Arylboronate Ester Based Diazeniumdiolates (BORO/NO), a Class of Hydrogen Peroxide Inducible Nitric Oxide (NO) Donors

Here, we report the design, synthesis, and evaluation of arylboronate ester based diazeniumdiolates (BORO/NO), a class of nitric oxide (NO) donors activated by hydrogen peroxide (H₂O₂), a reactive oxygen species (ROS), to generate NO. We provide evidence for the NO donors’ ability to permeate bacteria to produce NO when exposed to H₂O₂ supporting possible applications for BORO/NO to study molecular mechanisms of NO generation in response to elevated ROS

Substituent Effects on Reactive Oxygen Species (ROS) Generation by Hydroquinones

In order to understand the structural aspects of stabilization of hydroquinones and their ability to generate reactive oxygen species (ROS), we designed and synthesized a series of 6-aryl-2,3-dihydro-1,4-benzoquinones. These compounds equilibrate with the corresponding 6-aryl-1,4-dihydroxybenzenes in an organic medium; a linear free energy relationship analysis gave ρ = +2.37, suggesting that this equilibrium was sensitive to electronic effects. The propensity of the compound to enolize appears to determine ROS-generating capability, thus offering scope for tunable ROS generation

Chemoproteomics of an Indole-Based Quinone Epoxide Identifies Druggable Vulnerabilities in Vancomycin-Resistant Staphylococcus aureus

Publisher's version (útgefin grein)The alarming global rise in fatalities from multidrug-resistant Staphylococcus aureus (S. aureus) infections has underscored a need to develop new therapies to address this epidemic. Chemoproteomics is valuable in identifying targets for new drugs in different human diseases including bacterial infections. Targeting functional cysteines is particularly attractive, as they serve critical catalytic functions that enable bacterial survival. Here, we report an indole-based quinone epoxide scaffold with a unique boat-like conformation that allows steric control in modulating thiol reactivity. We extensively characterize a lead compound (4a), which potently inhibits clinically derived vancomycin-resistant S. aureus. Leveraging diverse chemoproteomic platforms, we identify and biochemically validate important transcriptional factors as potent targets of 4a. Interestingly, each identified transcriptional factor has a conserved catalytic cysteine residue that confers antibiotic tolerance to these bacteria. Thus, the chemical tools and biological targets that we describe here prospect new therapeutic paradigms in combatting S. aureus infections.The authors thank the Department of Biotechnology (DBT), Government of India (BT/PR15848/MED/29/1025/2016 to H.C. and S.C.), a Wellcome Trust DBT India Alliance Intermediate Fellowship (IA/I/15/2/502058 to S.S.K.) and a DST-FIST Infrastructure Development Grant (to IISER Pune Biology) for the financial support for our research. The Council for Scientific and Industrial Research (CSIR) and the Department of Science and Technology—Innovation in Science Pursuit for Inspired Research (DST-INSPIRE) for graduate student fellowships.Peer Reviewe

Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination.

Proteomic