title: Synthesis of Amino-ADT Provides Access to Hydrolytically Stable Amide-Coupled Hydrogen Sulfide Releasing Drug Targets.
abstract: As additional physiological functions of hydrogen sulfide (H2S) are discovered, developing practical methods for exogenous H2S delivery is important. In particular, nonsteroidal anti-inflammatory drugs (NSAIDs) functionalized with H2S-releasing anethole dithiolethione (ADT-OH) through ester bonds are being investigated for their combined anti-inflammatory and antioxidant potential. The chemical robustness of the connection between drug and H2S-delivery components, however, is a key and controllable linkage in these compounds. Because esters are susceptible to hydrolysis, particularly under acidic conditions such as stomach acid in oral drug delivery applications, we report here a simple synthesis of amino-ADT (ADT-NH2) and provide conditions for successfulADT-NH2derivatization with the drugs naproxen and valproic acid. Using UV-vis spectroscopy and HPLC analysis, we demonstrate that amide-functionalized ADT derivatives are significantly more resistant to hydrolysis than ester-functionalized ADT derivatives.
authors.affiliation: Department of Chemistry and Biochemistry, Institute of Molecular Biology, Materials Science Institute, University of Oregon, Eugene, OR 97403-1253, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hammers
authors.affiliation: Department of Chemistry and Biochemistry, Institute of Molecular Biology, Materials Science Institute, University of Oregon, Eugene, OR 97403-1253, USA.
authors.forename: Loveprit
authors.initials: L
authors.lastname: Singh
authors.affiliation: Department of Chemistry and Biochemistry, Institute of Molecular Biology, Materials Science Institute, University of Oregon, Eugene, OR 97403-1253, USA.
authors.forename: Leticia A
authors.initials: LA
authors.lastname: Montoya
authors.affiliation: Department of Chemistry and Biochemistry, Institute of Molecular Biology, Materials Science Institute, University of Oregon, Eugene, OR 97403-1253, USA.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Moghaddam
authors.affiliation: Department of Chemistry and Biochemistry, Institute of Molecular Biology, Materials Science Institute, University of Oregon, Eugene, OR 97403-1253, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Pluth
keywords: ADT-OH; H2S donors; dithiolethione; hydrogen sulfide; sulfur