MIC-14, MIC-16

Semiempirical AM1-TDHF calculations of the static first hyperpolarizabilities, β(0), of 1,3-thiazolium-5-thiolate mesoionic derivatives were performed. Guided by these results, two new mesoionic compounds - 2-(4-nitrophenyl)-3-methyl-4-(methylphenyl)-1,3-thiazolium-5-thiolate and 2-(4-nitrophenyl)-3-methyl-4-(methoxyphenyl)-1,3-thiazolium-5-thiolate - were synthesized and characterized by analytical and spectroscopic means.











The ¹³C NMR (APT, 50 MHz, DMSO-d6) study of the compound MIC-14 showed thirteen chemical shifts. Of these, seven were assigned to the quaternary carbons, two to the primary aliphatic carbons and four to the aromatic tertiary carbons. The carbons of the mesoionic ring of MIC-14 have chemical shifts in 152.1; 141.4 and 161.9 ppm assigned, respectively, to C2, C4 e C5 (see Figure 5a). The carbons C10 and C15 have chemical shifts of 40.6 and 21.4 ppm, while the aromatic carbons have chemical shifts of 132.7 (C6); 129.4 (C7, 7'); 123.8 (C8, 8'); 148.5(C9); 129.6 (C11); 129.8 (C12, 12'); 128.2 (C13, 13') and 139.1 (C14).
The ¹H NMR (200 MHz, DMSO-d6) spectrum of MIC-14 shows six hydrogen signals. Of these, two intense singlets were observed in the aliphatic region with an integral of 6H for the hydrogens H10 and H15 of the methyl groups, respectively in 3.64 and 2.38 ppm. There was also a signal between 8.27 and 7.23 assigned to the eight aromatic hydrogens.
For compound MIC-16 we observed a similar chemical behavior. The ¹³C NMR (APT, 50 MHz, DMSO-d6) spectrum showed thirteen signals. The carbons of the mesoionic ring showed chemical shifts of 148.7; 142.5 and 162.5 for C2, C4 and C5, respectively (see Figure 5b). Carbons C10 and C15 show values of chemical shifts that are compatible with the N-methyl group in 40.8 and the methoxy group in 55.2. The aromatic carbons have chemical shifts of 132.6 (C6); 130.4 (C7, 7'); 124.6 (C8, 8'); 148.5 (C9); 121.3 (C11); 132.6 (C12, 12'); 114.3 (C13, 13') and 160.4 (C14).
The ¹H NMR (200 MHz, DMSO-d6) spectrum of MIC-16 has six hydrogen signals. Of these, two intense singlets were observed in the aliphatic region with an integral of six hydrogens, three hydrogens were assigned to the N-methyl group of the heterocyclic ring in 3.69 ppm and three were assigned to the methoxy group in 3.90 ppm. In the region between 8.34 and 7.07 ppm we observed corresponding signals the eight aromatic hydrogens.
The results above are in agreement with the results observed by Athayde-Filho et al.¹⁴

