Development Of Photoactivatable Nitroxyl Hno Donor Molecules Using Photolabile Protecting Groups

Download or read book Development of Photoactivatable Nitroxyl (hno) Donor Molecules Using Photolabile Protecting Groups written by Yang Zhou (Writer on chemistry and biochemistry) and published by . This book was released on 2017 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Nitroxyl (HNO) has attracted increasing attention because it has important and unique chemical and biological properties distinct from nitric oxide (NO). Especially, prodrugs of HNO show much promise in treating congestive heart failure. However, HNO is a very reactive molecule that rapidly dimerizes and spontaneously dehydrates to yield nitrous oxide (N2O) and H2O. Thus, precursor molecules named HNO donors are required to generate HNO in situ for chemical and biological studies. Current HNO donors release HNO with half-lives of minutes to hours. Due to the rapid reaction between HNO and biomolecules (k ~ 103-107 M-1s-1), the decomposition of current HNO donors to release HNO is invariably the rate-determining step during the mechanistic studies. Therefore, directly obtaining kinetic and mechanistic data for the reactions of HNO with biomolecules is not feasible because of the slow release of HNO (t1/2 ~ minutes to hours) from current available HNO donors. To address this limitation, we have sought to develop a novel family of photoactivatable HNO donors incorporating various photolabile protecting groups (PPG), which rapidly release HNO on demand. Initial work focused on the development of three N-alkoxysulfonamides incorporating the (3-hydroxy-2-naphthalenyl)methyl (3,2-HNM) phototrigger as HNO donors. Photochemical studies of these 3,2-HNM-based HNO donors revealed the presence of a photo-induced redox O-N cleavage pathway, in addition to the desired HNO generation pathway. Trifluoromethanesulfonyl-based donors maximally released ~ 70% HNO under optimal solvent conditions, and decomposed with a half-life ~ 7 s under a direct xenon light source. The HNO generation was found to occur via a concerted fashion rather than a stepwise mechanism. We also explored the role of 2-nitrobenzyl and 4,5-dimethoxy-2-nitrobenzyl phototriggers in these photoactivatable N-alkoxysulfonamides in an effort to improve the selectivity for the desired HNO generation pathway. However, the photo-induced redox O-N bond cleavage was observed as the major pathway even in the trifluoromethanesulfonyl-based donors. Then the (6-hydroxy-2-naphthalenyl)methyl (6,2-HNM) phototrigger was used to replace the isomeric 3,2-HNM-based moiety in these photoactivatable N-alkoxysulfonamides. The selectivity for the HNO generation pathway from the trifluoromethanesulfonyl-based donor was greatly increased up to ~ 98%. Upon irradiation by a direct xenon lamp, photodecomposition of the trifluoromethanesulfonyl-based donor proceeded rapidly with a half-life ~ 5 s. Finally, we investigated the impact on the selectivity of HNO generation of gem-disubstitution at the benzylic position of the 6,2-HNM-based HNO donor system. Relative to the desphenyl analog, the selectivity for the HNO generation pathway in the methanesulfonyl-based HNO donor was greatly increased up to ~ 42%, and the N-O bond cleavage was greatly suppressed (~ 17%).