Original article
Synthesis and in vivo anti-mutagenic activity of novel melatonin derivatives

https://doi.org/10.1016/j.ejmech.2007.06.003Get rights and content

Abstract

Extensive literature suggests that melatonin play a role against the degenerative effect of central neurotoxins by its acting as free radical scavenger. This study aimed at evaluation of the anti-mutagenic activity of novel synthesized indole derivatives 2, 4a, and 8 in albino male mice in comparison with the parent melatonin. Efficacy of melatonin and its derivatives to influence cyclophosphamide (CP)-induced genotoxicity was tested using micronuclei (MN) formation in the bone marrow cells and determination of DNA, RNA and protein levels as well as cholinesterase and peroxidase activities in several organs of male mice. Following intragastrical injection of melatonin or one of its derivatives daily for 1 week, CP was given intraperitoneally, i.p., as a single dose of 25 mg/kg BW. Pyridazin-4-yl thiadiazoloindole derivative 8, diaminothiophen-5-yl thiadiazoloindole derivative 4a and melatonin were significantly able to reduce the number of micronucleated polychromatic erythrocytes (MnPCEs) in the bone marrow cells induced by CP (P < 0.0001, P < 0.001, P < 0.01, respectively). However, reduction of MN formation in the bone marrow cells was not significant when thiadiazoloindole derivative 2 was administered (P = 0.14). Examination of the protective effect of melatonin and its derivatives on the levels of DNA, RNA and protein as well as enzyme activities showed that compound 8 had the ability to inhibit the clastogenic effect of CP in several organs of male mice. These findings suggest that compounds 4a, 8 and melatonin were able to reduce the mutagenicity effect of CP in male mice. The ability of compounds 4a, 8 and melatonin to reduce CP-related genotoxicity is possibly attributed to their antioxidant activity.

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The purpose of this study was to evaluate the anti-mutagenic activity of the novel synthesized indole derivatives 2, 4a, and 8 in albino male mice in comparison with the parent melatonin. Efficacy of melatonin and its derivatives to influence cyclophosphamide (CP)-induced genotoxicity was tested using micronuclei (MN) formation in the bone marrow cells and determination of DNA, RNA and protein levels as well as cholinesterase and peroxidase activities in several organs of male mice. The present study suggests that compounds 4a, 8 and melatonin were able to reduce the mutagenicity effect of CP in male mice. The ability of compounds 4a, 8 and melatonin to reduce CP-related genotoxicity is possibly attributed to their antioxidant activity.

Introduction

Melatonin, the pineal gland indole, is a potent endogenous antioxidant. It is claimed to detoxify a variety of free radicals and reactive oxygen intermediates [1]. Melatonin prevents lipid membrane peroxidation and apoptosis [2], and protects the DNA from damage induced by free radicals [3]. Moreover, melatonin stimulates gene expression of antioxidative enzymes [4], [5]. Cyclophosphamide (CP) is a chemotherapeutic cancer medication. Serious side effects have been reported with the use of CP. It is a clastogenic agent which has been shown to produce gene mutations, chromosome aberrations, micronuclei (MN) formation and sister chromatid exchanges in rats, mice, Chinese hamsters and fish species [6], [7]. Melatonin leads to strong inhibition of the clastogenic activity of CP [8] and ameliorates bladder damage induced by CP by diminishing the oxidative stress and blocking iNOS and peroxynitrite production [9]. Also, the use of melatonin as anti-mutagenic agent for human protection against carbamazepine-induced chromosome damage was investigated [10]. The development of synthetic compounds capable of mimicking the effects of melatonin has progressed considerably during the past decade. These compounds are structurally diverse, and range from simple indole derivatives and its bioisosteres to phenylalkyl amides and constrained melatoninergic agents [11], [12].

In continuation with previous studies on the biologically active indole derivatives of melatonin [13], [14], this work aimed to study the possible protective effect of novel synthesized indole derivatives against the CP-induced genotoxicity in comparison with the parent melatonin. The frequency of MN in bone marrow cells and the rate of damage in DNA, RNA, protein, peroxidase and cholinesterase in several organs of male mice were investigated to verify the goal of the present study.

Section snippets

Chemistry

To improve the essential pharmacophoric features of the melatonin molecule, we have outlined the synthesis of several indole derivatives containing an important heterocyclic moiety starting with melatonin. In fact, therapeutic agents containing thiadiazole and thiophene have attracted the attention of researchers in pharmaceutical chemistry; these heterocycles have been found to show various biological activities such as antimicrobial, anti-inflammatory, antiviral, antituberculosis, anti-tumor

Synthetic methods and spectral data

The starting pure powder of melatonin was obtained as a gift from Amoun Pharmaceutical Industries, Egypt. The appropriate precautions in handling moisture-sensitive compounds were undertaken. All melting points of the new compounds were measured using an electrothermal capillary melting point apparatus and are uncorrected. The IR spectra are expressed in cm−1 and recorded in KBr pellets on a Pa-9721 IR spectrometer. 1H and 13C NMR spectra were obtained on a Varian EM-390 90 MHz spectrometer in

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