2-(4-Nitrophenyl)-3-methyl-4-(4-methyphenyl)-1,3-thiazolium-5-thiolate, (MIC-14)
0.19 g, (0.51 mmol); IR (KBr) ν _max/cm^-1: 3117, 3062, 2994, 1607, 1542, 1495, 1429, 1351, 1294; ¹H NMR (300 MHz, CDCl₃): δ 2.38 (s, 3H), 3.64 (s, 3H), 7.23 (d, J 8.2 Hz, 2H), 7.28 (d, J 8.2 Hz, 2H), 7.64 (d, J 8.8 Hz, 2H), 8.27 (d, J 8.8 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃): δ 161.9, 152.1, 141.4. 139.1, 148.5, 132.7, 129.8, 129.6, 129.4, 128.2, 123.8, 40.6, 21.4; MS (EI, 70 eV): m/z (%) = 343 [M+1] (17.74), 342 [M] (100), 327 (8.07), 296 (19.94), 281 (15.43), 179 (20.14), 166 (2.99), 135 (9.43), 119 (4.41), 91 (4.23), 75 (2.08); Anal. Calc. for C₁₇H₁₄N₂O₂S₂: C, 59.63; H, 4.12; N, 8.18; S, 18.73. Found: C, 60.04; H, 4.71; N, 8.27; S, 19.03; yield 37%, mp 183-185 °C (recryst. EtOH:H₂O (1:1, v/v)).
2-(4-Nitrophenyl)-3-methyl-4-(4-metoxyphenyl)-1,3-thiazolium-5-thiolate, (MIC-16)
0.29 g, (0.78 mmol); IR (KBr) ν _max/cm^-1: 3009, 2967, 2897,1590, 1489, 1513, 1426, 1334, 1282; ¹H NMR (300 MHz, CDCl₃): δ 3.90 (s, 3H), 3.69 (s; 3H), 7.07 (d, J 8.8 Hz, 2H), 7.48 (d, J 8.8 Hz, 2H), 7.88 (d, J 8.4 Hz, 2H), 8.34 (d, J 8.4 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃): δ 162.5, 160.4, 148.7, 148.5, 142.5, 132.6, 130.4, 124.6, 121.3, 114.3, 55.2, 40.8; MS (EI, 70 eV): m/z (%) = 359 [M+1]⁺ (17), 358 [M] (94.62), 343 (9.58), 312 (47.77), 297 (32.37), 282 (11.51), 210 (9.95), 195 (100), 166 (6.64), 163 (18.62), 151 (29.44), 135 (40.27), 63 (17.59); Anal. Calc. for C₁₇H₁₄N₂O₃S_2, C, 56.96; H, 3.94; N, 7.82; S 17.89. Found: C, 57.13; H, 3.87; N, 8.03; S, 18.03; 56%, mp 215-217 °C (recryst. EtOH:H₂O (1:1, v/v)).

 

 

Journal of the Brazilian Chemical Society

Print version ISSN 0103-5053

J. Braz. Chem. Soc. vol.21 no.5 São Paulo  2010

http://dx.doi.org/10.1590/S0103-50532010000500024  

 http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532010000500024

SHORT REPORT

1,3-thiazolium-5-thiolates mesoionic compounds: semiempirical evaluation of their first static hyperpolarizabilities and synthesis of new examples


Bruno F. Lyra^I,II; Soraya A. de Morais^I; Gerd B. Rocha^*,I; Joseph Miller^II,III,†; Gustavo L. C. Moura^III; Alfredo M. Simas^III; Clovis Peppe^IV; Petrônio F. de Athayde-Filho^I,II
IDepartamento de Química, Universidade Federal da Paraíba, 58059-900 João Pessoa-PB, Brazil
^IILaboratório de Tecnologia Farmacêutica, Universidade Federal da Paraíba, CP 5009, 58051-970 João Pessoa-PB, Brazil
^IIIDepartamento de Química Fundamental, Universidade Federal de Pernambuco, 50670-901 Recife-PE, Brazil
^IVDepartamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria-RS, Brazil






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//////

MELATONIN 2/2

.


 

CHEMICAL IDENTIFICATION
 
 
¹H NMR assignment 

                    The chemical shifts and coupling constants of melatonin using CDCl₃ as the standard are shown in Table 1 below;
 
 

Bond	Chemical Shift/ppm	Coupling constant	Peak
3H, 2-CH3	1.87	-	Slinglet
3H, Acetone	2.32	-	Slinglet
2H and  b-CH2	2.87	6.5 Hz,	Triplet
2H and l-CH3	3.48	6.5 Hz	Quatet
3H, OCH3	3.84	-	Singlet
N, NH	5.7	-	Broad and Singlet
1H and 6-H	6.78	2 and 8.5 Hz	Quatet
1H and 4H	7.00	2 Hz	Doublet
1H and 7H	7.17	8.5 Hz	Doublet
H, NH	8.3	-	Broad and Singlet

IR Spectrum
 
 

Bond	Wavenumber / cm-1
NH	3240
C=O , amide I	1627
C=O , amide II	1555
Aromatic C=C	1620, 1587, 1492
C-O	1217, 1180
Aromatic Substitution	828, 810, 800

 
 

 
GCMS assay for melatonin
 

                    The melatonin assay in this case is based upon selected ion monitoring of the m/e 232 and /or 245 ions from trimethylsilyl (TMS) derivatives. An internal standard is simply an analoque of melatonin having a considerably longer retention time, with intensed ions at m/e 232 and m/e 245. These ions, which have exactly the same structure as those arising from melatonin, can be used as standards for high resolution measurements on melatonin as well as other methoxy indoles. This type of standard is preferred to deuterium labeled analoques because of problems with deuterium exchange, and difficulty in preparing such compounds with high isotopic purity.

