Glucocerebrosidase (GCase) activity modulation by 2-alkyl trihydroxypiperidines: Inhibition and pharmacological chaperoning

Clemente, Francesca; Matassini, Camilla; Faggi, Cristina; Giachetti, Sara; Cresti, C.; Morrone, Amelia; Paoli, Paolo De; Goti, Andrea; Martı́nez-Bailén, Macarena; Cardona, Francesca

doi:10.1016/j.bioorg.2020.103740

Cited by 18 publications

(50 citation statements)

References 57 publications

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“…These data overall show that GCase inhibition higher than 90% is guaranteed by the presence of a long alkyl chain (8, 9, or 12 carbon atoms, compounds 9 , 10 , 12, and 21 ). This parallels previous studies, which showed that alkylated imino- and azasugars are strong GCase inhibitors due to favorable interaction of the alkyl chain with the hydrophobic domain of the enzyme [ 24 , 44 , 45 ]. However, in terms of IC 50 values, a remarkable difference was found between compounds 9 and 21 , in agreement with previous observations by Compain and coworkers on differently configured ethers derived from 1,5-dideoxy and 1-5-imino- d -xylitol (DIX) [ 46 ].…”

Section: Resultssupporting

confidence: 90%

“…Conversely compound 33 , bearing the triple bond and a longer aliphatic substituent, showed 65% inhibition, which increased considerably after hydrogenation to 12 ( Table 4 , entry 10 vs. 4). This latter compound showed a moderate IC 50 = 60 µM, which is close to that observed for trihydroxypiperidines bearing an octyl chain at C-2, previously synthesized in our group ( 37 and 39 , Table 4 , entries 12 and 14) [ 23 , 24 ].…”

Section: Resultssupporting

confidence: 83%

“…The same behavior is evident by comparing the C-2 alkylated trihydroxypiperidines 38 and 37 : The best inhibitor was the dodecyl alkylated (compound 38 ) but the best chaperone was the octyl derivative 37 [ 24 ]. The inefficacy of dodecyl alkylated compounds 10 and 38 as PCs can be ascribed to the cytotoxicity imparted by the 12-carbon atom alkyl chains.…”

Section: Resultsmentioning

confidence: 81%

“…Based on our previous experience in the synthesis of imino- and azasugars as potential PCs [ 22 , 23 , 24 ], we envisaged that a new series of “all-cis ” trihydroxypiperidines and congeners with potential activity as β-Gal inhibitors could be synthesized starting from the common key ketone intermediate 8 [ 25 ] ( Scheme 1 ). We report the synthesis of compounds 9 – 15 ( Scheme 1 ) and their assessment as inhibitors of β-Gal and other glycosidases.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of “All-Cis” Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase Inhibitors

et al. 2020

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Pharmacological chaperones (PCs) are small compounds able to rescue the activity of mutated lysosomal enzymes when used at subinhibitory concentrations. Nitrogen-containing glycomimetics such as aza- or iminosugars are known to behave as PCs for lysosomal storage disorders (LSDs). As part of our research into lysosomal sphingolipidoses inhibitors and looking in particular for new β-galactosidase inhibitors, we report the synthesis of a series of alkylated azasugars with a relative “all-cis” configuration at the hydroxy/amine-substituted stereocenters. The novel compounds were synthesized from a common carbohydrate-derived piperidinone intermediate 8, through reductive amination or alkylation of the derived alcohol. In addition, the reaction of ketone 8 with several lithium acetylides allowed the stereoselective synthesis of new azasugars alkylated at C-3. The activity of the new compounds towards lysosomal β-galactosidase was negligible, showing that the presence of an alkyl chain in this position is detrimental to inhibitory activity. Interestingly, 9, 10, and 12 behave as good inhibitors of lysosomal β-glucosidase (GCase) (IC50 = 12, 6.4, and 60 µM, respectively). When tested on cell lines bearing the Gaucher mutation, they did not impart any enzyme rescue. However, altogether, the data included in this work give interesting hints for the design of novel inhibitors.

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Section: Resultssupporting

confidence: 90%

Section: Resultssupporting

confidence: 83%

Section: Resultsmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

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Synthesis of “All-Cis” Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase Inhibitors

et al. 2020

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“…This choice is strongly supported by the World Laureates Association Shanghai Centre. Some iminosugars have also been found to act as chaperones 10 against lysosomal storage disorders, like Gaucher's 11 and Fabry's 12 diseases. Iminosugars have also been found to be effective against cystic fibrosis 13 , an autosomal recessive disease-causing severe multi-system organ damage, particularly to the respiratory system.…”

Section: Introductionmentioning

confidence: 99%

Tuning the activity of iminosugars: novel N-alkylated deoxynojirimycin derivatives as strong BuChE inhibitors

Ahuja-Casarín

Merino-Montiel

Vega-Báez

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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We have designed unprecedented cholinesterase inhibitors based on 1-deoxynojirimycin as potential anti-Alzheimer's agents. Compounds are comprised of three key structural motifs: the iminosugar, for interaction with cholinesterase catalytic anionic site (CAS); a hydrocarbon tether with variable lengths, and a fragment derived from 2-phenylethanol for promoting interactions with peripheral anionic site (PAS). Title compounds exhibited good selectivity towards BuChE, strongly depending on the substitution pattern and the length of the tether. The lead compounds were found to be strong mixed inhibitors of BuChE (IC 50 ¼ 1.8 and 1.9 mM). The presumptive binding mode of the lead compound was analysed using molecular docking simulations, revealing H-bond interactions with the catalytic subsite (His438) and CAS (Trp82 and Glu197) and van der Waals interactions with PAS (Thr284, Pro285, Asn289). They also lacked significant antiproliferative activity against tumour and non-tumour cells at 100 mM, making them promising new agents for tackling Alzheimer's disease through the cholinergic approach.

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Carbohydrate‐Based Therapeutics for Lysosomal Storage Disorders

Matassini,

Clemente,

Cardona

2023

Carbohydrate‐Based Therapeutics

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Glucocerebrosidase (GCase) activity modulation by 2-alkyl trihydroxypiperidines: Inhibition and pharmacological chaperoning

Cited by 18 publications

References 57 publications

Synthesis of “All-Cis” Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase Inhibitors

Synthesis of “All-Cis” Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase Inhibitors

Tuning the activity of iminosugars: novel N-alkylated deoxynojirimycin derivatives as strong BuChE inhibitors

Carbohydrate‐Based Therapeutics for Lysosomal Storage Disorders

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