Natural Product Chemistry for Nitric Oxide Based Therapeutics

Abstract

Nitric oxide (NO) production is essential for normal human health and physiology. NO controls and regulates blood pressure, nervous and immune function along with numerous other fundamental physiological processes. Loss of NO production is recognized as one of the earliest events in the onset and progression of many if not all chronic diseases. Development of FDA approved NO based therapeutics has been slow and largely unsuccessful. Historically, natural product chemistry has been a primary strategy for development of new drug compounds. Through plant based chemistry and bacterial metabolism, NO can be produced and harnessed for restoration of NO based signaling in humans. This strategy may provide opportunity for development of safe and effective NO based therapies.

White Matter Damage as a Consequence of Vascular Dysfunction in a Spontaneous Mouse Model of Chronic Hypoperfusion with eNOS Deficiency

“…Although more than a dozen clinical reports revealing signi cant bene cial effects from administration of nitrate or nitrite to humans in multiple symptoms, including blood pressure, abnormal platelet aggregation, reduced triglycerides/hypercholesterolemia cardiac ischemia, proving absolute safety [54]. It should be noted that so far the majority of the clinical testing in patients used inorganic nitrate.…”

“…Several mechanisms probably contributed to the decrease in NO bioavailability, including defects in the cascade of NO generation (e.g., eNOS activity) and reduced NO donors. Thus far there are only three agents are approved by FDA for uses in treating acute angina by organic nitroglycerine, NO inhalation for pulmonary hypertension in neonates and phosphodiesterase inhibitors to prevent the breakdown of the downstream second messenger of NO, cyclic guanosine monophosphate/cGMP [54]. Although the rst line cholesterol-lowering drugs statins also demonstrate a potential to enhance the bioavailability of EDNO, principally by up-regulating and activating eNOS [55,56]; convincing clinical data is still lacking [57,58].…”

“…In humans, a normal NO production scheme requires nitrate to rst be reduced to nitrite via two electron reduction, followed by another one electron reduction to NO. Inorganic nitrate is nearly inert in humans due to an intrinsic lack of the functional gene to reduce nitrate to nitrite; the conversion relies on symbiotic oral bacteria and host enzymes which is ine cient (5 %) [54]. Therefore, the required conditions for nitrate to have therapeutic e cacy in humans are di cult to meet.…”

Straightforward Access to the Nitric Oxide Donor Azasydnone Scaffold by Cascade Reactions of Amines

“…[3] One of the important subclasses of heterocyclic pharmaceutical ingredients are nitric oxide donors( NO donors). [4] NO is ac rucial gaseouss ignaling molecule which mediates variousp hysiological processes andm ay be useful for cancert reatment. [5] Various classes of nitrogenÀoxygen organic systemsa re known for their ability to release NO.…”

“…Overall, synthesized azasydnones have good physicochemical properties andr elease NO in aw ide range of concentrationsw hich is usefulf or variousbiomedical insights. [4,12,15] In summary,w eh ave developed as traightforward one-pot approacht ot he construction of azasydnone scaffold based on cascade reactions of amines. Awide array of azasydnones were produced with very good functional group tolerance (25 examples, up to 97 %y ield).…”