 

 : Partial mass spectrum of the TMS melatonin (b) and its derivatives (a) and (c).

SYNTHESIS

Chemical Synthesis of Melatonin
 

                        The methods for the chemical synthesis of melatonin are generally not so complicated and do not involve more than three steps of conversion. Three synthesis reactions of melatonin from primary literatures are shown below;

Reaction 1

                         In 1958 melatonin was first isolated and characterised by A.B.Lerner. It was know as one of a substituted 5-hydroxyindole derivative in the pineal gland that could lighten pigment cells. It had not been know to exist in biological tissue although it had been isolated as a urinary excretion product in rats after administration of 5-hydroxytryptamine.
                          Melatonin or N-acetyl-5-methoxytryptamine (40 mg) was prepared by reducing 100 mg of 5-methoxyindole-3-acetonitrile with 160 mg of sodium and 2 ml of ethanol. Then the product was acetylated with 4 ml of both glacial acetic acid and acetic anhydride at 100 ^oC for 1 minute. Purification was achieved by countercerrent distribution and silicic acid chromatography.

Reaction 2

                         5-Methoxytryptamine  hydrochloride (1g, 4.75 mmole) was dissolved in pyridine (10 ml) and acetic anhydride (10 ml) and kept overnight at 20 ^oC. The solution was poured onto iced, neutralised with dilute hydrochloric acid and extracted with chloroform (2x25 ml). The combined extracts were washed with water, dried in MgSO₄ and evaporated to afford a liquid of N,N diacetyltryptamine derivative. The liquid was then poured into water (50 ml) and extracted with chlroform (2x25 ml). The combined organic layers were washed with water (25 ml), dried in MgSO₄ and evaporated to dryness. The residual solid crystallised from benzene to afford melatonin 819 mg, 80% yield.

 
 

Reaction 3

                        The more reactive indoles (1a-1d) were alkylated at the 3 position by reaction with nitroethene generated in situ by thermolysis of nitroethyl acetate. The nitroethyl acetate used for this purpose was prepared by acetylation of nitroethanol with acetic anhydride using NaOAc as a catalyst. These conditions constitute a substantial improvement of the overal yield of the reation. Reduction of the nitroethylated indoles (2a-d) by hydrogenation over PtO₂, followed by acetylation fo the resluting tryptamines with acetic anhydride-pyridine completed the synthesis of melatonin and its derivatives (4a-d).

