Divergent unprotected peptide macrocyclisation by palladium-mediated cysteine arylation.
Divergent unprotected peptide macrocyclisation by palladium-mediated cysteine arylation.
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DOI：
10.1039/c6sc05454d
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发表时间：
2017-06-01
期刊：
影响因子：
8.4
通讯作者：
Buchwald SL
中科院分区：
文献类型：
--
作者：
Rojas AJ;Zhang C;Vinogradova EV;Buchwald NH;Reilly J;Pentelute BL;Buchwald SL
大环肽是重要的治疗候选物，因为它们与它们的线性对应物相比具有改善的物理化学性质。大环肽是重要的治疗候选物，因为它们与它们的线性对应物相比具有改善的物理化学性质。在这里，我们详细介绍了一种方法，通过交联两个半胱氨酸残基与双钯有机金属试剂的未受保护的肽的发散macrocyclisation。这些合成中间体由市售的芳基双卤化物在单一步骤中制备。分别在i，i + 4和i，i + 7位置具有半胱氨酸残基的两个生物活性线性肽被环化以引入不同阵列的芳基和联芳基接头。这两个系列的大环肽显示类似的接头依赖性亲脂性，磷脂亲和力，和独特的体积分布。此外，其中一种生物活性肽显示出主要受接头长度影响的靶标结合亲和力。总的来说，这种不同的策略允许快速和方便地获得各种芳基接头，从而能够系统地评价附加单元对大环肽的药用特性的影响。
Macrocyclic peptides are important therapeutic candidates due to their improved physicochemical properties in comparison to their linear counterparts. Macrocyclic peptides are important therapeutic candidates due to their improved physicochemical properties in comparison to their linear counterparts. Here we detail a method for a divergent macrocyclisation of unprotected peptides by crosslinking two cysteine residues with bis-palladium organometallic reagents. These synthetic intermediates are prepared in a single step from commercially available aryl bis-halides. Two bioactive linear peptides with cysteine residues at i, i + 4 and i, i + 7 positions, respectively, were cyclised to introduce a diverse array of aryl and bi-aryl linkers. These two series of macrocyclic peptides displayed similar linker-dependent lipophilicity, phospholipid affinity, and unique volume of distributions. Additionally, one of the bioactive peptides showed target binding affinity that was predominantly affected by the length of the linker. Collectively, this divergent strategy allowed rapid and convenient access to various aryl linkers, enabling the systematic evaluation of the effect of appending unit on the medicinal properties of macrocyclic peptides.
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影响因子：
7.8
作者：
Henchey, Laura K.;Jochim, Andrea L.;Arora, Paramjit S.
通讯作者：
Arora, Paramjit S.
影响因子：
15
作者：
Spokoyny, Alexander M.;Zou, Yekui;Ling, Jingjing J.;Yu, Hongtao;Lin, Yu-Shan;Pentelute, Bradley L.
通讯作者：
Pentelute, Bradley L.
影响因子：
4.9
作者：
Haney, Conor M.;Loch, Matthew T.;Horne, W. Seth
通讯作者：
Horne, W. Seth
DOI：
10.1073/pnas.1303002110
发表时间：
2013-09-03
影响因子：
11.1
作者：
Chang, Yong S.;Graves, Bradford;Sawyer, Tomi K.
通讯作者：
Sawyer, Tomi K.
影响因子：
15
作者：
Lautrette G;Touti F;Lee HG;Dai P;Pentelute BL
通讯作者：
Pentelute BL