Computational design of S‐nitrosothiol “click” reactions

Abstract

To address a long-standing problem of finding efficient reactions for chemical labeling of protein-based S-nitrosothiols (RSNOs), we computationally explored hitherto unknown (3+2) cycloaddition RSNO reactions with alkynes and alkenes. Nonactivated RSNO cycloaddition reactions have high activation enthalpy (>20 kcal/mol at the CBS-QB3 level) and compete with alternative S-N bond insertion pathway. However, the (3+2) cycloaddition reaction barriers can be dramatically lowered by coordination of a Lewis acid to the N atom of the -SNO group. To exploit this effect, we propose to use reagents with Lewis acid and a strain-activated carbon-carbon multiple bond linked by a rigid scaffold, which can react with RSNOs with small activation enthalpies (∼5 kcal/mol) and high reaction exothermicities (∼40 kcal/mol). The proposed efficient RSNO cycloaddition reactions can be used for future development of practical RSNO labeling reactions.

Modeling of S‐Nitrosothiol–Thiol Reactions of Biological Significance: HNO Production by S‐Thiolation Requires a Proton Shuttle and Stabilization of Polar Intermediates

“…Formation of intermediates or products with trivalent, sulfonium‐like sulfur appears to be common for the reactions that originate from the antagonistic structure D , which implies a trivalent sulfur atom with positive formal charge (Scheme ). For instance, 1,3‐dipolar cycloaddition reactions of RSNOs have been predicted to yield sulfonium ylide‐like products (Scheme A), whereas sulfur‐directed hydrolysis of O‐protonated RSNO has been predicted to proceed through a zwitterionic intermediate (Scheme B), which is very similar to the zwitterionic intermediate of the thiolation reaction reported here.…”

“… Sulfonium‐like products and intermediates of RSNO reactions promoted by antagonistic resonance structure D : A) 1,3‐dipolar cycloaddition and B) hydrolysis of O‐protonated RSNO …”

Computational Structural Biology of S-nitrosylation of Cancer Targets

“…Several compounds are known to react with S -nitrosothiols such as phosphine derivatives, sulfenic acids, and a large variety of nucleophiles. Some of them have biological relevance (e.g., thiols and seleno compounds), but an important aspect of this broad reactivity is to provide perspectives for the development of efficient RSNOs detection methods and RSNO-based therapies—e.g., biotin labeling, phosphine compounds, and metal complexes ( 257 – 261 ). Noteworthy, low-molecular weight S -nitrosothiols derivatives such as S -nitroso-N-acetyl penicillamine (SNAP), GSNO and L-/D-CysNO are commonly used in biological experiments.…”

Structure and Stability Studies of Pharmacologically Relevant S-Nitrosothiols: A Theoretical Approach

“…A better understanding of how the stability of RSNO compounds in aqueous media is related to their chemical structure is therefore clearly needed in view of developing novel drug candidates for therapeutic uses. Actually, this issue has already motivated a number of theoretical works that have tried to clarify the chemical properties of the SNO function, providing estimations for the BDEs of several model systems. − Calculations and experiments reported by Bartberger et al , have provided a new consistent picture of the conformational behavior of the RSNOs. Their results suggest a competing steric effect that favors the anti orientation of the RSNO group when the R group is large.…”