Biological Synthesis and Metabolism of Melatonin

                    The biosynthesis of melatonin (Fig.1) is initiated by the uptake of the essential amino acid tryptophan into pineal parenchymal cells. Tryptophan is  the least abundant of essential amino acids in normal diets. It is converted to another amino acid, 5-hydroxytryptophan, through the action of the enzyme tryptopahn hydroxylase and then to 5-hydroxytryptamine (serotonin) by the enzyme aromatic amino acid decarboxylase. Serotonin concentrations are higher in the pineal than in any other organ or in any brain region. They exhibit a striking diurnal rhythm remaining at a maximum level during the daylight hours and falling by more than 80% soon after the onset of darkness as the serotonin is converted to melatonin, 5-hydroxytryptophol and other methoxyindoles. Serotonin's conversion to melatonin involves two enzymes that are characteristic of the pineal : SNAT (serotonin-N-acetyltransferase) which converts the serotonin to N-acetylserotonin, and HIOMT (hydroxyindole-O-methyltrasferase) which trasfers a methyl group from S-adenosylmethionine to the 5-hydroxyl of the N-acetylserotonin. The activities of both enzymes rise soon after the onset of darkness because of the enhanced release of norepinephrine from sympathetic neurons terminating on the pineal parenchymal cells.
                        Another portion of the serotonin liberated from pineal cells after the onset of darkness is deaminated by the enzyme monoamine oxidase (MAO) and then either oxidized to form 5-hydroxyindole acetic acid or reduced to form 5-hydroxytryptophol (Fig.1). Both  of these compounds are also substrates for HIOMT and can thus be converted in the pineal to 5-methoxyindole acetic acid 5-methoxytryptophol (Fig.1). The level of this latter indole, like that of melatonin, rises markedly in the pineal with the onset of darkness. Since 5-methoxytryptophol synthesis does not require the acetylation of serotonin, the nocturnal increase in pineal SNAT activity cannot be the trigger that causes pineal methoxyindole levels to rise. More likely, a single unexplained process- the intraparenchymal release of stored pineal serotonin, which then becomes accessible to both SNAT and MAO. This process ultimately controls the rates at which all three major pineal methoxyindoles are synthesized and generates the nocturnal increases in pineal melatonin and 5-methoxytryptophol. The proportion of available serotonin acetylated at any particular time of day or night depends on the relative activities of pineal SNAT and MAO at that time. The rates of methylation of all three 5-hydroxyindoles formed from pinela serotonin depends on HIOMT activity.

Fig.1 Biosynthesis of pineal methoxyindoles from serotonin
Serotonin may be either acetylated to form N-acetylserotonin through the action of the enzyme serotonin-N-acetyltransferase (SNAT), or oxidatively deaminated by monoamine oxidase (MAO) to yield an unstable aldehyde. This compound is then either oxidized to 5-hydroxyindole acetic acid by the enzyme aldehyde dehydrogenase (ADH), or reduced to from 5-hydroxytryptophol by aldehyde reductase (AR). Each of these 5-hydroxyindole derivatives of serotonin is a substrate for hydroxyindole-O-methyltrasferase (HIMOT). The enzymatic trasfer of a methyl group from S-adenosylmethionine to these hydroxyindoles yields melatonin (5-hydroxy-N-acetyltryptamine), 5-methoxyindole acetic acid and 5-methoxytryptophol respectively.  Pineal serotonin is synthesized from the essential amino acid tryptophan by 5-hydroxylation folloed by decarboxylation. The first step in ths enzymic sequence is catalysed by tryptophan hydroxylase. The second step is catalysed by aromatic L-amino acid decarboxylase.

