Design, Solid-Phase Synthesis, and Evaluation of a Phenyl-Piperazine-Triazine Scaffold as 伪-Helix Mimetics
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- 作者：Heejo Moon ; Woo Sirl Lee ; Misook Oh ; Huisun Lee ; Ji Hoon Lee ; Wonpil Im ; Hyun-Suk Lim
- 刊名：ACS Combinatorial Science
- 出版年：2014
- 出版时间：December 8, 2014
- 年：2014
- 卷：16
- 期：12
- 页码：695-701
- 全文大小：347K
- ISSN：2156-8944
文摘
伪-Helices play a critical role in mediating many protein鈥損rotein interactions (PPIs) as recognition motifs. Therefore, there is a considerable interest in developing small molecules that can mimic helical peptide segments to modulate 伪-helix-mediated PPIs. Due to the relatively low aqueous solubility and synthetic difficulty of most current 伪-helix mimetic small molecules, one important goal in this area is to develop small molecules with favorable physicochemical properties and ease of synthesis. Here we designed phenyl-piperazine-triazine-based 伪-helix mimetics that possess improved water solubility and excellent synthetic accessibility. We developed a facile solid-phase synthetic route that allows for rapid creation of a large, diverse combinatorial library of 伪-helix mimetics. Further, we identified a selective inhibitor of the Mcl-1/BH3 interaction by screening a focused library of phenyl-piperazine-triazines, demonstrating that the scaffold is able to serve as functional mimetics of 伪-helical peptides. We believe that our phenyl-piperazine-triazine-based 伪-helix mimetics, along with the facile and divergent solid-phase synthetic method, have great potential as powerful tools for discovering potent inhibitors of given 伪-helix-mediated PPIs.