New acyloxy nitroso compounds with improved water solubility and nitroxyl (HNO) release kinetics and inhibitors of platelet aggregation

Abstract

New acyloxy nitroso compounds, 4-nitrosotetrahydro-2H-pyran-4-yl 2,2,2-trichloroacetate and 4-nitrosotetrahydro-2H-pyran-4-yl 2,2-dichloropropanoate were prepared. These compounds release HNO under neutral conditions with half-lives between 50 and 120 minutes, identifying these HNO donors as kinetically intermediate to the much slower acetate derivative and the faster trifluoroacetic acid derivative. These compounds or HNO-derived from these compounds react with thiols, including glutathione, thiol-containing enzymes and heme-containing proteins in a similar fashion to other acyloxy nitroso compounds. HNO released from these acyloxy nitroso compounds inhibits activated platelet aggregation. These acyloxy nitroso compounds augment the range of release for this group of HNO donors and should be valuable tools in the further study of HNO biology.

Recent advances in the chemical biology of nitroxyl (HNO) detection and generation

“…26,102,104 Acyloxy nitroso compounds relax pre-constricted rat aorta with the rapid donors following a profile similar to AS and acyloxy nitroso compounds also activate soluble guanylate cyclase. 97,102,106 Acyloxy nitroso compounds increase rat cardiac muscle contractility by modifying cardiac myofilament proteins by increasing both maximum force and calcium sensitivity in both intact and skinned muscle.…”

“…97 King engineered several cyclohexanone-derived acyloxy nitroso donors with half-lives ranging from milliseconds to days. 97,102–104 Replacement of a methylene group with an oxygen atom in these compounds improves their water solubility allowing for more biological applications. 103,104 Chemical analysis reveals acyloxy nitroso compounds also directly react with both small molecule and protein thiols to yield disulfides, suflinamides and sulfinic acids indicating that hydrolytically stable acyloxy nitroso compounds retain the ability to act as thiol modifying agents.…”

[Retracted] Nitroxyl (HNO): A Reduced Form of Nitric Oxide with Distinct Chemical, Pharmacological, and Therapeutic Properties

“…A new class of HNO donors, acyloxy nitroso derivatives of cyclohexane, has been developed by King's group [ 40 , 41 ]. They are easily synthesized from oxidation of cyclohexanone oxime or dihydro-2H-pyran-4(3H)-one oxime by either lead tetraacetate (LTA) [ 40 ] or (diacyloxyiodo)benzene [ 42 ].…”

NO and HNO donors, nitrones, and nitroxides: Past, present, and future

“…Acyl and acyloxy nitroso compounds are another class of HNO donors (Fig. ), which also elicit several biological actions, namely vasodilation, enhanced cardiac contractility, and inhibition of platelet aggregation . These derivatives can also inhibit platelet aggregation and thrombus formation, in a mechanism directly linked to • NO and HNO release .…”

“…5), which also elicit several biological actions, namely vasodilation, enhanced cardiac contractility, and inhibition of platelet aggregation. 115,116 These derivatives can also inhibit platelet aggregation and thrombus formation, in a mechanism directly linked to • NO and HNO release. 117 Kinetic analysis shows that the rate of hydrolysis is highly dependent on pH the chemical structure of the acyloxy nitroso compound.…”