Rapid Photoactivated Generation of Nitroxyl (HNO) under Neutral pH Conditions

Abstract

Directly obtaining kinetic and mechanistic data for the reactions of nitroxyl (HNO) with biomolecules (k≈10 -10 m s ) is not feasible for many systems because of slow HNO release from HNO donor molecules (t is typically minutes to hours). To address this limitation, we have developed a photoactivatable HNO donor incorporating the (3-hydroxy-2-naphthalenyl)methyl phototrigger, which rapidly releases HNO on demand. A "proof of concept" study is reported, which demonstrates that, upon continuous xenon light excitation, rapid decomposition of the HNO donor occurs within seconds. The amount of HNO generated is strongly dependent on solvent and the rate of the reaction is dependent on the light intensity.

Development of Photoactivatable Nitroxyl (HNO) Donors Incorporating the (3‐Hydroxy‐2‐naphthalenyl)methyl Phototrigger

“…Steady‐state irradiation experiments of 1 , 2 , and 3 were performed in a mixture of phosphate buffer (pH 7.00, 5.0 m m ) and CD 3 CN (40:60, v/v) using a Rayonet photochemical reactor (RMR‐600, 350 nm bulbs, 8 × 4 W bulbs) under strictly anaerobic conditions. The results for 1 have been reported in a recent communication, with CF 3 SO 2 – [Pathway (a), Scheme ] and CF 3 SO 2 NH 2 [Pathway (b), Scheme ] generated in a approximately 40:60 ratio (determined from 19 F NMR spectroscopic analysis) . The observed rate constant for the photodecomposition of 1 was determined by 19 F NMR spectroscopy from a plot of the peak area of the CF 3 group of 1 vs. time, giving k obs = 0.171 min –1 (t 1/2 ca.…”

“…The observed rate constant for the photodecomposition of 1 was determined by 19 F NMR spectroscopy from a plot of the peak area of the CF 3 group of 1 vs. time, giving k obs = 0.171 min –1 (t 1/2 ca. 4.1 min; Figure ) …”

“…The synthesis of HNO donors 1 – 3 incorporating the 3,2‐HNM phototrigger was achieved from commercially available methyl 3‐hydroxy‐2‐naphthoate ( 6 ) via the route outlined in Scheme . The preliminary synthesis and photodecomposition of compound 1 have been reported in a recent communication . Following triisopropylsilyl (TIPS) protection of naphthol 6 , the reduction of the resulting ester 7 was attempted.…”

“…Recently, we communicated the first example of a new class of photoactivatable HNO donors RSO 2 NHO‐PT (PT = phototrigger) incorporating the well‐studied (3‐hydroxy‐2‐naphthalenyl)methyl (3,2‐HNM) phototrigger coupled to a trifluoromethanesulfonamidoxy moiety (R = CF 3 ) . Herein, full details of this investigation are provided alongside parallel studies with two other related sulfohydroxamate analogues (R = Me and Ph).…”

Development and cellular application of visible-light-controllable HNO releasers based on caged Piloty's acid

“…In order to control HNO release more precisely, photocontrollable HNO donors have been developed by our group based on a retro Diels-Alder reaction 12 and by Sampson's group based on N-alkoxysulfonamide bearing a O-(3-hydroxy-2-naphthalenyl)-methyl (HNM) photolabile protecting group (PPG). 13 However, these compounds are not suitable for cellular experiments, because HNO release is triggered by ultraviolet (UV) irradiation, which is cytotoxic.…”