Exploring the Potential of 2-(2-Nitrophenyl)ethyl-Caged N-Hydroxysulfonamides for the Photoactivated Release of Nitroxyl (HNO).

The emergence of nitroxyl (HNO) as a biological signaling molecule is attracting increasing attention. HNO-based prodrugs show considerable potential in treating congestive heart failure, with HNO reacting rapidly with metal centers and protein-bound and free thiols. A new class of 2-(2-nitrophenyl)ethyl (2-NPE)-photocaged N-hydroxysulfonamides has been developed, and the mechanisms of photodecomposition have been investigated. Three photodecomposition pathways are observed: the desired concomitant C-O/N-S bond cleavage to generate HNO, sulfinate, and 2-nitrostyrene, C-O bond cleavage to give the parent sulfohydroxamic acid and 2-nitrostyrene, and O-N bond cleavage to release a sulfonamide and 2-nitrophenylacetaldehyde. Laser flash photolysis experiments provide support for a Norrish type II mechanism involving 1,5-hydrogen atom abstraction to generate an aci-nitro species. A mechanism is proposed in which the (Z)-aci-nitro intermediate undergoes either C-O bond cleavage to release RSO2NHO(H), concerted C-O/N-S bond cleavage to generate sulfinate and HNO, or isomerization to the (E)-isomer prior to O-N bond cleavage. The pKa of the N(H) of the N-hydroxysulfonamide plays a key role in determining whether C-O or concerted C-O/N-S bond cleavage occurs. Deprotonating this site favors the desired C-O/N-S bond cleavage at the expense of an increased level of undesired O-N bond cleavage. Triplet state quenchers have no effect on the observed photoproducts.

Mechanistic Insights into Rapid Generation of Nitroxyl from a Photocaged N-Hydroxysulfonamide Incorporating the (6-Hydroxynaphthalen-2-yl)methyl Chromophore.

HNO is a highly reactive molecule that shows promise in treating heart failure. Molecules that rapidly release HNO with precise spatial and temporal control are needed to investigate the biology of this signaling molecule. (Hydroxynaphthalen-2-yl)methyl-photocaged N-hydroxysulfonamides are a new class of photoactive HNO generators. Recently, it was shown that a (6-hydroxynaphthalen-2-yl)methyl (6,2-HNM)-photocaged derivative of N-hydroxysulfonamide incorporating the trifluoromethanesulfonamidoxy group (1) quantitatively generates HNO. Mechanistic studies have now been carried out on this system and reveal that the ground state protonation state plays a key role in whether concerted heterolytic C-O/N-S bond cleavage to release HNO occurs versus undesired O-N bond cleavage. N-Deprotonation of 1 can be achieved by adding an aqueous buffer or a carboxylate salt to an aprotic solvent. Evidence is presented for C-O/N-S bond heterolysis occurring directly from the singlet excited state of the N-deprotonated parent molecule on the picosecond time scale, using femtosecond time-resolved transient absorption spectroscopy, to give a carbocation and 1NO-. This is consistent with the observation of significant fluorescence quenching when HNO is generated. The carbocation intermediate reacts rapidly with nucleophiles including water, MeOH, or even (H)NO in the absence of a molecule that reacts rapidly with (H)NO to give an oxime.

Stoichiometric Nitroxyl Photorelease Using the (6-Hydroxy-2-naphthalenyl)methyl Phototrigger.

The design and synthesis of a photoactivatable HNO donor incorporating the (6-hydroxynaphthalen-2-yl)methyl (6,2-HNM) photocage coupled to the trifluoromethanesulfonamidoxy analogue of the well-established HNO generator Piloty's acid is described. The photoactive HNO donor stoichiometrically generates HNO (∼98%) at neutral pH conditions, and evidence for concerted C-O and N-S bond cleavage was obtained. The methanesulfonamidoxy analogue primarily undergoes undesired N-O bond cleavage.

Synthesis and HNO Donating Properties of the Piloty's Acid Analogue Trifluoromethanesulphonylhydroxamic Acid: Evidence for Quantitative Release of HNO at Neutral pH Conditions.

Trifluoromethanesulphonylhydroxamic acid, CF3 SO2 NHOH, is shown to release HNO under physiological pH conditions. A two-step synthesis is presented with the first complete characterization of CF3 SO2 NHOH. This molecule rapidly decomposes in neutral aqueous solution to cleanly release HNO and CF3 SO2- , which was demonstrated using the HNO traps TXPTS and HOCbl, and by 19 F NMR spectroscopy.

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

Directly obtaining kinetic and mechanistic data for the reactions of nitroxyl (HNO) with biomolecules (k≈103 -107 m-1 s-1 ) is not feasible for many systems because of slow HNO release from HNO donor molecules (t1/2 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.

Preparation of brominated 2-alkoxythiophenes via oxidation and etherification of 2-thienyltrifluoroborate salts.

The synthesis of ring brominated long-chain 2-alkoxythiophenes is reported, involving mild (Oxone) oxidation of readily prepared 2-thienyltrifluoroborate salts followed by Mitsunobu etherification. Both procedures are operationally straightforward and use inexpensive reagents. Using this approach, several novel mono- and dibrominated octyloxythiophenes with previously elusive substitution patterns were prepared. One such compound was elaborated to a novel 5-alkoxythieno[3,2-b]thiophene-2-carboxylate ester, marking the first synthetic entry into this family of compounds.