Abstract

Nitroxyl (HNO) is a biologically relevant small molecule with considerable clinical promise for the treatment of heart failure. However, studies of the chemistry and biology of nitroxyl are hampered by its short lifetime in aqueous solution. To aid in biological and chemical studies, various nitroxyl donors (molecules that degrade to release HNO) have been synthesized. Our group’s focus is on the synthesis of nitroxyl donors that rapidly release HNO under physiological conditions through photoactivation of a pendent 3-hydroxy-2-naphthyl methyl (3,2-HNM) group. First generation 3,2-HNM-based HNO donor 1 released HNO upon photoactivation, but competition was also observed from a redox side reaction. In this study, we are probing the impact of a methyl substituent at C* (2) on these competing processes. Difficulty in the synthesis of key alkoxylamine intermediate 3 has led to studies of variant Mitsunobu reactions that might be suitable for the efficient synthesis of 3. Ongoing studies involve use of various N-hydroxyphthalimide nucleophiles and applying differnet protecting groups (PG) in the key Mitsunobu step. This poster will present progress made to date on the Mitsunobu step leading to 3 and its elaboration to the final target 2.

Modified Abstract

Nitroxyl (HNO) is a biologically relevant molecule with considerable clinical promise for the treatment of heart failure. To aid in biological and chemical studies, various nitroxyl donors (molecules that degrade to release HNO) have been synthesized. Our group’s focus is on the synthesis of nitroxyl donors that rapidly release HNO under physiological conditions through photoactivation. First generation donors (1) released HNO but also experienced a side reaction. In this study, we are probing the impact of a methyl substituent at C* (2) on these competing processes. Difficulty in the synthesis of alkoxylamine intermediate 3 has led to studies of variant Mitsunobu reactions. This poster will present progress made to date on the Mitsunobu step leading to 3 and its elaboration to the final target 2.

Research Category

Physics/Chemisty/Liquid Crystal

Author Information

Mark CampbellFollow

Primary Author's Major

Biochemistry

Mentor #1 Information

Dr. Paul Sampson

Mentor #2 Information

Dr. Alex Seed

Presentation Format

Poster

Start Date

21-3-2017 12:00 AM

MWC_bio.docx (85 kB)

Research Area

Organic Chemistry

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Mar 21st, 12:00 AM

Synthesis of New Photoactivatable (3-Hydroxy-2-naphthyl)methyl (HNM)-Based Nitroxyl (HNO) Donors

Nitroxyl (HNO) is a biologically relevant small molecule with considerable clinical promise for the treatment of heart failure. However, studies of the chemistry and biology of nitroxyl are hampered by its short lifetime in aqueous solution. To aid in biological and chemical studies, various nitroxyl donors (molecules that degrade to release HNO) have been synthesized. Our group’s focus is on the synthesis of nitroxyl donors that rapidly release HNO under physiological conditions through photoactivation of a pendent 3-hydroxy-2-naphthyl methyl (3,2-HNM) group. First generation 3,2-HNM-based HNO donor 1 released HNO upon photoactivation, but competition was also observed from a redox side reaction. In this study, we are probing the impact of a methyl substituent at C* (2) on these competing processes. Difficulty in the synthesis of key alkoxylamine intermediate 3 has led to studies of variant Mitsunobu reactions that might be suitable for the efficient synthesis of 3. Ongoing studies involve use of various N-hydroxyphthalimide nucleophiles and applying differnet protecting groups (PG) in the key Mitsunobu step. This poster will present progress made to date on the Mitsunobu step leading to 3 and its elaboration to the final target 2.