们还发现了一种简单的方法，可以用β-肽(已知对哺乳动物的多肽酶稳定)构建普遍存在的β-转角基序。
The known solid-state structure of cyclo(β-HAla)4 was used to model the structure of the cyclo-β-tetrapeptide (β-HPhe-β-HThr-β-HLys-β-HTrp) as a prospective somatostatin mimic. The synthesis started with the N-protected natural amino acids Boc-Phe-OH, Boc-Trp-OH, Boc-Lys(2-Cl-Z)-OH (2-Cl-Z = o-chlorobenzyloxycarbonyl), and Boc-Thr(OBn)-OH (Bn = benzyl), which were homologated to the corresponding β-amino-acid derivs. and coupled to the β-tetrapeptide Boc-β-HTrp-β-HPhe-β-HThr(OBn)-β-HLys(2-Cl-Z)-OMe. The (N-Me)-β-HThr-(N-Me)-β-HPhe analog was also prepd. C- and N-terminal deprotection and cyclization through the pentafluorophenyl ester gave the insol. beta-tetrapeptide with protected Thr and Lys side chains. Solubilization and debenzylation could only be effected in LiCl-contg. THF (ca. 10% yield; with ca. 55% recovery). HPLC Purifn. provided a sample of the title compd., the structure of which, as detd. by NMR-spectroscopy, was drastically different from the "theor." model. There is a transannular H-bond dividing the macrocyclic 16-membered ring, thus forming a ten- and a twelve-membered H-bonded ring, the former mimicking, or actually being superimposable on, an alpha-peptide so-called beta-turn. The four side chains occupy equatorial positions on the ring, as planned, albeit with somewhat different geometry as compared to the "original". The cyclo-β-tetrapeptide has micromolar affinities to the human somatostatin receptors. Thus, we have demonstrated for the first time that it is possible to mimic a natural peptide hormone with a small beta-peptide. Furthermore, we have discovered a simple way to construct the ubiquitous beta-turn motif with beta-peptides (which are known to be stable to mammalian peptidases).