CHEMICAL REACTIONS

Reactions of  melatonin and other 1-hydroxyindole derivatives

SCHEME 1

Click on image for enlarged version
 
                          Melatonin (2) was used to prepared 1-hydroxy indole derivative as shown in the scheme 1 above. Yield of melatonin was raised by up to 80% by reacting it with BF₃-MeOH complex in reflusing MeOH. Then it was reduced to 2,3-dihydroindole (3a) with triethylsilane (Et₃SiH) and trifluoroacetic acid (TFA) in 86% yield. Subsequence oxidation of (3a) with sodium tungstate dihydrate (Na₂WO₄.2H₂O) afforded the desired 1-hydroxymelatonin (4a) in 28% yield.While bromination of 2,3-dihydro-N-methoxycarbonyltryptamine (5) with bromine in acetic acid generated monobromo (3b) and dibromo (3c) compounds in 61% and 30% yields respectively. Oxidation of (3b) and (3c) with Na₂WO₄.2H₂O and 30% H₂O₂ produced the corresponding 1-hydroxytryptamines (4b)  and (4c) in 57% and 51% yields . For the preparation of 1,4-dihydroxy-5-nitroindole (13), 4-hydroxy -5-nitroindole (11) was required as a starting material. It was also possible to form (11) by oxidation of 5-aminoindole (6) with m-chloroperbenzoic acid (mCPBA) in acetone. However, the yield was miserable (4%). In order to incrase the yield, an alternative synthesis method was developed. First, the reaction for obtaining 4-hydroxyindole-3-carboxaldehyde (8) from indole carboxaldehyde (7). The yield is now incrased to 70% with good reproducibility employing thallation with thallium tris(tris-fluoroacetate) and subsequenct treatment of the resultant thallium compound with cupric sulfate pentahydrate (2 mol eq.) in  N,N-dimethylformamide and H₂O at 120-130 ^oC. Nitration of (8) with cupric nitrate and acetic anhydride produced 5-nitro (9a) and 7-nitro (9b) compounds in 45% and 46% yields respectively. Since,direct conversion of (9a) to (11) was unsuccessful, (9a) was transformed to diacetyl compound  (10) in 82% yield by treatment with refluxing acetic anhydride. Oxidation of 3-formyl group of (10 ) to carboxyl group with sodium chloride and subsequent treatment with 1N aqeuous sodium hydroxide caused hydrolysis and simultaneous decarboxylation to afford (11) in 90% yield. The reduction of (11) with Et₃SiH and TFA  afforded (12) in 91% yield. Subsequent oxidation of (12) with mCPBA (3 mol eq.) afforded the desired (13) in 66% yield, whereas with  Na₂WO₄.2H₂O and 30% H₂O₂ only 14% yield of (13) was produced.
                        1-hydroxy-3-methlsulfinylmethylindole (16a) was prepared as followed. 3-Methylthiomethylindole (14) was first prepared in 80% yield by reacting gramine with sodium methyl sulfide. Reduction of (14)  with sodium cyanoborohydride (NaBH₃CN) in AcOH successfully generated 2,3-dihydroindole (15) in 55% yield. Subsequent oxidation of (15) with  Na₂WO₄.2H₂O and 30% H₂O₂ produced (16a) in 27% yield. Formation of unstable 1-hydroxy-3-methylsulfonylmethylindole (16b) is confirmed as a 1-methoxy derivative but its isolation was not successful.
                        5-Acetyl-1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline (18) is a readily available from 4-nitroindole-3-acetonitrile (17).  (18) was reduced with NaBH₃CN in AcOH and TFA to afford 90% yield of 2,3-dihydroindole (19). Oxidation of (19) with Na₂WO₄.2H₂O and 30% H₂O₂ produced the desired 5-acetyl-1,3,4,5-tetrahydro-1-hydroxypyrrolo[4,3,2-de]quinoline (20) in 69% yield.

STRUCTURE OF MELATONIN

picture of melatonin (2D) with labelled atoms

                    The molecular structure and configuration of melatonin  (N-acetyl- 5 - methoxy tryptamine) can be determined by X-ray diffraction method.  It is crystallized from benzene solution as yellow plates (m.p. 118-119 ^oC ), which are shown to be monoxlinic with unit cell parameters of a= 7.711, b=9.282, c=17.107 A^o  and ß =96.77 ^o from systematic extinctions. The density value of 1.269 g/cc measured by the flotation method in calsium chloride aqueous solution, indicates that there are four molecules in a unit cell.
                    The main C-C distance in the benzene ring is 1.402 A^o, while those of C-C and C-N distances in the pyrrole ring are 1.405 A^o and 1.394 A^o respectively.  The indole part of melatonin is planar, the average deviation of the atoms from the plane is 0.011 A^o and the maximum deviation  is 0.022 A^o for N(2). C(1), C(2) and O(1) of acetyl groul and N(1) are almost strictly in a plane. This plane forms a dihedral angle of 12 ^o with that of the indole ring. The atomic parameters and temperature factors (B_ij) for heavy atoms are listed in Table 1 below;

Table 1 : The atomic parameters and temperature factors (B_ij) for heavy atoms  in melatonin molecule

