DEVELOPMENT OF A PHOTOCHROMIC NITROXYL DELIVERY SYSTEM

David Spivey

Mentor: Dr. Kevin P. Schultz

Goucher College

Nitroxyl (HNO)

HNO has been found to have pharmacological effects: Positive cardiac inotropy Vasodilation Inhibits breast cancer tumor growth

Potential therapeutic agent for heart disease

Downside: highly unstable in physiological conditions

Current HNO Donors

A stable and controllable nitroxyl donor is needed to further study its therapeutic benefits and potential usefulness as a drug

Chromism

A process that induces a reversible color change in compounds

Types of chromism: Photochromism - color change caused by light Thermochromism - color change caused by heat Electrochromism - color change caused by an

electrical current Solvatochromism - color change caused by

solvent polarity Tribochromism - color change caused by

mechanical friction

Photochromism

The reversible transformation of a chemical species between two forms by the absorption of electromagnetic radiation, where the two forms have different absorption spectra.

Electrocyclic ring closing reaction

Diene Synthesis

Nitroxyl Binding and Release

UV/Vis Studies of Photochromic Transformation

First compound used produced results indicative of degradation

200217234251268285302319336353370387404421438455472489506523540557574591-0.2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

3 sec A6 sec A11 sec A16 sec A26 sec A36 sec A56 sec A

Wavelength (nm)

Absorb

ance

UV/Vis of New Compound

Photostationary State

The equilibrium chemical composition under a specific kind of electromagnetic radiation

0 10 20 30 40 50 60 700

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

440 nm Peak

Time (s)

Absorb

ance

0 10 20 30 40 50 60 703.6

3.8

4

4.2

4.4

4.6

4.8

5

237 nm Peak

Time (s)

Absorb

ance

Parallel vs. Antiparallel

UV light

Monitoring Closing by NMR

Open form

After 10 min of irradiation

Isolation of Closed Isomer

Nitroxyl Release

Tried heating open ring form in xylene/water at 140° C

Future Plans

Optimize retro-Diels Alder reaction and HNO release

Optimize side groups to obtain a higher percent in the closed conformation

References

Fukuto, J.M.; Dutton, A.S.; Houk, K.N. “The chemistry and biology of nitroxyl (HNO): a chemically unique species with novel and important biological activity,” Chembiochem, 2005, 6, 612–619.

Lopez, B. E.; Shinyashiki, M.; Han, T. H.; Fukuto, J. M. “Antioxidant actions of nitroxyl (HNO),” Free Radical Biol. Med. 2007, 42, 482–91.

Atkinson, R. N.; Storey, B. M.; King, S. B. “Reactions of Acyl Nitroso Compounds with Amines : Production of Nitroxyl (HNO) with the Preparation of Amides” Tetrahedron Lett. 1996, 37, 9287–9290.

Irie, M., “Diarylethenes for Memories and Switches,” Chem. Rev. 2000, 100, 1685–1716.

Lemieux, V.; Gauthier, S.; Branda, N. R. “Selective and sequential photorelease using molecular switches,” Ang. Chem. Int. Ed. 2006, 45, 6820–6824.

Erno, Z.; Asadirad, A. M.; Lemieux, V.; Branda, N. R. “Using light and a molecular switch to “lock” and “unlock” the Diels-Alder reaction,” Org. Biomol. Chem. 2012, 10, 2787–2792.

Acknowledgements

Kevin Schultz, Ph.D Goucher Chemistry Department Claasen Summer Research Fund Kirkbride Loya Jaclyn Kellon Kat Flanagan Marie McConville