Esterase-activated chromane–sydnonimine prodrug hybrids

The preparation and characterization of two vitamin E analogs–sydnonimine conjugates, δ-tocopheryloxycarbonyl-3-morpholinosydnonimine (2) and troloxoxycarbonyl-3-morpholinosydnonimine (3), in which the hydroxyl group of the tocopheryl moieties is linked via an enzymatically cleavable urethane group to the sydnone moiety is described. In the presence of porcine liver esterase, these tocopheryl–sydnonimine conjugates generated the expected antioxidant moieties, i.e., δ-tocopherol or Trolox®, and were found to convert oxyhemoglobin to methemoglobin at 37 °C in 50 mM phosphate buffer at pH 7.4, thus providing evidence for nitric oxide release. Their potency as antioxidants was indirectly studied by associating the two products of the hydrolysis, SIN-1, and δ-tocopherol or Trolox®. Our findings suggest that unlike the other members of the sydnonimine family these chromane–sydnonimine derivatives do not act as peroxynitrite donors, and require enzymatic bioactivation before nitric oxide or nitroxyl anion (NO−) can be released.