Improved Access to Huprine Derivatives Functionalized at Position 9

Oukoloff, Killian; Chao, Sovy; Cieslikiewicz-Bouet, Monika; Mougeot, Romain; Jean, Ludovic; Renard, Pierre

doi:10.1002/ejoc.201501433

Cited by 7 publications

(4 citation statements)

References 38 publications

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“…For the synthesis of the 9-HC hybrid 5i, featuring the N-(4hydroxy-3-methoxybenzyl)carboxamide moiety of capsaicin linked through a triazolylbutyl tether on position 9 of huprine, we first attempted a copper-catalyzed azide−alkyne cycloaddition (CuAAC) of an O-protected capsaicin-based 3butynamide to the previously reported racemic 9-azidobutylhuprine 13 60,64 capsaicin-based 3-butynamide, generated by coupling amine 6 with 3-butynoic acid, led to an inseparable 25:75 mixture of the desired 3-butynamide and its 2,3-butadienamide isomerization product. Fortunately, the amount of the isomerization byproduct was much lower (12%) when the O-TBDMS-protected amine 11 65 was used instead of 6.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice

et al. 2020

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The combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in C57BL6 mice, with one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced Aβ42/Aβ40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound 5i emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms.

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Section: ■ Results and Discussionmentioning

confidence: 99%

“…To a solution of azide 13 (50 mg, 136 μmol) and alkyne 12 (54 mg, 162 μmol) in acetonitrile (5.4 mL), CuI (26 mg, 136 μmol) was added. The reaction mixture was stirred with protection from light at rt for 12 h and concentrated at reduced pressure.…”

Section: Methodsmentioning

confidence: 99%

Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice

et al. 2020

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“…[1]. It is involved in a wide range of cellular processes, including cell development and maturation [2,3]. The induction of apoptosis is usually accompanied by an increase of AChE expression.…”

Section: Introductionmentioning

confidence: 99%

Two Fluorescent Probes for Recognition of Acetylcholinesterase: Design, Synthesis, and Comparative Evaluation

Lin,

Yi,

Qing

et al. 2024

Molecules

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In this study, two “on–off” probes (BF2-cur-Ben and BF2-cur-But) recognizing acetylcholinesterase (AChE) were designed and synthesized. The obtained probes can achieve recognition of AChE with good selectivity and pH-independence with a linear range of 0.5~7 U/mL and 0.5~25 U/mL respectively. BF2-cur-Ben has a lower limit of detection (LOD) (0.031 U/mL), higher enzyme affinity (Km = 16 ± 1.6 μM), and higher inhibitor sensitivity. A responsive mechanism of the probes for AChE was proposed based on HPLC and mass spectra (MS) experiments, as well as calculations. In molecular simulation, BF2-cur-Ben forms more hydrogen bonds (seven, while BF2-cur-But has only four) and thus has a more stable enzyme affinity, which is mirrored by the results of the comparison of Km values. These two probes could enable recognition of intracellular AChE and probe BF2-cur-Ben has superior cell membrane penetration due to its higher log p value. These probes can monitor the overexpression of AChE during apoptosis of lung cancer cells. The ability of BF2-cur-Ben to monitor AChE in vivo was confirmed by a zebrafish experiment.

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“…Hup1, Hup2 and Cy 5.0 were prepared according to the procedures reported in the literature. 12,17,18 Then, we characterised the photophysical properties of HupNIR1 and HupNIR2 in PBS buffer and the results are summarized in Table 1. In comparison with Cy 5.0, the fluorescent probes show similar photophysical properties with absorption maxima at 650 nm and emission maxima at 668 nm and 665 nm respectively.…”

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confidence: 99%

A selective and sensitive near-infrared fluorescent probe for acetylcholinesterase imaging

et al. 2016

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Two near infra-red (NIR) fluorescent probes HupNIR1 and HupNIR2 based on the huprine scaffold and cyanine 5.0 dye have been synthesised and evaluated in situ for the detection of acetylcholinesterases in different tissues. As anticipated by the initial properties of huprine, both probes displayed a high affinity and selectivity for AChE toward BChE, with IC50 values in the nanomolar range and without any non-specific binding in the tissues. HupNIR2 appears the best probe for AChE with a great selectivity and sensitivity for AChE even in the brain region displaying a low AChE concentration as striatum. Moreover, the binding of HupNIR2 is affected when AChE is inhibited with toxic molecules such as organophosphates. This work provides a new tool to visualize active AChE in biological applications.

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Improved Access to Huprine Derivatives Functionalized at Position 9

Cited by 7 publications

References 38 publications

Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice

Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice

Two Fluorescent Probes for Recognition of Acetylcholinesterase: Design, Synthesis, and Comparative Evaluation

A selective and sensitive near-infrared fluorescent probe for acetylcholinesterase imaging

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