Melatonin Analogues Research Articles

Antiproliferative and pro-apoptotic activity of melatonin analogues on melanoma and breast cancer cells

Melatonin plays different physiological functions ranging from the regulation of circadian rhythms to tumor inhibition, owing to its antioxidant, immunomodulatory and anti-aging properties. Due to its pleiotropic functions, melatonin has been shown to elicit cytoprotective processes in normal cells and trigger pro-apoptotic signals in cancer cells. The therapeutic potential of melatonin analogues prompted us to investigate the in vitro and in vivo antitumor activity of new melatonin derivatives and explore the underlying molecular mechanisms. The experiments revealed that the new melatonin analogues inhibited the growth of melanoma and breast cancer cells in a dose- and time-dependent manner. In addition, our results indicated that melatonin derivative UCM 1037 could induce apoptosis in melanoma and breast cancer cells, as well as cell necrosis, in MCF-7. Together, apoptosis and necrosis could be two possible mechanisms to explain the cytotoxic effect of the melatonin analogue against cancer cells. The suppression of tumor growth by the melatonin analogues was further demonstrated in vivo in a xenograft mice model. A decrease in the activation of MAPK pathway was observed in all cancer cells following UCM 1037 treatment. Overall, this study describes a promising antitumor compound showing antiproliferative and cytotoxic activity in melanoma and breast cancer cells.

Possibilities of using melatonin in gynecology

For the modern gynecologist, the problem of human aging acquires a special urgency – the tasks of preserving the reproductive potential of a woman, alleviating the symptoms of perimenopause come to the fore. Clinical manifestations of climacteric syndrome are very diverse and polysymptomatic and can vary from the presence of several symptoms to the development of the entire symptom complex. In the article the modern strategies of conducting women during menopausal transition and postmenopause are considered: hormone replacement therapy as the main method of correction and prevention of climacteric disorders, as well as auxiliary methods – phytoestrogens, anticonvulsants, antidepressants, agents acting on the autonomic nervous system, multivitamin complexes, plant extracts that are used more or less successfully in clinical practice.Melatonin preparations, analogues of one of the main endogenous adaptogens, are of particular interest in this series. This review describes the main effects of melatonin, its place in the complex treatment of the proliferative processes of the reproductive system, in particular, in the treatment of premenstrual syndrome, dysphoria, correction of sleep disorders in the perimenopause, its special role in the maturation of the follicle and ovulation. Melatonin is a universal natural adaptogen with a sleep effect, which is recommended by the National Consensus on the management of patients in menopause as a preparation of additional non-hormonal therapy. In the treatment of climacteric syndrome, it can be used at a dose of 1.5 mg 30 minutes before sleep for three months. It can be recommended as a monotherapy in the mild course of menopause and the prevalence of sleep disorders. If symptoms are more pronounced, melatonin should be combined with hormone replacement therapy.Synthetic analogue of melatonin is represented in Ukraine by drug Vita-Melatonin produced by PJSC “Kiev Vitamin Plant”. The drug allows to perform the task of increasing the effectiveness of therapy for various gynecological diseases. Not being selectively tropic to the reproductive system, melatonin promotes adaptation, improvement of the general condition and well-being of women in the climacteric period.

Novel agonists of melatonin receptors as promising hypotensive and neuroprotective agents for therapy of glaucoma

Melatonin is a pineal hormone that has a capacity to lower intraocular pressure; it exhibits neuroprotective and antioxidant properties that make it possible to use melatonin in the therapy of glaucoma. Analogs of melatonin having affinity to melatonin receptors are promising candidates for application as antiglaucomatous drugs. Chemical modification of the melatonin structure can in-crease efficiency, bioavailability and selectivity of these analogs. We have designed and synthe-sized a number of new 2-oxindole derivatives – ligands of melatonin MT3 subtype receptors that displayed ability to lower intraocular pressure in normotensive rabbits and high antioxidant activity against hydroxyl radical and superoxide anion-radical. The antioxidant activity of new ligands was several times higher than one of melatonin that makes them prospective therapeutic tools for the diseases that include oxidative stress. The maximal hypotensive effect of analogs was comparable to that of melatonin itself but prolonged. Combination of these properties gives an opportunity of using the presented melatonin analogs in complex therapy of glaucoma.