Atoms	x	y	z	B11	B22	B33	B12	B13	B23
C(1)	1.1750	0.2986	0.8350	247	128	29	-21	-15	13
C(2)	1.0969	0.3563	0.7550	205	86	32	3	52	-8
C(3)	0.9357	0.3088	0.6258	271	101	20	-19	-19	-3
C(4)	0.8703	0.1735	0.5814	215	81	25	-19	-1	-1
C(5)	0.8194	0.2067	0.4943	166	84	28	17	28	1
C(6)	0.8395	0.3324	0.4541	195	95	31	20	17	14
C(7)	0.7145	0.1739	0.3648	172	96	28	33	15	2
C(8)	0.7398	0.1041	0.4383	154	85	25	-5	24	0
C(9)	0.6887	-0.0144	0.4458	165	89	34	-1	22	-10
C(10)	0.6186	-0.1087	0.3775	182	101	40	-1	11	-12
C(11)	0.5943	-0.0400	0.3032	186	131	36	16	9-	-18
C(12)	0.6419	0.1030	0.2956	183	138	33	34	12	-1
C(13)	0.5866	-0.3313	0.4485	296	88	55	-26	22	24
N(1)	1.0081	0.2636	0.7059	212	79	25	-12	11	-7
N(2)	0.7730	0.3155	0.3754	215	95	36	8	20	11
O(1)	1.1145	0.4863	0.7368	297	75	33	-55	29	-6
O(2)	0.5659	-0.2539	0.3756	282	108	52	-95	7	-38

 

• B_ij are temperature factors ( x 10⁴)
• Anisotropic temperature factors are in the form : T= exp[-(B₁₁h² + B₂₂K₂ + B₃₃l₂ + B₁₂hk + B₁₃hl +B₂₃kl)].
• The average standard deviations of the coordinations are about 0.007, 0.006 and 0.005 ao for carbon, nitrogen and oxygen atoms     respectively

            The torsion angle as defined by Klyne and Prelog (W. Klyne and V; Prolog, Experientia, 16, 521 (1960) ) is +0.4^o (syn-periplanar) for the atoms C(13)-O(2)-C(10)-C(9), while the equivalent angle in 5-methoxy-(N,N)-dimethyltryptamine hydrochloride is +2.5^o .
                     Three important torsion angles C(2)-N(1)-C(3)-C(4),  N(1)-C(3)-C(4)-C(5) and C(3)-C(4)-C(6) are +171^o (anti-periplanar), -171^o (anti-periplanar) and +6^o (syn-periplanar) respectively. The extended configuration of the side chain attached to C(5) atom is also found in serotonin-creatinine sulphate complex .
                    The crystal structure of melatonin reviews that two melatonin molecules are hydrogen-bonded through N(2)-H----O(1)  (2.87 A^o)  into dimer related by centre of symmetry. These dimers are linked together by N(1)-H----O(1) hydrogen bonds (2.95 A^o ) in the directions of b and c-axes. The normal van der Waals contacts are found between adjacent indole rings or methoxy groups to stabilise the crystal structure.

INTRODUCTION

structure of melatonin or ( N-Acetyl-5-methoxytryptamine)

                  Melatonin or 5-methoxy-N-acetyltryptamine is an important hormone that plays a role in regurating the neuroendocrine system. It  plays an important role in the reguration of the circadian sleep-wake cycle. It also controls essential functions such as metabolism, sex drive, reproduction, appetite, balance, muscular coordination and immune system in fighting off diseases triggered by bacteria, viruses, chemical pollutants and excessive free radical activity. It is normally released during the night in response to environmental changes in light levels by the peneal gland which is a tiny gland burried deep in the brain behind the eyes of mammals. The pineal itself is controlled by a paired cluster of nerve cells located just above the optic chiasm in the hypothalamus. These cells are known as the suprachiasmatic nuclei (SCN) and they contain the circadian pacemaker. Each night the SCN send impulses, via a series of neurons in the hypothalamus and spinal cord, up to the pineal gland to stimulate melatonin secretion. The timing mechanism in the SCN itself is controlled by sunlight that enters the retina and reaches the SCN via the retinohypothalamic pathway. The amount of melatonin circulating in the blood has been shown to rise and fall during a day.  The 24-hour cycle of melatonin production in Human is shown in figure 1 below;

Figure 1: the amount of melatonin secretion from human pineal gland during various time of day
                    From the graph above it can be seen that melatonin levels reach the highest value during the middle of the night and decline to the lower amounts during daytime.

                    Since its structure was first discovered in 1958 by A.B. Lerner, melatonin has been studied extensively. There are over 4,000 published studied in the scientific literature about melatonin. Every week, five to fifteen new studies are published, making melatonin one of the hottest subjects of life extension research. In toxicity studies conducted on humans, doses of melatonin ranging from 300 mg a day for nine months to 1000 mg a day for six weeks porduced no toxicity or adverse reactions other than daytime fatigue.

