Curtailing the Hydroxylaminobarbituric Acid–Hydantoin Rearrangement To Favor HNO Generation

Due
to its inherent reactivity, HNO must be generated in situ through
the use of donor compounds. One of the primary strategies for the
development of new HNO donors has been modifying hydroxylamines with
good leaving groups. A recent example of this strategy is the (hydroxylamino)­barbituric
acid (HABA) class of HNO donors. In this case, however, an undesired
intramolecular rearrangement pathway to the corresponding hydantoin
derivative competes with HNO formation, particularly in the absence
of chemical traps for HNO. This competitive non-HNO-producing pathway
has restricted the development of the HABA class to examples with
fast HNO release profiles at physiological pH and temperature (t1/2 < 1 min). Herein, the factors that favor
the rearrangement pathway have been examined and two independent strategies
that protect against rearrangement to favor HNO generation have been
developed. The timecourse and stoichiometry for the in vitro conversion
of these compounds to HNO (trapped as a phosphine aza-ylide) and the
corresponding barbituric acid (BA) byproduct have been determined
by 1H NMR spectroscopy under physiologically relevant conditions.
These results confirm the successful extension of the HABA class of
pure HNO donors with half-lives at pH 7.4, 37 °C ranging from
19 to 107 min.