Pharmacophore modeling and conformational analysis in the gas phase and in aqueous solution of regioisomeric melatonin analogs. A theoretical and experimental study

In this work, 2-(N-acylaminoalkyl)indoles 1a–1d, that incorporate a pMeOBn group at the 3-position of the indole ring were virtual screened as potential melatoninergic ligands by analog-based design study using pharmacophore modeling. Pharmacophore models for melatoninergic agonist and antagonist activity were developed in order to identify the molecular constraints that define the geometric relationship among chemical features in each model. The best hypothesis consisted of six features for agonists and eight features for antagonists. The models suggest that the agonists and antagonists can share the same 3D arrangement for the six common pharmacophoric elements identified: two hydrogen bond acceptors (HBA), one hydrogen bond donor (HBD), one hydrophobic area (H), and two aromatic rings (AR). The extra hydrofobic interaction might be used as criterion for identified the pharmacological antagonist profile. Based on the pharmacophore fit, it was found that structures 1c and 1d show a good structural overlay that meets the requirements for the antagonistic pharmacophore hypothesis. Molecular modeling studies using the PCM solvation model predicted that the most stable conformers of 1a–1d match the antagonist pharmacophore hypothesis in contrast to those in the gas phase. Structures 1a–1c were synthesized only but the activities were not tested.

“Singing” Fish Rely on Circadian Rhythm and Melatonin for the Timing of Nocturnal Courtship Vocalization

The patterning of social acoustic signaling at multiple timescales, from day-night rhythms to acoustic temporal properties, enhances sender-receiver coupling and reproductive success [1-8]. In diurnal birds, the nocturnal production of melatonin, considered the major vertebrate timekeeping hormone [9, 10], suppresses vocal activity but increases song syllable duration over circadian and millisecond timescales, respectively [11, 12]. Comparable studies are lacking for nocturnal vertebrates, including many teleost fish species that are also highly vocal during periods of reproduction [4, 13-20]. Utilizing continuous sound recordings, light cycle manipulations, hormone implants, and in situ hybridization, we demonstrate in a nocturnally breeding teleost fish that (1) courtship vocalization exhibits an endogenous circadian rhythm under constant dark conditions that is suppressed under constant light, (2) exogenous delivery of a melatonin analog under inhibitory constant light conditions rescues courtship vocal activity as wellas the duration of single calls, and (3) melatonin receptor 1b is highly expressed in evolutionarily conserved neuroendocrine and vocal-acoustic networks crucial for patterning reproductive and vocal behaviors in fishes and tetrapods. Our findings, together with those in birds, show melatonin's remarkable versatility as a timing signal in distantly related lineages. It exerts opposing effects on vocalization in nocturnal versus diurnal species at the circadian timescale but comparable effects at the finer timescale of acoustic features. We propose that melatonin's separable effects at different timescales depends on its actions within distinct neural networks that control circadian rhythms, reproduction, and vocalization, which may be selected upon over evolutionary time as dissociable modules to pattern and coordinate social behaviors. VIDEO ABSTRACT.

Base-Free Synthesis of CF3-Containing β-Tryptamine Derivatives from N-Nosyl-2-CF3-Aziridine and Indoles

Introduction of the Ns (o-nitrobenzenesulfonyl) group into 2-F3C-aziridine enhanced the useful electrophilic character of the ring, which in turn enabled a base-free ring-opening reaction with indoles under thermal conditions. This method constitutes a practical synthetic route to a variety of CF3-containing β-tryptamine derivatives, one of which could be transformed to the CF3-containing melatonin analogue in high overall yields.

Indole-based melatonin analogue compounds as cellular ROS inhibitors: Investigation on the peroxidation of human erythrocyte membranes and oxidative hemolysis

Indole-based melatonin analogue compounds as cellular ROS inhibitors: Investigation on the peroxidation of human erythrocyte membranes and oxidative hemolysis

Synthesis and in vitro antioxidant activity studies of melatonin analogue compounds

Synthesis and in vitro antioxidant activity studies of melatonin analogue compounds

Characterizing novel metabolic pathways of melatonin receptor agonist agomelatine using metabolomic approaches