So what is so hot about melatonin ?

Melatonin is an effective sleeping pill. Taking low dose of melatonin on a nightly basis at appropriate sleep times allows the body to naturally adapt to altered day and night patterns. Synthesis of melatonin in the human body declines with advancing age and this is one of the reasons why elders have more sleep disorder problems than children.

Research shows that the administration of melatonin  improves the sleep onset in blind subjects unable to synchronize with the solar cycle.It may also be an effective hypnotic for insominiacs or travellers who suffer from jet lag. In 1994 Wurtman et al. at the Massachusetts Institute of Technology reported the results of a sleep laboratory study involving 20 subjects with normal sleep habits. Subjects were administered melatonin in low doses (1-10 mg) or placebo, and sleep was monitired in the lab during five 8-hour test sessions. Compared with placebo, melatonin (all doses) decreased the time it took to fall asleep and increased sleep duration. Subjects who received melatonin 1 mg fell asleep in an average of 6 minutes compared with 17 minutes for subjects who received placebo. The investigators concluded that melatonin may be as effective a hypnotic as the benzodiazepines.

 Apart from its treat with sleeping disorders, there is also a correlation between the low level of melatonin and increase in risk of cancer. Research studies have demonstrated that melatonin can prevent chemically induced mammary tumors in laboratory rats and can also inhibit the proliferation of human breast cancer cells in tissue culture. For more detail about role of melatonin concerning cancer and tumer see melatonin immunity and cancer in human.

Melatonin is available commercially from several unregurated health-food suppliers. Soon after the publication of the Wurtman report, health food stores began selling out of melatonin and consumers flooded Wurtman's lab with requests for melatonin for insominia or jet lag. The response to these requests has been to point out that melatonin is not FDA approved. There is no labeling for dosage and side effects, there are no controls for purity and self-medicating with an unregulated product is a mistake.However, melatonin demand has not yet declined. In 1994, one manufacturer of melatonin in  USA  increased the amount of melatonin sold the previous year by three-fold.
 
 

What to consider before using melatonin
supplement?
The first thing to consider is that sometimes, less is more. Although melatonin plays an extremely important role in our bodies, it is present only in tiny amounts, even when we are at our youthful peak. Melatonin capsules vary in dosage from less than 0.1 mg up to 6 mg. Although  no severe side effects have been reported at dosages up to 10 mg daily, in some people it may cause morning drowsiness.  Melatonin is not recommended for pregnent women nor should be intended to use by persons under 25 years of age. People who have serious illnesses such as autoimmune disorder, leukemia or lymphoma should consult a physician familear with melatonin before usage. Immune suppressing drugs such as cortisol and cyclosporine may react adversely with melatonin as may anti-depressants. People who are diabetic, experience major depression or have a hormonal imbalance should also take caution. Pregnent of nursing mather should avoid melatonin supplements. They are already transmitting melatonin to fetus or infant via the placenta or their milk. It is unknown if increasing their own melatonin levels might adversely affect the child.

  Melatonin   

Chemical names :        N-acetyl-5-methoxytrptamine   
                                     N-[2-(5-methoxy-1H-indol-3-yl)ethyl]         
                                     3-(N-Acetyl-2-aminoethyl)-5-methoxy indole   
                                     N-[2-(5-Methoxy-1H-indol-3-yl]  

Empirical formula :       C₁₃H₁₆N₂O₂   

Molecular mass :           232.28 amu   

Melting point :               116~118 ^oC  

Possible harzard :          No possible harzard has been reported 

Normal state :               Crystalline solid

Density:                          1.29 g/cc 

Colour :                         Pale yellow   

Prices :                          Laboratory analytical proposes :  
                                      £ 29.10   (1 g)  
                                      £ 7.90     (100 mg)  
                                      £ 12.00    (250 mg)  
                                      £ 32.00    (1 g)  
   
                                      Melatonin tablet retail prices :  
                                      £ 20.00    (100 x 300 mcg)  

BNN  :                         205542  

EC no.  :                      2007977

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