Switching Futile para‐Quinone to Efficient Reactive Oxygen Species Generator: Ubiquitin‐Specific Protease‐2 Inhibition, Electrocatalysis, and Quantification

Abstract

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.

The diverse mechanisms and anticancer potential of naphthoquinones

“…Within this type of enzymes, ubiquitin-specific proteases 1 and 2 (USP1 and USP2) are linked with DNA damage repair. Particularly, USP2 has been associated with apoptosis resistance by cancer cells through stabilization of Fas and cyclin D1 [59]. It has been reported that both enzymes are susceptible to ROS and are inhibited by the natural ortho -quinone β-lapachone ( 12 ), suggesting that they are interesting targets for the development of compounds for cancer therapy.…”

Unprecedented Sensitivity in a Probe for Monitoring Cathepsin B: Chemiluminescence Microscopy Cell‐Imaging of a Natively Expressed Enzyme

“…[22] Thed esign of these probes allows the enzymatic hydrolysis and chemiexcitation process to occur concurrently under physiological conditions with remarkable light-emission intensities. [23][24][25][26][27] We sought to use this design strategy to prepare achemiluminescence probe that is suitable for activation by cathepsin B. Herein, we report the development of the first chemiluminescence probe for the detection and imaging of cathepsin B that is suitable for use under physiological conditions.…”

Direct Real‐Time Monitoring of Prodrug Activation by Chemiluminescence

“…Removal of the substrate by an enzyme or an analyte of choice triggers the direct chemiexcitation mechanism of the dioxetane luminophore. This meant that, for the first‐time, an intense light‐emission signal could be obtained under physiological conditions to image endogenous molecular activities in vitro and in vivo . The insights obtained from analysis of the chemiexcitation pathway prompted us to develop a distinct molecular unit that intrinsically integrates a chemiexcitation turn‐on signal with a self immolative release mechanism .…”