Synthesis of 6,7‐dimethoxy‐1‐halobenzyl‐1,2,3,4‐tetrahydroisoquinolines

Cho, Su‐Dong; Kweon, Deok‐Heon; Kang, Youngjin; Lee, Sang‐Gyeong; Lee, Woo Song; Yoon, Yong‐Jin

doi:10.1002/jhet.5570360507

“…A shortlist was generated by sampling from the compound clusters and the final shortlist of 13 compounds was made using actual compound availability and using cost as a proxy for synthetic accessibility. Of the thirteen shortlisted, only compound 3 is reported in the scientific literature 30 according to a search using the Chemical Abstracts service, SciFinder. The similarity of the compound set with the 50 CSI ligands currently present as tubulin complexes 31 in the PDB was assessed using DataWarrior and the results (Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification and validation of novel microtubule suppressors with an imidazopyridine scaffold through structure-based virtual screening and docking

Elseginy

¹

,

Oliveira

²

,

Shoemark

³

et al. 2022

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“…Starting 1-methyl (isopropyl-, benzyl-, phenyl-, tolyl-, p -methoxyphenyl- and p -fluorophenyl)-1-methoxymethylethynyl-1,2,3,4-tetrahydroisoquinolines 2a–h were obtained from 3,4-dihydroisoquinolinium methyl iodide 1 derived via the Bischler–Napieralski reaction [ 18 ], followed by alkylation and subsequent methoxymethyl ethynylation in the presence of cuprous bromide in methylene chloride ( Scheme 1 , Table 1 ) [ 19 ].…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Isomeric 3-Benzazecines Decorated with Endocyclic Allene Moiety and Exocyclic Conjugated Double Bond and Evaluation of Their Anticholinesterase Activity

Титов

¹

,

Purgatorio

²

,

Obydennik

³

et al. 2022

Molecules

9

0

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Transformations of 1-methoxymethylethynyl substituted isoquinolines triggered by terminal alkynes in alcohols were studied and new 3-benzazecine-containing compounds synthesized, such as 6-methoxymethyl-3-benzazecines incorporating an endocyclic C6–C8 allene fragment and the -ylidene derivatives 6-methoxymethylene-3-benzazecines. The reaction mechanisms were investigated and a preliminary in vitro screening of their potential inhibitory activities against human acetyl- and butyrylcholinesterases (AChE and BChE) and monoamine oxidases A and B (MAO-A and MAO-B) showed that the allene compounds were more potent than the corresponding -ylidene ones as selective AChE inhibitors. Among the allenes, 3e (R3 = CH2OMe) was found to be a competitive AChE inhibitor with a low micromolar inhibition constant value (Ki = 4.9 μM), equipotent with the corresponding 6-phenyl derivative 3n (R3 = Ph, Ki = 4.5 μM), but 90-fold more water-soluble.

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“…A shortlist was generated by sampling from the compound clusters and the final shortlist of 13 compounds was made using actual compound availability and using cost as a proxy for synthetic accessibility. Of the thirteen shortlisted, only compound 3 is reported in the scientific literature 30 according to a search using the Chemical Abstracts service, SciFinder. The similarity of the compound set with the 50 CSI ligands currently present as tubulin complexes 31 in the PDB was assessed using DataWarrior and the results (Figure S3) with the Flexophore descriptor 32 show partial overlap at the 60% level.…”

Section: Resultsmentioning

confidence: 99%

Identification and Validation of Novel Microtubule Suppressors with an Imidazopyridine Scaffold through Structure-Based Virtual Screening and Docking

Elseginy

¹

,

Oliveira

²

,

Shoemark

³

et al. 2021

Preprint

0

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Targeting the colchicine binding site of alpha/beta tubulin microtubules can lead to suppression of microtubule dynamics, cell cycle arrest and apoptosis. Therefore, development of microtubule (MT) inhibitors is considered a promising route to anticancer agents. Our approach to identify novel scaffolds as MT inhibitors depends on a 3D-structure based pharmacophore approach and docking using three programmes MOE, Autodock and BUDE (Bristol University Docking Engine) to screen a library of virtual compounds. From this work we identified the compound 7-(3-Hydroxy-4-methoxy-phenyl)-3-(3-trifluoromethyl-phenyl)-6,7-dihydro-3H-imidazo[4,5-b] pyridin-5-ol (6) as a novel inhibitor scaffold. This compound inhibited several types of cancer cell proliferation at low micromolar concentrations with low toxicity. Compound 6 caused cell cycle arrest in the G2/M phase and blocked tubulin polymerization at low micromolar concentration (IC50 = 6 micromolar, inducing apoptosis via activation of caspase 9, increasing the level of the pro-apoptotic protein Bax and decreasing the level of the anti-apoptotic protein Bcl2. In summary, our approach identified a lead compound with potential antimitotic and antiproliferative activity.

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Synthesis of 6,7‐dimethoxy‐1‐halobenzyl‐1,2,3,4‐tetrahydroisoquinolines

Abstract: Some 6,7‐dimethoxy‐1‐halobenzyl‐1,2,3,4‐tetrahydroisoquinolines were synthesized from 2‐(3,4‐dimethoxyphenyl)ethylamine and halophenylacetic acids in three steps in good yield.

Cited by 13 publications

References 5 publications

Identification and validation of novel microtubule suppressors with an imidazopyridine scaffold through structure-based virtual screening and docking

Identification and validation of novel microtubule suppressors with an imidazopyridine scaffold through structure-based virtual screening and docking

Synthesis of Isomeric 3-Benzazecines Decorated with Endocyclic Allene Moiety and Exocyclic Conjugated Double Bond and Evaluation of Their Anticholinesterase Activity

Identification and Validation of Novel Microtubule Suppressors with an Imidazopyridine Scaffold through Structure-Based Virtual Screening and Docking

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