NO‐donor melatonin derivatives: synthesis and in vitro pharmacological characterization

Abstract

Numerous studies document that melatonin possesses a broad-spectrum antioxidant activity. It traps a number of reactive oxygen species (ROS) such as hydroxyl and peroxyl radicals, singlet oxygen and hypochlorous acid. It also inhibits peroxynitrite-induced reactions. It is known that atherosclerosis progression involves ROS-induced oxidation of low-density lipoproteins in sub-endothelial space and the depletion of nitric oxide (NO) in blood vessels, as well as a decreased sensitivity of the vessels to the actions of NO. Considering this, a series of new NO-donor antioxidants were designed and synthesized by joining melatonin with NO-donor nitrooxy and furoxan moieties as polyvalent agents potentially useful for the treatment of cardiovascular diseases involving atherosclerotic vascular changes. The in vitro antioxidant properties of the resulting products were assessed in the thiobarbituric acid reactive substances assay (TBARS), the ABTS(+.) as well as in the alkaline phosphatase (ALP) assay. The antioxidant capacities of NO-donor melatonins to inhibit lipoperoxidation (TBARS-IC(50)) was predominantly dependent on their lipophilicity, and therefore on their partitioning process into membranes. On the other hand, their comparable capacity to inhibit protein oxidation (ALP-IC(50)) was independent of their lipophilicity and was consistent with their similar ability to participate in electron transfer reactions. All the NO-donor melatonins were also evaluated for their ability to relax rat aorta strips precontracted with 1 microM phenylephrine. Finally, binding affinities and intrinsic activity studies, carried out at MT(1) and MT(2) receptor subtypes, showed a rather complex picture in need of further investigation.

Analysis of N1-acetyl-N2-formyl-5-methoxykynuramine/N1-acetyl-5-methoxy-kynuramine formation from melatonin in mice

“…Melatonin is also a potent endogenous free-radical scavenger and antioxidant [4–12]. Melatonin interacts with a variety of reactive oxygen and nitrogen species, including hydroxyl radical [13], singlet oxygen [14], nitric oxide [13], hydrogen peroxide [15], peroxynitrite anion [7], hypocholorous acid [16], and the superoxide anion [17]. The antioxidant properties of melatonin are considerably different from classical antioxidants such as vitamin C and vitamin E. These classic antioxidants are usually electron donors and undergo redox cycling.…”

“…Melatonin is also a potent endogenous free-radical scavenger and antioxidant [4][5][6][7][8][9][10][11][12]. Melatonin interacts with a variety of reactive oxygen and nitrogen species, including hydroxyl radical [13], singlet oxygen [14], nitric oxide [13], hydrogen peroxide [15], peroxynitrite anion [7], hypocholorous acid [16], and the superoxide anion [17]. The antioxidant properties of melatonin are considerably different from classical antioxidants Abstract: The interactions of melatonin, a potent endogenous antioxidant, with reactive oxygen species generate several products that include N 1 -acetyl-N 2 -formyl-5-methoxykynuramine (AFMK) and N 1 -acetyl-5-methoxykynuramine (AMK).…”

Melatonin protects liver from intestine ischemia reperfusion injury in rats

“…It has been recently shown that liver is the final metabolic place of melatonin and melatonin protects liver from intestinal IR injury [24][25][26] . Studies have shown that melatonin has no side effect when a large dose is used [27,28] .…”

Carnosine analogues containing NO-donor substructures: Synthesis, physico-chemical characterization and preliminary pharmacological profile

“…Analysis (C, H, N) of the target compounds was performed by Service de Microanalyse, Université de Genève, Genève (CH), and the results were within 0.4% of theoretical values. Derivatives 7a [21], 3c [29], 11 [30], and 12 [31] were synthesised by the methods reported. HNE (4-hydroxy-trans-2,3-nonenal) was prepared by acid treatment (1mM HCl) of HNE-DMA (4-hydroxy-trans-2,3-nonenaldimethylacetal; Sigma).…”

“…The amines bearing dinitrooxy functionalities 3d,e were synthesized by nitration with fuming nitric acid in CH2Cl2 following the method reported elsewhere [29]. Compound 3f was obtained by reacting tosylate 11 [30] with Boc-protected benzylaminophenol 12 [31] followed by CF3COOH-mediated deprotection (scheme 2).…”