原位点击化学：按需定制的酶抑制剂。

In situ click chemistry: enzyme inhibitors made to their own specifications.

作者信息

Manetsch Roman, Krasiński Antoni, Radić Zoran, Raushel Jessica, Taylor Palmer, Sharpless K Barry, Kolb Hartmuth C

机构信息

Contribution from the Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

出版信息

J Am Chem Soc. 2004 Oct 13;126(40):12809-18. doi: 10.1021/ja046382g.

DOI:10.1021/ja046382g

PMID:15469276

Abstract

The in situ click chemistry approach to lead discovery employs the biological target itself for assembling inhibitors from complementary building block reagents via irreversible connection chemistry. The present publication discusses the optimization of this target-guided strategy using acetylcholinesterase (AChE) as a test system. The application of liquid chromatography with mass spectroscopic detection in the selected ion mode for product identification greatly enhanced the sensitivity and reliability of this method. It enabled the testing of multicomponent mixtures, which may dramatically increase the in situ screening throughput. In addition to the previously reported in situ product syn-TZ2PA6, we discovered three new inhibitors, syn-TZ2PA5, syn-TA2PZ6, and syn-TA2PZ5, derived from tacrine and phenylphenanthridinium azides and acetylenes, in the reactions with Electrophorus electricus and mouse AChE. All in situ-generated compounds were extremely potent AChE inhibitors, because of the presence of multiple sites of interaction, which include the newly formed triazole nexus as a significant pharmacophore.

摘要

用于先导化合物发现的原位点击化学方法利用生物靶标自身，通过不可逆连接化学从互补的构建块试剂组装抑制剂。本出版物讨论了以乙酰胆碱酯酶（AChE）作为测试系统对这种靶标导向策略的优化。在选定离子模式下应用液相色谱与质谱检测进行产物鉴定极大地提高了该方法的灵敏度和可靠性。它能够测试多组分混合物，这可能会显著提高原位筛选通量。除了先前报道的原位产物syn-TZ2PA6外，我们在与电鳗和小鼠AChE的反应中发现了三种新的抑制剂，即源自他克林和苯基菲啶鎓叠氮化物及乙炔的syn-TZ2PA5、syn-TA2PZ6和syn-TA2PZ5。由于存在多个相互作用位点，包括新形成的三唑连接作为重要药效团，所有原位生成的化合物都是极强的AChE抑制剂。