Agomelatine (AGM), an analog of melatonin, is a potential agonist at melatonin receptors 1/2 and a selective antagonist at 5-hydroxytryptamine 2C receptors. AGM is widely used for the treatment of major depressive episodes in adults. However, multiple adverse effects associated with AGM have been reported in clinical practice. It is little known about AGM metabolism in vitro and in vivo, although metabolism plays a pivotal role in its efficacy and safety. To elucidate metabolic pathways of AGM, we systemically investigated AGM metabolism and its bioactivation in human liver microsomes (HLM) and mice using metabolomic approaches. We identified thirty-eight AGM metabolites and adducts, among which thirty-two are novel. In HLM, we uncovered five GSH-trapped adducts and two semicarbazide-trapped aldehydes. Moreover, we characterized three N-acetyl cysteine conjugated-AGM adducts in mouse urine and feces, which were formed from the degradation of AGM_GSH adducts. Using recombinant CYP450 isoenzymes and chemical inhibitors, we demonstrated that CYP1A2 and CYP3A4 are primary enzymes contributing to the formation of AGM_GSH adducts and AGM_hydrazones. This study provided a global view of AGM metabolism and identified the novel pathways of AGM bioactivation, which could be utilized for further understanding the mechanism of adverse effects related to AGM and possible drug–drug interactions.

Novel indole-based melatonin analogues: Evaluation of antioxidant activity and protective effect against amyloid β-induced damage

Oxidative stress has been recognized as a contributing factor in ageing and various diseases including cancer and neuropathological disorders. Indole derivatives such as the neurohormone melatonin (MLT) constitute an important class of therapeutic agent in medicinal chemistry. MLT can scavenge different reactive oxygen species and can also stimulate the synthesis of antioxidant enzymes. As a part of our ongoing studies, a series of new indole-based hydrazide/hydrazone derivatives were synthesized as MLT analogues. Their antioxidant activity was investigated in human erythrocytes by evaluating their reducing effect against oxidation of a redox-sensitive fluorescent probe. Possible inherent cytotoxicity of the compounds was investigated in CHO-K1 cells by lactate dehydrogenase leakage test. Protection of neuronal PC12 cells against amyloid β-induced damage was examined by MTT assay and their ability in reduction of ROS generation induced by amyloid β was tested. MLT analogues having an o-halogenated aromatic moiety exhibited effective antioxidant properties without having any membrane-damaging effect. Moreover, derivatives having o-halogenated and dihalogenated aromatic side chain significantly protected neuronal cells at concentrations of 10 and 100μM. In conclusion, MLT derivatives represent promising scaffolds for discovery of effective antioxidant and neuroprotective agents.

Modular Approach to 9-Monosubstituted Fluorene Derivatives Using Mo(V) Reagents.

Oxidative coupling using molybdenum(V) reagents provides fast access to highly functionalized 9-monosubstituted fluorenes. This synthetic approach is highly modular, is high yielding, and tolerates a variety of labile moieties, e.g. amides or iodo groups. The established protocol leads to promising precursors for pharmacologically important analogues of melatonin.

Melatonergic Treatment: Focus on Metabolism and Chronobiology

Introduction: Melatonin is produced in various organs, but its preferentially nocturnal synthesis and release by the pineal gland is decisive for its chronobiological actions. The short half-life of circulating melatonin has been reason for developing synthetic melatonergic agonists. With regard to age- and disease-related dysfunction of the melatonergic system, treatment with melatonin or its synthetic analogs may be used for alleviating health problems with a respective etiology. This review addresses limitations arising from drug-specific metabolism and disregarded chronobiological rules. Metabolism: Differences are illustrated by comparing the metabolism of melatonin and two approved synthetic melatonergic agonists, ramelteon and agomelatine. Apart from hydroxylation and dealkylation reactions, melatonin can be converted to methoxylated kynuramines, a route absent in the two synthetic drugs. An unsual property is present in the ramelteon metabolite M-II, which still displays melatonergic activity, but attains 30 to 100 times higher levels than the parent compound. Two double hydroxylated agomelatine metabolites may be involved in sometimes occurring hepatotoxicity. Chronobiology of Melatonergic Drugs: Sleep latency facilitation and readjustment of circadian rhythms require only short actions. Circadian entrainment must consider the phase response curve and requires repetitive well-timed administration. Findings in nocturnally active rodents cannot be generally translated to humans, especially not regarding sleep and, perhaps, not in insulin resistance. Conclusions: Melatonin and synthetic analogs can be suitable for treating sleep-onset difficulties, circadian rhythm sleep disorders and subtypes of depression with an etiology of circadian dysfunction. Applications in the field of metabolic syndrome and insulin resistance have to be seen with caution.

