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 3 -10 7 m À1 s À1 )i sn ot feasible for many systems because of slow HNO release from HNO donor molecules (t 1/2 is typically minutes to hours). To address this limitation, we have developed ap hotoactivatable 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.T he amount of HNO generated is strongly dependent on solvent and the rate of the reaction is dependent on the light intensity.Nitroxyl (HNO,n itrosyl hydride) is attracting increasing attention because it has chemical and biological properties distinct from the more widely studied nitric oxide (NO). [1] Furthermore HNO prodrugs show considerable promise as congestive heart failure therapeutics. [2] However,understanding the biological roles of HNO has been hindered by its propensity to dimerize rapidly in aqueous solution (k = 8 10 6 m À1 s À1 ). [3] Thus,p recursor molecules (HNO donors) are required to generate HNO in situ for chemical and biological studies.Many HNO donors have been reported, [4] including Angeliss alt (AS), Pilotysa cid (PA) and related derivatives, [5] N-substituted hydroxylamines, [6] primary amine-based diazeniumdiolates, [7] acyloxy nitroso compounds, [8] precursors of acyl nitroso species, [9] and metal nitrosyls. [10] Although HNO donors are widely used in biochemical studies, [4,9d] factors limiting their utility include requiring alkaline (pH > 9) conditions to trigger HNO release, [4a, 11] and NO release at neutral pH conditions. [7c, 8a, 9b,c] Most importantly,in terms of mechanistic studies of HNO with biomolecules, HNO generation is invariably the rate-determining step, [12] since HNO reacts rapidly with biomolecules (k % 10 3 -10 7 m À1 s À1 ) [13] but is typically released more slowly (t 1/2 ca.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under http://dx.

Azanone (HNO): generation, stabilization and detection

“…Light-driven azanone release had been previously reported using N-alkoxysulfonamide donors and Xe light irradiation. 44 In this case, HNO was released due to an uncaging mechanism and not because of a pH shift. Other examples for photochemical HNO release have also been reported based on the same family of donors 45,46 , caged Piloty's Acid, 47 and even {FeNO} 6 complexes with a pendant thiol moiety.…”