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Switching Futile para ‐Quinone to Efficient Reactive Oxygen Species Generator: Ubiquitin‐Specific Protease‐2 Inhibition, Electrocatalysis, and Quantification
Author(s) -
Gopinath Pushparathinam,
Mahammed Atif,
EilonShaffer Tal,
Nawatha Mickal,
Ohayon Shimrit,
Shabat Doron,
Gross Zeev,
Brik Ashraf
Publication year - 2017
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201700330
Subject(s) - reactive oxygen species , chemistry , protease , electrocatalyst , biochemistry , combinatorial chemistry , enzyme , electrode , electrochemistry
Understanding the correlation between structural features of small‐molecule drugs and their mode of action is a fascinating topic and crucial for the drug‐discovery process. However, in many cases, knowledge of the exact parameters that dictate the mode of action is still lacking. Following a large screening for ubiquitin specific protease 2 (USP2) inhibition, an effective para ‐quinone‐based inhibitor with an unclear mode of action was identified. To gain a deeper understanding of the mechanism of inhibition, a set of para ‐quinones were prepared and studied for USP2 inhibition, electrocatalysis, and reactive oxygen species (ROS) quantification. The excellent correlation obtained from the above‐mentioned studies disclosed a distinct pattern of “N−C=O−N” in the bicyclic para ‐quinones to be a crucial factor for ROS generation, and demonstrated that minor changes in such a skeleton drastically altered the ROS‐generating ability. The knowledge acquired herein would serve as an important guideline for future medicinal chemistry optimization of related structures to select the preferred mode of action.