Novel indole-based melatonin analogues substituted with triazole, thiadiazole and carbothioamides: studies on their antioxidant, chemopreventive and cytotoxic activities

Melatonin (MLT) is a well-known free-radical scavenger, involving in the prevention of cellular damage that can lead to cancer, ageing and a variety of neurodegenerative diseases. Research on MLT-related compounds has been required to optimise the maximum pharmaceutical activity with the lowest side effects. In our ongoing research, we have synthesized new indole-based MLT analogues as potential antioxidant agents by modifying the MLT molecule. In this study, we build on previous findings, through the synthesis, characterization and in vitro antioxidant profiling of a series of new indole-based MLT analogues which possess triazole, thiadiazole and carbothioamides on the third position on the indole ring. In vitro antioxidant activity was investigated by evaluating their reducing effect against oxidation of a redox sensitive fluorescent probe and their radical scavenging activity was assessed via the DPPH assay. In addition, in vitro cytotoxic effects of newly synthesized compounds were investigated in CHO-K1 cells using the MTT assay.

New coumarin-based fluorescent melatonin ligands. Design, synthesis and pharmacological characterization

The design and synthesis of a series of new fluorescent coumarin-containing melatonin analogues is presented. The combination of high-binding affinities for human melatonergic receptors (h-MT1R and h-MT2R) and fluorescent properties, derived from the inclusion of melatonin pharmacophoric elements in the coumarin scaffold, yielded suitable candidates for the development of MT1R and MT2R fluorescent probes for imaging in biological media.

Synthesis and evaluation of antioxidant activity of new quinoline-2-carbaldehyde hydrazone derivatives: bioisosteric melatonin analogues

Overproduction of reactive oxygen species results in oxidative stress that can cause fatal damage to vital cell structures. It is known that the use of antioxidants could be beneficial in the prevention or delay of numerous diseases associated with oxidative stress. Melatonin (MLT) is known as a powerful free-radical scavenger and antioxidant. It was found that indole ring of MLT can be employed by bioisosteric replacement by other aromatic rings. Quinoline derivatives constitute an important class of compounds for new drug development. Owing to quinoline and hydrazones appealing physiological properties and are mostly found in numerous biologically active compounds a series of quinoline-2-carbaldehyde hydrazone derivatives were synthesized as bioisosteric analogues of MLT, characterized and in vitro antioxidant activity was investigated by evaluating their reducing effect against oxidation of a redox-sensitive fluorescent probe. Cytotoxicity potential of all compounds was investigated both by lactate dehydrogenase leakage assay and by MTT assay.

Experience with sustained-release melatonin for the treatment of sleep disorders in depression

The data available in the literature on the role of melatonin in the regulation of circadian rhythms and sleep disorders in the population and in patients with mental diseases are analyzed. The cause of insomnia may be circadian rhythm disorders due to the age-related decline in the elaboration of the endogenous hormones that are responsible for the quality and duration of sleep, one of which is melatonin. Sustained-release melatonin is a synthetic analogue of the endogenous human pineal hormone melatonin. According to clinical findings, the main proven clinical effects of sustained-release melatonin 2 mg are a reduction in the latency of sleep, improvement of its quality, and lack of daytime sleepiness. The drug causes no dependence on its long use and rebound symptoms (increased insomnia symptoms), positively affects cognitive functions, and lowers nocturnal blood pressure in hypertensive patients. The paper describes a clinical case of a female patient with recurrent depressive disorder, in whom sustained-release melatonin 2 mg has demonstrated high efficacy and good tolerability in the combination therapy of sleep disorders in the pattern of depression.

Contraceptive Method Mix Utilization and its Associated Factors among Married Women in Gedeo Zone, Southern Nations, Nationality and People Region-Ethiopia: A Community based Cross Sectional Study

One of the core symptoms of the menopausal transition is sleep disturbance. Peri-menopausal women often complain of difficulties initiating and/or maintaining sleep with frequent nocturnal and early morning awakenings. Factors that may play a role in this type of insomnia include vasomotor symptoms, changing reproductive hormone levels, circadian rhythm abnormalities, mood disorders, coexistent medical conditions, and lifestyle. Other common sleep problems in this age group, such as obstructive sleep apnea and restless leg syndrome, can also worsen the sleep quality. Exogenous melatonin use reportedly induces drowsiness and sleep and may ameliorate sleep disturbances, including the nocturnal awakenings associated with old age and the menopausal transition. Recently, more potent melatonin analogs (selective melatonin-1 (MT1) and melatonin-2 (MT2) receptor agonists) with prolonged effects and slow-release melatonin preparations have been developed. They were found effective in increasing total sleep time and sleep efficiency as well as in reducing sleep latency in insomnia patients. The purpose of this review is to give an overview on the changes in hormonal status to sleep problems among menopausal and postmenopausal women.

