Dominican University, Chemistry, Park Ridge, IL 60068
Nitroxyl (HNO), the 1-electron reduced and protonated congener of nitric oxide, has emerged as a potential pharmacological agent due to its biological properties. It has been implicated in the mechanism of cyanamide’s inhibitory effect on aldehyde dehydrogenase in treating alcohol abuse as well as in treating heart failure. It has been suggested that HNO donors may represent a new class of inodilators for treatment of heart failure. In addition to the cardiovascular effects observed, HNO has shown initial promise in the realm of cancer therapy. Due to the fleeting nature of nitroxyl, vis-à-vis dimerization and formation of N2O, HNO must be generated in situ from donor compounds. Currently, only a few reasonable HNO donors are available to researchers.
Diazeniumdiolate ions, also known as NONOates, are extensively used in biochemical, physiological and pharmacological studies due to their ability to slowly release nitric oxide (NO.). In fact, NONOates of secondary amines have traditionally been used as NO donors and have become the standard for NO donating compounds in chemistry and biology. On the other hand, primary amine diazeniumdiolates have been less studied, and essentially IPA/NO, the NONOate of isopropylamine, has always been chosen as the representative of this class of compounds. Studies show that IPA/NO has the potential to release HNO under certain conditions and moreover it mimics Angeli’s salt in its chemical and biological properties.
In the search for new, organic-based compounds that release HNO, we have focused on the synthesis and evaluation of novel diazeniumdiolates using different primary amines. This project describes the synthesis of isobutylamine diazeniumdiolate as a novel HNO donor. Given that the diazeniumdiolate sodium salts are very difficult to purify and the rates and extents of HNO generation are difficult to adjust, the next step of this project was to alkylate the diazeniumdiolate ion as a “prodrug approach” for targeting HNO release. Kinetic studies have been performed for this diazeniumdiolate. Several buffer solutions (pH = 4 -10) were used in order to study the stability for our HNO donor. The rate constants was measured spectrophotometrically by monitoring the decrease in absorbance ~250 nm characteristic of the diazeniumdiolate functionality. From these data, the half-life of the compound in the various buffer solutions was calculated. Our results showed that at pH =7.4, the prodrug has a much longer half life (t1/2 = 41min) compared with the sodium salt (t1/2 = 13.4 sec). However, in basic solution (pH= 8.71) the prodrug has a half life t1/2 = 7.56 min and the sodium salt has a half life t1/2 =1.5 min.
[Abstract (DOCX)]