73-31-4Relevant academic research and scientific papers
Selective hydroformylation of N-allylacetamide in an inverted aqueous two-phase catalytic system, enabling a short synthesis of melatonin
Verspui, Goeran,Elbertse, Guido,Sheldon, Frank A.,Hacking, Michiel A. P. J.,Sheldon, Roger A.
, p. 1363 - 1364 (2000)
Water increases the selectivity in the Rh-phosphine catalysed hydroformylation of N-allylacetamide; an aqueous-organic biphasic system, containing a hydrophobic Rh-catalyst, provided facile catalyst/product separation, after which the aqueous product phase could be used in a one-pot synthesis of N-acetyl-5-methoxytryptamine (melatonin).
Significantly improved catalytic efficiency of caffeic acid O-methyltransferase towards N-acetylserotonin by strengthening its interactions with the unnatural substrate's terminal structure
Wang, Wenya,Su, Sisi,Wang, Shizhuo,Ye, Lidan,Yu, Hongwei
, p. 1 - 5 (2019)
O-Methylation of N-acetylserotonin (NAS) has been identified as the bottleneck in melatonin biosynthesis pathway. In the present paper, caffeic acid O-methyltransferase from Arabidopsis thaliana (AtCOMT) was engineered by rational design to improve its catalytic efficiency in conversion of NAS to melatonin. Based on the notable difference in the terminal structure of caffeic acid and NAS, mutants were designed to strengthen the interactions between the substrate binding pocket of the enzyme and the terminal structure of the unnatural substrate NAS. The final triple mutant (C296F-Q310L-V314T) showed 9.5-fold activity improvement in O-methylation of NAS. Molecular dynamics simulations and binding free energy analysis attributed the increased activity to the higher affinity between the substrate terminal structure and AtCOMT, resulting from the introduction of N–H?π interaction by Phe296 substitution, hydrophobic interaction by Thr314 substitution and elimination of electrostatic repulsion by substitution of Gln310 with Leu310. This work provides hints for O-methyltransferase engineering and meanwhile lays foundation for biotechnological production of melatonin.
Mechanisms of NO release by N1-nitrosomelatonin: Nucleophilic attack versus reducing pathways
De Biase, Pablo M.,Turjanski, Adrian G.,Estrin, Dario A.,Doctorovich, Fabio
, p. 5790 - 5798 (2005)
A new type of physiologically relevant nitrosamines have been recently recognized, the N1-nitrosoindoles. The possible pathways by which N1-nitrosomelatonin (NOMel) can react in physiological environments have been studied. Our results show that NOMel slowly decomposes spontaneously in aqueous solution, generating melatonin as the main organic product (k = (3.7 ± 1.1) × 10-5 s-1, Tris-HCl (0.2 M) buffer, pH 7.4 at 37°C, anaerobic). This rate is accelerated by acidification (kpH 5.8 = (4.5 ± 0.7) × 10-4 s-1, kpH 8.8 = (3.9 ± 0.6) × 10-6 s-1 Tris-HCl (0.2 M) buffer at 37°C), by the presence of O2 (k o = (9.8 ± 0.1) × 10-5 s-1 pH 7.4, 37°C, [NOMel] = 0.1 mM, P(O2) = 1 atm), and by the presence of the spin trap TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl; ko = (2.0 ± 0.1) × 10-4 s-1, pH 7.4, 37°C, [NOMel] = 0.1 mM, [TEMPO] = 9 mM). We also found that NOMel can transnitrosate to L-cysteinate, producing S-nitrosocysteine and melatonin (k = 0.127 ± 0.002 M-1 s-1, Tris-HCl (0.2 M) buffer, pH 7.4 at 37°C). The reaction of NOMel with ascorbic acid as a reducing agent has also been studied. This rapid reaction produces nitric oxide and melatonin. The saturation of the observed rate constant (k = (1.08 ± 0.04) × 10-3 s-1, Tris-HCl (0.2 M) buffer, pH 7.4 at 37°C) at high ascorbic acid concentration (100-fold with respect to NOMel) and the pH independence of this reaction in the pH range 7-9 indicate that the reactive species are ascorbate and melatonyl radical originated from the reversible homolysis of NOMel. Taking into account kinetic and DFT calculation data, a comprehensive mechanism for the denitrosation of NOMel is proposed. On the basis of our kinetics results, we conclude that under physiological conditions NOMel mainly reacts with endogenous reducing agents (such as ascorbic acid), producing nitric oxide and melatonin.
Preparations of 1-hydroxyindole derivatives and their potent inhibitory activities on platelet aggregation
Somei, Masanori,Yamada, Koji,Hasegawa, Masakazu,Tabata, Mutsuko,Nagahama, Yoshiyuki,Morikawa, Harunobu,Yamada, Fumio
, p. 1855 - 1858 (1996)
1-Hydroxymelatonin, 5-bromo- and 5,7-dibromo-1-hydroxytryptamine derivatives, 1,4-dihydroxy-5-nitroindole, 1-hydroxy-3-methylsulfinylmethylindole, and 5-acetyl-1,3,4,5-tetrahydro-1-hydroxypyrrolo[4,3,2-de]quinoline were synthesized for the first time. 1-Hydroxyindoles revealed potent inhibitory activities on platelet aggregation.