Hybrid formulations of liposomes and bioadhesive polymers improve the hypotensive effect of the melatonin analogue 5-MCA-NAT in rabbit eyes.

For the treatment of chronic ocular diseases such as glaucoma, continuous instillations of eye drops are needed. However, frequent administrations of hypotensive topical formulations can produce adverse ocular surface effects due to the active substance or other components of the formulation, such as preservatives or other excipients. Thus the development of unpreserved formulations that are well tolerated after frequent instillations is an important challenge to improve ophthalmic chronic topical therapies. Furthermore, several components can improve the properties of the formulation in terms of efficacy. In order to achieve the mentioned objectives, we have developed formulations of liposomes (150–200 nm) containing components similar to those in the tear film and loaded with the hypotensive melatonin analog 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT, 100 µM). These formulations were combined with mucoadhesive (sodium hyaluronate or carboxymethylcellulose) or amphiphilic block thermosensitive (poloxamer) polymers to prolong the hypotensive efficacy of the drug. In rabbit eyes, the decrease of intraocular pressure with 5-MCA-NAT-loaded liposomes that were dispersed with 0.2% sodium hyaluronate, 39.1±2.2%, was remarkably higher compared to other liposomes formulated without or with other bioadhesive polymers, and the effect lasted more than 8 hours. According to the results obtained in the present work, these technological strategies could provide an improved modality for delivering therapeutic agents in patients with glaucoma.

The melatonin analog 5-MCA-NAT increases endogenous dopamine levels by binding NRH:quinone reductase enzyme in the developing chick retina

NRH:quinone reductase (QR2) is present in the retinas of embryonic and post-hatched (PH) chicks. 5-Methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT) is a QR2 ligand that increases cAMP levels in developing retinas, but it does not affect cAMP levels in CHO-QR2 cells. The dopamine quinone reductase activity of QR2 retrieves dopamine, which increases cAMP levels in developing retinas. The objective of the present study was to investigate whether 5-MCA-NAT increases endogenous dopamine levels in retinas from chick embryos and post-hatched chicks. Endogenous dopamine was measured by enzyme-linked immunosorbent assay (ELISA). 5-MCA-NAT increased retinal endogenous dopamine levels at all developmental stages studied and in PH chicks (−logEC50=11.62±0.34M). This effect was inhibited by non-selective antagonists of receptors and melatonin binding sites N-acetyl-2-benzyltryptamine (luzindole, 5μM), but it was not inhibited by the Mel1b melatonin receptor antagonist 4-phenyl-2-propionamidotetralin (4-P-PDOT, 10nM). The QR2 cosubstrate, N-methyl-dihydronicotinamide (NMH) (−logEC50=6.74±0.26M), increased endogenous dopamine levels in controls and in retinas stimulated with 5-MCA-NAT (3nM). The QR2 inhibitor benzo[e]pyrene inhibited endogenous dopamine levels in both control (−logIC50=7.4±0.28M) and NMH-stimulated (at 100nM and 1μM benzo[e]pyrene concentrations) retinas. Theoretical studies using Molegro Virtual Docking software corroborated these experimental results. We conclude that 5-MCA-NAT increases the level of endogenous dopamine via QR2. We suggest that this enzyme triggers double reduction of the dopamine quinone, recovering dopamine in retinal development.

К вопросу комплексного лечения больных раком яичников III–IV стадий методом аутогемохимиотерапии, ассоциированной с «Мелаксеном»

This paper presents the positive characteristics of preoperative autohemochemotherapy associated with the drug "Melaxen” as a synthetic analogue of the epiphysial hormone melatonin, produced by Unipharm-USA in the complex treatment of patients with ovarian cancer on the stage III-IV. The authors emphasize that the "Melaxen" has a powerful antioxidant, anticarcinogenic and adaptogenic action, reduces stress response and regulates neuroendocrine function and biological rhythms. The authors believe that neoadjuvant autohemotherapy by the "Melaxen" with a powerful immunomodulatory and lipoic effects, improves general non-specific resistance of the organism, has a positive effect on the immediate and remote results of complex treatment of patients. In comparison with polychemotherapy, the autohemotherapy in combination with the “Melaxen" has the advantages. This therapy is significant in several basic methods of treatment of malignant tumors of the localization.
 It was found that with autohemochemotherapy by the "Melaxen" improves efficiency polychemotherapy, reduces its toxicity, consequently, clinically warranted and expedient in this connection, can be used as subsidiary means complex treatment of ovarian cancer recurrence in the spread process. The drug allows to improve the quality of life, to increase its duration in critically ill patients.