Psychedelic Mechanism for the Liberation of Nitric Oxide From a Substituted Acetohydroxamate

These articles [Samuni et al., 2009: (http://www.ncbi.nlm.nih.gov/pubmed/19447172); Gantt et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16681389); King, 2004: (http://www.ncbi.nlm.nih.gov/pubmed/15304249)] are relevant to the psychedelic mechanism shown below, in which the oxidation of a substituted acetohydroxamate (a "secondary" hydroxylamine) to its nitrosonium/oxoammonium species allows for the activation of the oxoammonium species toward a "modified Cope elimination," through a hydrogen abstraction. The third step is actually consistent with the mechanism proposed by King et al. (2004) for the formation of nitric oxide from an "unsubstituted" acylhydroxamate (a.k.a. a "primary" or terminal hydroxylamine), and King et al. (2004) argued that only those compounds with a terminal hydroxylamine moiety could serve as nitric oxide or nitrate donors. But Samuni et al. (2009) found that suberoylanilide hydroxamate, a substituted acylhydroxamate (a secondary hydroxylamine) histone deacetylase inhibitor, could serve as a nitric oxide donor, albeit by an unknown mechanism. It's interesting that a major class of histone deacetylase (HDAC) inhibitors are hydroxamate compounds that are thought to inhibit HDAC enzymes by chelating the zinc ions that are coordinated by amino acid residues on or near the active sites of the enzymes. The hydroxamate then "stays" there or something like that. But Gantt et al. (2006) found evidence and cited research to indicate that iron(II), not Zn2+, is required for the catalytic activity of HDAC enzymes. There's a lot of research showing that HDAC inhibitors are neuroprotective, and so a decrease in the availability of nonheme iron(II) to HDAC enzymes could serve an indirect, HDAC inhibitory effect, even if Zn2+ is, in fact, the metal cofactor. Or, either Zn2+ or Fe(II) could serve as the cofactor, as is the case for other enzymes, etc. The activities of HDAC enzymes can be decreased by various antioxidants, and there are "fringe" interactions through which HDAC activity can regulate HIF-1alpha expression, etc. Those are some "far out" things, in any case, that are lacking in mass appeal, probably. This is one of the last obnoxious heme drawings I'll probably be able to come up with, for the time being, as this stuff winds down. I don't know what would happen to that reactive alkene product of the "modified Cope elimination." The actual nitrogen-containing species would probably be something else, or the product I've shown would react to form something else.