1 research outputs found
Synthesis and Chemical and Biological Comparison of Nitroxyl- and Nitric Oxide-Releasing Diazeniumdiolate-Based Aspirin Derivatives
Structural
modifications of nonsteroidal anti-inflammatory drugs
(NSAIDs) have successfully reduced the side effect of gastrointestinal
ulceration without affecting anti-inflammatory activity, but they
may increase the risk of myocardial infarction with chronic use. The
fact that nitroxyl (HNO) reduces platelet aggregation, preconditions
against myocardial infarction, and enhances contractility led us to
synthesize a diazeniumdiolate-based HNO-releasing aspirin and to compare
it to an NO-releasing analogue. Here, the decomposition mechanisms
are described for these compounds. In addition to protection against
stomach ulceration, these prodrugs exhibited significantly enhanced
cytotoxcity compared to either aspirin or the parent diazeniumdiolate
toward nonsmall cell lung carcinoma cells (A549), but they were not
appreciably toxic toward endothelial cells (HUVECs). The HNO-NSAID
prodrug inhibited cylcooxgenase-2 and glyceraldehyde 3-phosphate dehydrogenase
activity and triggered significant sarcomere shortening on murine
ventricular myocytes compared to control. Together, these anti-inflammatory,
antineoplasic, and contractile properties suggest the potential of
HNO-NSAIDs in the treatment of inflammation, cancer, or heart failure