Unusual In-plane Aromaticity Facilitates Intramolecular Hydrogen Transfer in Long-Bonded cis-Isonitrosyl Methoxide.

The hydrogen-atom transfer from methoxy radical to nitric oxide, leading to the formation of formaldehyde and nitroxyl, represents a secondary reaction of photodissociation of methyl nitrite, which is used as rocket fuel. In this study, we explored the potential energy profile of the hydrogen-atom transfer using the electronic structure calculations at the DLPNO-CCSD(T)/aug-cc-pVTZ level of theory for two isomeric forms (cis and trans) of the pre-reaction complex. The cis-oriented pre-reaction complex has a weak elongated O─O bond, which gets further elongated in the hydrogen transfer transition state. This O─O bond stabilizes the pre-reaction complex by 32.9 kJ/mol. The O─O-induced stabilization is even greater for the transition state (48.2 kJ/mol), which was unexpected because of the larger O─O distance in the transition state structure. To address this paradox, we performed the electronic structure analysis of the reaction participants using the valence bond (VB) theory, natural resonance theory, topological analysis of the electron density and its derivatives, and analysis of the electron localization function distribution. This combined analysis led to the conclusion that the cis-transition state for hydrogen transfer, instead of being directly stabilized by the O─O interaction, gained substantial stabilization from the in-plane five-center six-electron aromaticity.

Discovery and Characterization of Halogenated Xanthene Inhibitors of DUSP5 as Potential Photodynamic Therapeutics.

Dual specific phosphatases (DUSPs) are an important class of mitogen-activated protein kinase (MAPK) regulators, and are drug targets for treating vascular diseases. Previously we had shown that DUSP5 plays a role in embryonic vertebrate vascular patterning. Herein, we screened a library of FDA-approved drugs and related compounds, using a para-nitrophenylphosphate substrate (pNPP)-based assay. This assay identified merbromin (also known as mercurochrome) as targeting DUSP5; and, we subsequently identified xanthene-ring based merbromin analogs eosin Y, erythrosin B, and rose bengal, all of which inhibit DUSP5 in vitro. Inhibition was time-dependent for merbromin, eosin Y, 2',7'-dibromofluorescein, and 2',7'-dichlorofluorescein, with enzyme inhibition increasing over time. Reaction progress curve data fit best to a slow-binding model of irreversible enzyme inactivation. Potency of the time-dependent compounds, except for 2',7'-dichlorofluorescein, was diminished when dithiothreitol (DTT) was present, suggesting thiol reactivity. Two additional merbromin analogs, erythrosin B and rose bengal also inhibit DUSP5, but have the therapeutic advantage of being less sensitive to DTT and exhibiting little time dependence for inhibition. Inhibition potency is correlated with the xanthene dye's LUMO energy, which affects ability to form light-activated radical anions, a likely active inhibitor form. Consistent with this hypothesis, rose bengal inhibition is light-dependent and demonstrates the expected red shifted spectrum upon binding to DUSP5, with a Kd of 690 nM. These studies provide a mechanistic foundation for further development of xanthene dyes for treating vascular diseases that respond to DUSP5 inhibition, with the following relative potencies: rose bengal > merbromin > erythrosin B > eosin Y.

Ab Initio Study Predicts That Enigmatic Isonitrosyl Fluoride Should Be Stable at Low Temperatures yet Unnoticeable Due to Its Photoreactivity.

Isonitrosyl fluoride F-ON remains an undetected molecule despite multiple attempts to generate it and successful identification of other isonitrosyl halides (X-ONs) via phototransformations of corresponding X-NOs. We investigated this problem using ab initio methods and found no evidence of instability of F-ON at low temperatures of 8-10 K. Instead, experimental observation of F-ON is likely challenged by the (1) different nature of photoexcitation of F-NO and its quantum yield being lower than those of other X-NOs and (2) the presence of a bright charge-transfer transition in the F-ON spectrum that likely overlaps with the weak band of F-NO used for photoexcitation. Formation of F-ON via symmetry-prohibited photoexcitation of F-NO is followed by its immediate photodecomposition to the charge-transfer excited state and its conversion to F-NO upon de-excitation. Thus, F-ON should be readily observable using non-photochemistry methods such as microwave spectroscopy.