Methoxy-Substituted Nitrodibenzofuran-Based Protecting Group with an Improved Two-Photon Action Cross-Section for Thiol Protection in Solid Phase Peptide Synthesis
Methoxy-Substituted Nitrodibenzofuran-Based Protecting Group with an Improved Two-Photon Action Cross-Section for Thiol Protection in Solid Phase Peptide Synthesis
复制标题
DOI：
10.1021/acs.joc.9b02751
复制
发表时间：
2020-02-07
影响因子：
3.6
通讯作者：
Distefano, Mark D.
中科院分区：
文献类型：
--
作者：
Bader, Taysir K.;Xu, Feng;Distefano, Mark D.
光可去除的笼化基团可用于生物学应用，因为脱保护过程可以通过用光照射来引发，而不需要添加额外的试剂，例如可以干扰生物活性的酸或碱。在固相肽合成（SPPS）中，用于巯基保护的最常见的光可去除基团是邻硝基苄基和相关类似物。在早期的工作中，我们探索了使用硝基二苯并呋喃（NDBF）基团进行硫醇保护，并发现它相对于简单的硝基藜芦基保护基团和有用的双光子截面表现出更快的UV光解速率。在这里，我们描述了一种新的NDBF基保护基团的合成，带有一个甲氧基取代基，并使用它来制备一种保护形式的半胱氨酸适用于SPPS。然后，该试剂用于组装两个生物相关的肽，并在UV和双光子介导的反应中表征其光解动力学;新保护基的0.71-1.4 GM的双光子作用截面特别值得注意。最后，通过UV或双光子活化将这些受保护的肽解开，以通过酶法尼基转移酶启动其随后的酶促加工。这些实验突出了这种新的保护基用于SPPS和生物学实验的效用。
Photoremovable caging groups are useful for biological applications because the deprotection process can be initiated by illumination with light without the necessity of adding additional reagents such as acids or bases that can perturb biological activity. In solid phase peptide synthesis (SPPS), the most common photoremovable group used for thiol protection is the o-nitrobenzyl group and related analogues. In earlier work, we explored the use of the nitrodibenzofuran (NDBF) group for thiol protection and found it to exhibit a faster rate toward UV photolysis relative to simple nitroveratryl-based protecting groups and a useful two-photon cross-section. Here, we describe the synthesis of a new NDBF-based protecting group bearing a methoxy substituent and use it to prepare a protected form of cysteine suitable for SPPS. This reagent was then used to assemble two biologically relevant peptides and characterize their photolysis kinetics in both UV- and two-photon-mediated reactions; a two-photon action cross-section of 0.71-1.4 GM for the new protecting group was particularly notable. Finally, uncaging of these protected peptides by either UV or two-photon activation was used to initiate their subsequent enzymatic processing by the enzyme farnesyltransferase. These experiments highlight the utility of this new protecting group for SPPS and biological experiments.