Published: Kem. Ind. 52 (4) (2003) 157–172
Paper reference number: KUI-25/2002
Paper type: Review
ARY Nitric Oxide Donors and Their Application in Treatment of Certain Diseases
I. Ozimec Landek
First described in 1987 as an endothelium-derived vascular relaxing factor, nitric oxide (NO) is now recognised as a ubiquitous signaling molecule able to elicit a wide variety of biological responses. Among its diverse functions, NO has been implicated in vascular smooth muscle relaxation, inhibition of platelet aggregation, neuro-transmission and immune regulation (Figure 1). NO is synthesised in mammalian cells via a sequential oxidation of the amino acid L-arginine by a family of enzymes known as NO synthases (NOSs) (Scheme 1). Due to its free radical properties, NO readily interacts with many biological molecules present in cells. The chemical properties of NO are crucial in defining its physiological roles and positive effects, as well as for adverse developments at higher fluxes of NO. Emerging evidence suggests that some diseases are related to defects in the NO generation or action. Chemicals that have the capacity to release NO by in vivo activation can be used in the treatment of such diseases, as well as in the treatment of other disorders not primarily caused by NO deficit. This article reviews major classes of organic molecules with NO donating properties: organic nitrates and nitrites, S-nitrosothiols, diazeniumdiolates, heterocyclic compounds and oximes (Table 1). A short description of remaining classes of NO donors is also given. Each class of compounds offers distinct biochemical properties. Some of them are illustrated in corresponding figures and schemes. The use of NO donors for medical purposes, mostly for treatment of acute disorders in cardiovascular system, dates back to more than a century (nitroglycerin). Current trends on the development of NO donor compounds in pharmaceutical industry are focused on the hybridization of NO donor moieties with currently available drugs (Scheme 4), which might overcome or reduce the drug toxicity as well as provide an additional NO-dependent biological activity. This innovative approach has resulted in the development of novel gastrointestinal-sparing nonsteroidal anti-inflammatory drugs (Figure 3). Also summarized are other indications that could potentially be treated with NO releasing drugs. Very promising biological results have given an impetus to a rapid development of the chemistry of NO donors.
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nitric oxide, nitric oxide donors, therapy, cardiovascular drugs, nonsteroidal anti-inflammatory drugs