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Relevant academic research and scientific papers

Synthesis, characterization and crystal structure of new tetrahydro-β-carboline as acetylcholinesterase inhibitor

In this study, a new tetrahydro-β-carboline derivative, 2-benzoyl-6-methoxy-9-methyl-1-phenyl-1,2,3,4-tetrahydro-β-carboline has been synthesized through a three-steps reaction in good yield (76%). The structure of this compound was characterized by different spectroscopic methods including NMR (1D and 2D), UV, IR and MS. Molecular structure of the synthesized compound was also confirmed by single crystal X-ray diffraction technique. Further, evaluation of in vitro acetylcholinesterase (AChE) inhibitory activity showcased the potential of this compound as AChE inhibitor with an IC50 value of 26.52 ± 0.79 μM. In addition, this compound showed minimal toxicological profile at cellular level. Docking simulation illustrated a highly selective binding at peripheral side of AChE via hydrophobic interactions. In silico prediction of blood-brain barrier (BBB) permeation and ADMET properties of the compound was also reported.

Structural simplification of evodiamine: Discovery of novel tetrahydro-β-carboline derivatives as potent antitumor agents

Natural products (NPs) have played a crucial role in the discovery and development of antitumor drugs. However, the high structural complexity of NPs generally results in unfavorable physicochemical profiles and poor drug-likeness. A powerful strategy to tackle this obstacle is the structural simplification of NPs by truncating nonessential structures. Herein, a series of tetrahydro-β-carboline derivatives were designed by elimination of the D ring of NP evodiamine. Structure-activity relationship studies led to the discovery of compound 45, which displayed highly potent antitumor activity against all the tested cancer cell lines and excellent in vivo antitumor activity in the HCT116 xenograft model with low toxicity. Further mechanistic research indicated that compound 45 acted by dual Top1/2 inhibition and induced caspase-dependent cell apoptosis coupled with G2/M cell cycle arrest. This proof-of-concept study validated the effectiveness of structural simplification in NP-based drug development, discovered compound 45 as a potent antitumor lead compound and enriched the structure–activity relationships of evodiamine.

Selective construction of alkaloid scaffolds by alcohol-based direct and mild aerobic oxidative Pictet-Spengler reactions

Employing TBN/TEMPO as the catalysts and oxygen as the oxidant, the biologically and pharmaceutically significant tetrahydro-β-carboline and β-carboline alkaloid scaffolds that used to be obtained by multi-step processes can now be selectively obtained in only one-stepviadirect aerobic oxidative Pictet-Spengler reactions of tryptamines with alcohols under mild conditions, with water generated as the byproduct. In this reaction, TBN/TEMPO was interestingly found to be able to facilitate the cyclization step of the whole reaction. This method tolerates a variety ofC- andN-substituted tryptamines, and both the more reactive benzylic and allylic alcohols and the less reactive aliphatic alcohols. This method can also be extended to dihydro-β-carboline synthesis and applied to the more available and more economical tryptophan for β-carboline synthesis, revealing its broad substrate scope and potential in synthetic applications.

Iodine-Catalyzed Metal-Free Oxidative Ring Opening of 1-Aryltetrahydro-β-carbolines: Facile Synthesis of C-2 Aroyl and Aryl Methanimino Indole Derivatives

Indole derivatives bearing C-2 substituents have garnered a lot of attention due to their diverse biological activities. Various methods forthe synthesis of these compounds have been reported. Inspired by the hydrolysis of imines, an oxidative ring-opening reaction of 1-aryltetrahydro-β-carbolines with catalytic iodine in aqueous hydrogen peroxide, and also in the presence of appropriate amines, is described for the generation of 2-aroyl and arylmethanimine indole derivatives. The reaction proceeds under mild reaction conditions with ethanol as the solvent or under solvent-free conditions, respectively. This metal-free strategy facilitates the formation of the desired substituted C-2 indoles in moderate to excellent yields. The utility of this reaction is demonstrated by a facile multigram-scale synthesis of Luzindole, a selective melatonin receptor antagonist and an investigational drug against depression and disruption of the circadian rhythm.

A facile and efficient synthesis of tetrahydro-β-carbolines

This Letter describes a convenient, efficient, and clean synthesis of various tetrahydro-β-carbolines catalyzed by propane phosphonic acid anhydride T3P under microwave irradiation.

Antioxidant activity of pinoline analogues in the LDL oxidation model

Recently it has been shown that pinoline (6-methoxy-1,2,3,4-tetrahydro-β-carboline) is as potent as melatonin in the inhibition of lipid peroxidation. We have synthesized some 1-aryl-1,2,3,4-tetrahydro-β-carbolines and investigated their ability to prevent LDL copper-induced peroxidation in comparison with melatonin and pinoline. In this model, we found that the introduction of a phenyl group in position 1 of the β-carboline skeleton resulted in more active compounds. The presence ofa methoxy group in position 6 of the β-carboline skeleton had a beneficial influence on this activity, whereas replacement of this methoxy by an ethyl side chain increased the antioxidant potency. On the other hand, substitution of the 1-phenyl substituent with a methoxy group did not affect the activity. Finally, compounds bearing a propyl group on position 2 of the β-carboline skeleton are the most active. Taken together these results confirm the role of lipophilicity in the ability to inhibit LDL oxidation.

Mild Oxidation of 1,2,3,4-Tetrahydro-β-carbolines

Oxidation of 1-(aryl or heteroaryl)-1,2,3,4-tetrahydro-β-carbolines (1a-r) with KMnO4 in dry THF afforded in the most cases almost exclusively 3,4-dihydro products (2) with a yield of 28-94percent.Only in few cases (1c, 1i, 1m) the reaction was non-selective and a significant amount of the fully aromatized products (3) (30-40percent of the reaction mixture) was observed.The influence of both the substituent nature and the substitution modes on the observed yield and selectivity of the reaction was discussed.Key words: 1,2,3,4-tetrahydro-β-carbolines, 3,4-dihydro-β-carbolines, selective oxidation, oxidation with KMnO4 in cold THF, substituent effect