Intellectual Merit: Nitroxyl (HNO), a close relative of the well-known biological cell signaling molecule nitric oxide, shows extremely promising pharmacological properties.  Recent advanced clinical trials with nitroxyl donors suggest that such drugs may find important clinical applications for the treatment of congestive heart failure.  Furthermore, there is increasing evidence that nitroxyl is itself generated naturally in cells as a signaling molecule, making its detailed study of increased importance. Since nitroxyl rapidly dimerizes in aqueous solution, studies aimed at fully understanding its biological chemistry require new nitroxyl donor compounds that release nitroxyl rapidly on demand. In the present study, we have developed a series of new nitroxyl donor molecules that release nitroxyl upon irradiation with light (photoactivation), with concomitant loss of another innocuous molecule (leaving group).  Our goal was to achieve sub-second in situ stoichiometric generation of nitroxyl, which can then be used for detailed mechanistic studies of the rapid biologically important reactions that are known to occur between nitroxyl and a series of sulfur and metal centers in relevant biomolecules.  One of the targets synthesized in this study was shown to release essentially stoichiometric quantities of nitroxyl (~98%) at neutral pH conditions within 1 microsecond upon excitation by light, putting this work at the very forefront of the field.

Several other families of potential photoactivatable nitroxyl donors were prepared that similarly exploit loss of a leaving group during nitroxyl formation but employ different types of chemical structures to drive the desired photolysis chemistry.  The photolytic chemistry of each target system was probed, and some understanding was achieved of their potential for selective nitroxyl release vis-à-vis other competing photolytic pathways.

Broader Impacts: Educational opportunities were provided to both graduate and undergraduate students. In the research environment, two students (including one female) received their Ph.D. degrees, with one student expected to defend his dissertation in the spring 2019 semester. An additional three students (one female) continue to carry out their Ph.D. studies in this area. Three undergraduates have successfully defended honors theses based on work in this area, and an additional two students have participated in individual investigation projects. All of these students have received advanced training in chemical synthesis, chemical analysis, photochemistry, and safety. Many of the students have disseminated their work through the publication of papers and presentations at local, national and international conferences.  In the classroom setting, the PI developed and taught a new Special Topics course for junior and senior undergraduates, “Nitroxyl – an Interdisciplinary Seminar.” The course aimed to foster among the department’s chemistry and biochemistry major cohort an appreciation for this interdisciplinary area of science.  The course focused on the development of an integrated approach to understanding the chemistry, biochemistry and pharmacology surrounding nitroxyl.  It also emphasized the development of important “soft skills” that are often under-developed in undergraduate students such as searching and reading the technical literature, technical writing and oral presentation skills, and in-class analytical discussion of primary, review and patent technical literature. 

Last Modified: 10/31/2018
Modified by: Alexander J Seed