A practical synthesis of N-acetyl-5-methoxy-tryptamine (melatonin)
Hwang, Ki-Jun,Lee, Tae-Suk
, p. 2099 - 2104 (1999)
The pineal hormone melatonin is conveniently prepared in simple one pot operation by treating 4-methoxyphenylhydrazine hydrochloride(6) with acetic anhydride and 4-aminobutyraldehyde dimethylacetal(4) in a mixed solvent system of acetic acid/ethanol/water.
Melatonin- And Ferulic Acid-Based HDAC6 Selective Inhibitors Exhibit Pronounced Immunomodulatory Effects in Vitro and Neuroprotective Effects in a Pharmacological Alzheimer's Disease Mouse Model
He, Feng,Chou, C. James,Scheiner, Matthias,Poeta, Eleonora,Yuan Chen, Natalia,Gunesch, Sandra,Hoffmann, Matthias,Sotriffer, Christoph,Monti, Barbara,Maurice, Tangui,Decker, Michael
, p. 3794 - 3812 (2021)
The structures of melatonin and ferulic acid were merged into tertiary amide-based histone deacetylase 6 (HDAC6) inhibitors to develop multi-target-directed inhibitors for neurodegenerative diseases to incorporate antioxidant effects without losing affinity and selectivity at HDAC6. Structure-activity relationships led to compound 10b as a hybrid molecule showing pronounced and selective inhibition of HDAC6 (IC50 = 30.7 nM, > 25-fold selectivity over other subtypes). This compound shows comparable DPPH radical scavenging ability to ferulic acid, comparable ORAC value to melatonin and comparable Cu2+ chelating ability to EDTA. It also lacks neurotoxicity on HT-22 cells, exhibits a pronounced immunomodulatory effect, and is active in vivo showing significantly higher efficacy in an AD mouse model to prevent both Aβ25-35-induced spatial working and long-term memory dysfunction at lower dose (0.3 mg/kg) compared to positive control HDAC6 inhibitor ACY1215 and an equimolar mixture of the three entities ACY1215, melatonin and ferulic acid, suggesting potentially disease-modifying properties.
Synthesis method of melatonin
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Paragraph 0020-0025, (2021/08/07)
The invention discloses a synthesis method of melatonin, and belongs to the technical field of pharmaceutical chemistry synthesis. According to the method, 5-hydroxytryptamine hydrochloride is used as a raw material, 5-methoxytryptamine is obtained through a methylation reaction of hydroxyl through a one-pot feeding method, a crude melatonin product is prepared through an acetylation reaction of amino, and finally, the finished melatonin is obtained through one-step refining and purification. The melatonin synthesis method provided by the invention avoids waste caused by step-by-step purification of the product, and has the characteristics of short synthesis route, short synthesis period, few raw material types and the like, the obtained product is high in yield, and the purity can meet the market demand. The synthesis method of the melatonin provided by the invention saves the cost and is easy for industrial production.
Recyclable and reusablen-Bu4NBF4/PEG-400/H2O system for electrochemical C-3 formylation of indoles with Me3N as a carbonyl source
Cheng, Didi,Li, Jingyi,Li, Yujin,Ling, Fei,Liu, Lei,Liu, Tao,Zhong, Weihui
supporting information, p. 4107 - 4113 (2021/06/17)
A safe, practical and eco-friendly electrochemical methodology for the synthesis of 3-formylated indoles has been developed by the utilization of Me3N as a novel formylating reagent. Stoichiometric oxidants, metal catalysts, and activating agents were avoided in this method, and an aqueous biphasic system ofn-Bu4NBF4/PEG-400/H2O was used as a recyclable and reusable reaction medium, which made this electrosynthesis approach more sustainable and environmentally friendly. This process expanded the substrate scope and functional group tolerance for bothN-EDG andN-EWG indoles. Furthermore, late-stage functionalization and total/formal synthesis of drugs and natural products were realized by means of this route.
A facile and versatile electro-reductive system for hydrodefunctionalization under ambient conditions
Huang, Binbin,Guo, Lin,Xia, Wujiong
supporting information, p. 2095 - 2103 (2021/03/26)
A general electrochemical system for reductive hydrodefunctionalization is described, employing the inexpensive and easily available triethylamine (Et3N) as a sacrificial reductant. This protocol is characterized by facile operation, sustainable conditions, and exceptionally wide substrate scope covering the cleavage of C-halogen, N-S, N-C, O-S, O-C, C-C and C-N bonds. Notably, the selectivity and capability of reduction can be conveniently switched by simple incorporation or removal of an alcohol as a co-solvent.
Preparation method of melatonin
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Paragraph 0049; 0056-0058; 0090-0093, (2020/03/03)
The invention relates to the technical field of chemical synthesis of medicines, in particular to a preparation method of melatonin. The preparation method of the melatonin comprises the following steps: (a) subjecting phthalimide, 1,3-dichloropropane, sodium iodide and ethyl acetoacetate to a reaction in a solvent under the action of alkali to obtain a compound I; (b) performing a ring closing reaction on the compound I and p-methoxyphenyl diazonium salt in the presence of alkali and a solvent to obtain a compound II; (c) hydrolyzing the compound II under an alkaline condition, and carrying out decarboxylating under an acidic condition to obtain a compound III; and (d) carrying out an acetylation reaction on the compound III to obtain melatonin. According to the preparation method, phthalimide, 1,3-dichloropropane, ethyl acetoacetate and the like are used as raw materials, and the price of the raw materials is low; the intermediate compound I can be obtained through a one-step method,so reaction steps and time are shortened; moreover, the conditions of each reaction step are relatively mild, the raw materials are easy to obtain, and high yield can be obtained.
