A One-Pot "Triple-C" Multicyclization Methodology for the Synthesis of Highly Constrained Isomerically Pure Tetracyclic Peptides.,ChemBioChem

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A One-Pot "Triple-C" Multicyclization Methodology for the Synthesis of Highly Constrained Isomerically Pure Tetracyclic Peptides.
ChemBioChem ( IF 2.6 ) Pub Date : 2018-08-02 , DOI: 10.1002/cbic.201800346
Gaston J J Richelle ₁ , Marcel Schmidt _{1,

2} , Hans Ippel ₃ , Tilman M Hackeng ₃ , Jan H van Maarseveen ₁ , Timo Nuijens ₂ , Peter Timmerman _{1,

4}

Affiliation

A broadly applicable one-pot methodology for the facile transformation of linear peptides into tetracyclic peptides through a chemoenzymatic peptide synthesis/chemical ligation of peptides onto scaffolds/copper(I)-catalyzed reaction (CEPS/CLIPS/CuAAC; "triple-C") locking methodology is reported. Linear peptides with varying lengths (≥14 amino acids), comprising two cysteines and two azidohomoalanines (Aha), were efficiently cyclized head-to-tail by using the peptiligase variant omniligase-1 (CEPS). Subsequent ligation-cyclization with tetravalent (T41/2 ) scaffolds containing two bromomethyl groups (CLIPS) and two alkyne functionalities (CuAAC) yielded isomerically pure tetracyclic peptides. Sixteen different functional tetracycles, derived from bicyclic inhibitors against urokinase plasminogen activator (uPA) and coagulation factor XIIa (FXIIa), were successfully synthesized and their bioactivities evaluated. Two of these (FF-T41/2 ) exhibited increased inhibitory activity against FXIIa, compared with a bicyclic control peptide. The corresponding hetero-bifunctional variants (UF/FU-T41/2 ), with a single copy of each inhibitory sequence, exhibited micromolar activities against both uPA and FXIIa; thus illustrating the potential of the "bifunctional tetracyclic peptide" inhibitor concept.

中文翻译：

一锅“三重C”多环化方法，用于合成高度受限的异构纯四环肽。

通过化学酶促肽合成/肽在支架/铜（I）催化反应上的化学连接（CEPS / CLIPS / CuAAC；“ triple-C”）将线性肽轻松转化为四环肽的一种广泛应用的一锅法报告了锁定方法。包含两个半胱氨酸和两个叠氮高丙氨酸（Aha）的长度可变的线性肽（≥14个氨基酸）通过使用肽酶的变体omniligase-1（CEPS）从头到尾有效地环化。随后与包含两个溴甲基（CLIPS）和两个炔烃官能团（CuAAC）的四价（T41 / 2）支架进行连接-环化反应，得到了异构体纯的四环肽。十六种不同的功能四环，成功地合成了由抗尿激酶纤溶酶原激活物（uPA）和凝血因子XIIa（FXIIa）的双环抑制剂衍生而来的生物活性。与双环对照肽相比，其中两个（FF-T41 / 2）对FXIIa的抑制活性增强。每个抑制序列都有一个拷贝的相应的异双功能变体（UF / FU-T41 / 2）对uPA和FXIIa均表现出微摩尔活性。因此说明了“双功能四环肽”抑制剂概念的潜力。每个抑制序列的一个拷贝具有针对uPA和FXIIa的微摩尔活性；因此说明了“双功能四环肽”抑制剂概念的潜力。每个抑制序列的一个拷贝具有针对uPA和FXIIa的微摩尔活性；因此说明了“双功能四环肽”抑制剂概念的潜力。

更新日期：2018-08-02

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