Reactive oxygen (ROS) and reactive nitrogen species can cause vital damages to all cellular macromolecules, including nucleic acids, proteins, carbohydrates and lipids. Membrane lipids are most important targets of, and lipid peroxidation (LP) may lead to membrane dysfunction and change the cell permeability. Oxidative stress is associated in wide selection of disorders including ischaemia–reperfusion injury, neurodegenerative diseases, diabetes, inflammatory diseases and ageing (1).
It is known that indole derivatives are significant substances for their medicinal and biological features. Some 3-substituted indoles (2), indolyl thiohydantoin derivatROSives (3) and indolyl triazoles (4) have anticancer activity, melatonin has (5) antioxidant activity, indolin-2-one derivatives (6) and indol-5-carbonyl hydrazines (7) show antirheumatoidal activity, and indolyl thiohydantoins have anti-HIV activity (8). Series of 2-(hydrazinocarbonyl)-3-substituted-phenyl-1H-indole-5-sulphonamide derivatives (9,10) are known as carbonic anhydrase inhibitors.
Antioxidant effects of the indole ring-containing melatonin (MLT) have been well described and evaluated by Tan et al. (11). It acts as a free radical scavenger and has a broad-spectrum antioxidant (12). Owing to its free radical scavenger and antioxidant properties, MLT-related compounds such as MLT metabolites and synthetic analogues are under investigation to determine which exhibit the highest activity with the lowest side-effects (13–15). Antioxidant activity of synthetic indole derivatives such as indole-3-propionic acid (16), indole amine-triazoles (17) and stobadine (18) was studied extensively. Moreover, our group previously identified the antioxidant activity of MLT analogue indole derivatives such as 2-phenylindole derivatives (19), indole hydrazide and hydrazones (20,21) and indole-amides (22). Recently, we observed the relationship between aldose reductase and superoxide dismutase inhibition capacities of indole-based analogues of MLT derivatives (23).
It is known that many amino acids have potential antioxidant activity. In a study, troloxyl-methionine and Troloxyl-cysteine showed significant antioxidant activity (24,25). Several tryptophan derivatives function as a free radical scavengers and antioxidants. Furthermore, they stimulate a number of antioxidative enzymes and stabilize cell membranes that help to resist free radical damage (26,27). N-(4-pyridoxylmethylene)-l-serine was found as an antioxidant to suppress iron-catalysed ROS generation (28). l-alanine stimulates expression of the antioxidant defence proteins and ferritin in endothelial cells (29). Fullerene-substituted phenylalanine and lysine derivatives were determined to be significantly more potent than Trolox (30). Dehydro amino acids and corresponding peptides can function as radical scavengers (31). In our earlier studies (32,33), we showed that substituted dehydroalanines scavenge ROS. In the first study (32), novel N-acyl dehydroalanine derivatives were studied as antioxidants on rat liver LP and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical-scavenging activity. Most of the compounds showed strong inhibitory effect on LP. In the second study (33), comparative effect of N-substituted dehydroamino acids and alpha-tocopherol on rat liver LP activities was investigated. The results indicated that all the synthesized compounds showed very good inhibitory effect on the LP.
Melatonin has a role in the regulation of many physiological processes but therapeutic use is limited because of two major problems. The first is very short biological half-life, owing to its fast metabolism to 6-hydroxymelatonin and N(1)-acetyl-N(2)-formyl-5-methoxykynuramine and the second is the non-selectivity of MLT at target sites (34,35). To increase the biological half-life, the acetyl amino ethyl side chain was replaced with bulky amino acid derivatives by making hydrazones. Hydrazone derivatives possess a range of pharmacological activities including antitumoural, anti-microbial, antimalarial, anti-convulsant and anti-inflammatory activity (36). Recently, hydrazones were found as potential antioxidants (37–40). It is possible that the synthesized compounds may undergo some hydrolysis under the in vivo conditions because oxidative stress induces a LP of cellular membranes, resulting in the generation of reactive carbonyl compounds that involves in the ‘carbonyl stress’ (41,42). Hydrazine derivatives also exhibit carbonyl scavenger activity by the reaction of ketones/aldehydes (43).
There has been no research published related to antioxidant properties of indole amino acid derivatives. In this study, 14 MLT-based analogue indole amino acid derivatives and N-protected amino acids (Figure 1) were synthesized. Their antioxidant activity was investigated in vitro by LP inhibition and DPPH radical-scavenging assays. The results were compared with MLT, butylhydroxytoluene (BHT) and vitamin E. All new MLT analogue compounds 4a–i and new amino acid derivatives 2c and 2f were characterized on the basis of 1H- and 13C-NMR, mass and FT-IR spectra.
Melatonin molecule was modified in the 5-methoxy and acylamino groups showed in Scheme 1. These chemically significant modulations of the lead structure were made at two different points: the methoxy group at the fifth position of the indole ring and replacement of acetyl with amino acids derivatives. Scientific rationales and perspectives for the synthesis of new MLT analogues can be summarized as combining indole aldehyde and amino acids which have antioxidant properties to create synergistic antioxidant activity, use of bulky amino acid derivatives by making hydrazones with indole aldehyde to create longer biological half-life than MLT, to have carbonyl scavenger activity as well as antioxidant activity from hydrazine in case of the possibility of hydrolysis of the molecules and to see the possibility of antioxidant activity of the molecules without having methoxy on the fifth position of the indole ring.