An Efficient Approach to Aromatic Aminomethylation Using Dichloromethane as Methylene Source

Ostacolo, Carmine; Sarno, Veronica Di; Musella, Simona; Ciaglia, Tania; Vestuto, Vincenzo; Pepe, Giacomo; Merciai, Fabrizio; Campiglia, Pietro; Monterrey, Isabel M. Gomez; Bertamino, Alessia

doi:10.3389/fchem.2019.00568

Cited by 6 publications

(3 citation statements)

References 56 publications

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“…Derivatives CPK7 and CPK8 were obtained following the procedures described in Scheme . The final compound CPK7 was obtained by a single-step procedure involving indole and 4-phenylbenzyl iodide that were subjected to an ultrasound-catalyzed reaction with NaH and dichloromethane, used as methylene source . For the synthesis of CPK8 , Fmoc-Arg(Pbf)–OH was reacted by Weinreib procedure to obtain the N , O -dimethylhydroxylamide 8a , that was reduced by the use of lithium aluminum hydride and then further reacted with l -Cys-OEt in basic medium to give the thiazolidine 8b .…”

Section: Results and Discussionmentioning

confidence: 99%

“…The final compound CPK7 was obtained by a single-step procedure involving indole and 4-phenylbenzyl iodide that were subjected to an ultrasound-catalyzed reaction with NaH and dichloromethane, used as methylene source. 58 For the synthesis of CPK8 , Fmoc-Arg(Pbf)–OH was reacted by Weinreib procedure to obtain the N , O -dimethylhydroxylamide 8a , that was reduced by the use of lithium aluminum hydride and then further reacted with l -Cys-OEt in basic medium to give the thiazolidine 8b . Reaction of 8b with benzylamine and triphosgene provided hydantoin derivative 8c , which, upon the deprotection step using TFA/TIS, gave final compound CPK8 in 74% yield.…”

Section: Results and Discussionmentioning

confidence: 99%

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In Silico Assisted Identification, Synthesis, and In Vitro Pharmacological Characterization of Potent and Selective Blockers of the Epilepsy-Associated KCNT1 Channel

Iraci,

Carotenuto,

Ciaglia

et al. 2024

J. Med. Chem.

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Gain-of-function (GoF) variants in KCNT1 channels cause severe, drug-resistant forms of epilepsy. Quinidine is a known KCNT1 blocker, but its clinical use is limited due to severe drawbacks. To identify novel KCNT1 blockers, a homology model of human KCNT1 was built and used to screen an in-house library of compounds. Among the 20 molecules selected, five (CPK4, 13, 16, 18, and 20) showed strong KCNT1-blocking ability in an in vitro fluorescence-based assay. Patch-clamp experiments confirmed a higher KCNT1-blocking potency of these compounds when compared to quinidine, and their selectivity for KCNT1 over hERG and Kv7.2 channels. Among identified molecules, CPK20 displayed the highest metabolic stability; this compound also blocked KCNT2 currents, although with a lower potency, and counteracted GoF effects prompted by 2 recurrent epilepsy-causing KCNT1 variants (G288S and A934T). The present results provide solid rational basis for future design of novel compounds to counteract KCNT1-related neurological disorders.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Results and Discussionmentioning

confidence: 99%

In Silico Assisted Identification, Synthesis, and In Vitro Pharmacological Characterization of Potent and Selective Blockers of the Epilepsy-Associated KCNT1 Channel

Iraci,

Carotenuto,

Ciaglia

et al. 2024

J. Med. Chem.

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“…S3 , Tables S9 , S10 ). In line with rare reports of unexpected reactions with amines 33 , it is therefore not recommended to store pirenzepine dissolved in DCM.…”

Section: Resultsmentioning

confidence: 99%

Unexpected scaffold rearrangement product of pirenzepine found in commercial samples

Ozenil

Skos

Roller

et al. 2021

Sci Rep

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Pharmacovigilance aims at a better understanding of the molecular events triggered by medications to prevent adverse effects, which despite significant advances in our analytical repertoire plague the use of drugs until today. In this study, we find that clinically prescribed and commercially available pirenzepine may not be the correct compound. Pirenzepine can undergo an unexpected scaffold rearrangement from the pharmaceutical active ingredient (API) to a previously uncharacterized benzimidazole. The rearrangement occurs under highly acidic conditions, which were believed to favour the dihydrochloride formation of pirenzepine. The rearranged products of pirenzepine and the structurally related telenzepine have significantly decreased affinity for the muscarinic acetylcholine receptor, the pharmacological target of these compounds. Fortunately, in situ rearrangement after oral application is no safety issue, as we show that reaction kinetics in gastric acid prevent rearrangement. The research community should consider appropriate measures to perform reliable receiving inspections in the commercial supply of well described and frequently used chemicals, in particular if experiments yield unexpected results.

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Organic Transformations with DCM , CCl ₄ , CHCl ₃ , and CHBr ₃ and Other Related Reactions

Liu

Wan

2022

The Chemical Transformations of C1 Compounds

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An Efficient Approach to Aromatic Aminomethylation Using Dichloromethane as Methylene Source

Cited by 6 publications

References 56 publications

In Silico Assisted Identification, Synthesis, and In Vitro Pharmacological Characterization of Potent and Selective Blockers of the Epilepsy-Associated KCNT1 Channel

In Silico Assisted Identification, Synthesis, and In Vitro Pharmacological Characterization of Potent and Selective Blockers of the Epilepsy-Associated KCNT1 Channel

Unexpected scaffold rearrangement product of pirenzepine found in commercial samples

Organic Transformations with DCM , CCl ₄ , CHCl ₃ , and CHBr ₃ and Other Related Reactions

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An Efficient Approach to Aromatic Aminomethylation Using Dichloromethane as Methylene Source

Cited by 6 publications

References 56 publications

In Silico Assisted Identification, Synthesis, and In Vitro Pharmacological Characterization of Potent and Selective Blockers of the Epilepsy-Associated KCNT1 Channel

In Silico Assisted Identification, Synthesis, and In Vitro Pharmacological Characterization of Potent and Selective Blockers of the Epilepsy-Associated KCNT1 Channel

Unexpected scaffold rearrangement product of pirenzepine found in commercial samples

Organic Transformations with DCM , CCl 4 , CHCl 3 , and CHBr 3 and Other Related Reactions

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Organic Transformations with DCM , CCl ₄ , CHCl ₃ , and CHBr ₃ and Other Related Reactions