Issue 12, 2016

Understanding and predicting the potency of ROS-based enzyme inhibitors, exemplified by naphthoquinones and ubiquitin specific protease-2

Abstract

Recent studies have suggested that selective targeting of overexpressed enzymes in cancer cells by small molecules that induce the formation of reactive oxygen species (ROS) could be a viable approach in cancer therapy. One such example is the inactivation of ubiquitin specific protease-2 (USP2)—an emerging drug target to combat prostate cancer—by β-lapachone, which has been identified to involve oxidation of the catalytic cysteine's thiol residue to sulfinic acid. A rational design of β-lapachone analogs with improved activity requires a much better understanding of the variables that determine ROS production by this class of molecules. This crucial aspect was addressed via modulation of its 1,2-naphthoquinone scaffold and establishment of a structure/activity relationship, regarding its ability to reduce molecular oxygen to a ROS. The same series of compounds was also examined in terms of their inhibitory effect on the enzymatic activity of USP2. One deduction from these investigations was that the ortho-quinone motif in β-lapachone is much better suited for the catalytic reduction of oxygen than the para-quinone motif and some approved quinone based drugs. A broader conclusion, obtained from the series of compounds with ortho-quinone motifs, is that only the agents whose redox potential is in the narrow range of −0.3 ± 0.1 V (vs. Ag/AgCl in pH 7.5 aqueous buffer) induce the formation of ROS. The excellent correlation between the ROS production ability and the USP2 inhibition potency emphasizes that the relatively easy, fast, and reliable testing of electrocatalytic oxygen reduction by small molecules might be applied to screening and evaluating new drug candidates for similar targets.

Graphical abstract: Understanding and predicting the potency of ROS-based enzyme inhibitors, exemplified by naphthoquinones and ubiquitin specific protease-2

Supplementary files

Article information

Article type
Edge Article
Submitted
22 Jūn. 2016
Accepted
03 Aug. 2016
First published
05 Aug. 2016
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2016,7, 7079-7086

Understanding and predicting the potency of ROS-based enzyme inhibitors, exemplified by naphthoquinones and ubiquitin specific protease-2

P. Gopinath, A. Mahammed, S. Ohayon, Z. Gross and A. Brik, Chem. Sci., 2016, 7, 7079 DOI: 10.1039/C6SC02758J

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements