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高通量竞争实验在肽中酪氨酸残基的天冬氨酸定向位点选择性修饰开发中的应用

Application of High-Throughput Competition Experiments in the Development of Aspartate-Directed Site-Selective Modification of Tyrosine Residues in Peptides.

作者信息

Chinn Alex J, Hwang Jaeyeon, Kim Byoungmoo, Parish Craig A, Krska Shane W, Miller Scott J

机构信息

Department of Chemistry, Yale University, P.O. Box 208107, New Haven, Connecticut 06520-8107, United States.

Discovery Chemistry, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.

出版信息

J Org Chem. 2020 Jul 17;85(14):9424-9433. doi: 10.1021/acs.joc.0c01147. Epub 2020 Jul 2.

DOI:10.1021/acs.joc.0c01147
PMID:32614587
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7966973/
Abstract

Herein we report a Cu-catalyzed, site-selective functionalization of peptides that employs an aspartic acid (Asp) as a native directing motif, which directs the site of O-arylation at a proximal tyrosine (Tyr) residue. Through a series of competition studies conducted in high-throughput reaction arrays, effective conditions were identified that gave high selectivity for the proximal Tyr in Asp-directed Tyr modification. Good levels of site-selectivity were achieved in the O-arylation at a proximal Tyr residue in a number of cases, including a peptide-small molecule hybrid.

摘要

在此，我们报道了一种铜催化的肽的位点选择性官能团化反应，该反应利用天冬氨酸（Asp）作为天然导向基序，将邻位酪氨酸（Tyr）残基的O-芳基化位点导向。通过在高通量反应阵列中进行的一系列竞争研究，确定了有效的反应条件，这些条件在天冬氨酸导向的酪氨酸修饰中对邻位酪氨酸具有高选择性。在许多情况下，包括肽-小分子杂化物，邻位酪氨酸残基的O-芳基化反应都实现了良好的位点选择性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c756/7966973/465740c5dac7/nihms-1679785-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c756/7966973/4d54ef89e749/nihms-1679785-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c756/7966973/e196b54997bf/nihms-1679785-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c756/7966973/90838dece6ce/nihms-1679785-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c756/7966973/ea190f71d056/nihms-1679785-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c756/7966973/538c9c28cff7/nihms-1679785-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c756/7966973/465740c5dac7/nihms-1679785-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c756/7966973/4d54ef89e749/nihms-1679785-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c756/7966973/e196b54997bf/nihms-1679785-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c756/7966973/90838dece6ce/nihms-1679785-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c756/7966973/ea190f71d056/nihms-1679785-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c756/7966973/538c9c28cff7/nihms-1679785-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c756/7966973/465740c5dac7/nihms-1679785-f0009.jpg

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