Biological activities of 3,4,5‐trihydroxypiperidines and their <i>N</i>‐ and <i>O</i>‐derivatives

Prichard, Kate L.; Campkin, David; O'Brien, Nicholas; Kato, Atsushi; Fleet, George W. J.; Simone, Michela I.

doi:10.1111/cbdd.13182

Cited by 31 publications

(31 citation statements)

References 63 publications

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“…Previous studies have shown that the N -alkylated derivative of DGJ N -nonyl-DGJ ( 2 , Figure 1 ) is able to rescue the intracellular activity of mutant β-Gal in GM1-gangliosidosis patient fibroblasts, thus highlighting the potential of PC therapy for patients with brain pathologies [ 15 , 16 ]. In addition, several azasugars, carbohydrate analogues in which nitrogen formally replaces the anomeric carbon, have shown interesting biological activities, as recently reviewed by Simone and coworkers [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…Recent investigations have explored the potential biological activities of several similar iminosugars, including 1-Deoxynojirimycin (DNJ) from mulberry and ido-BR1 from cucumber. Prichard et al [ 21 ] reviewed several iminosugar derivatives with reported activities including glycosidase inhibition, and immunosuppressant, antibacterial, antiviral and anti-inflammatory effects. The iminosugar found in mulberry, DNJ, has garnered interest for antihyperglycemic, anti-obesity, and anti-viral biological activities [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

Safety assessment of a standardized cucumber extract (Q-Actin™): Oral repeat-dose toxicity and mutagenicity studies

Kothari¹,

Saravana²,

Muthusamy³

et al. 2018

Toxicology Reports

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Cucumus sativus (cucumber) is one of the most widely consumed fruit vegetables worldwide. Recent discovery of iminosugars in commonly consumed fruits and vegetables has promoted the interest in isolating these compounds and understanding the potential benefits to human health. The objective of the present study was to investigate the general toxicity and mutagenic effects of an aqueous extract of cucumber (Q-Actin), standardized to ≥1% (1–2%) ido-BR1 iminosugar. Single dose of Q-Actin was well tolerated without mortality at 2000 mg/kg body weight (bw) in Sprague Dawley rats. Oral (gavage) administration of Q-Actin up to 1000 mg/kg bw/day was well tolerated followed by repeated administration for a maximum period of 90 days in Sprague-Dawley rats. There were no treatment related changes in clinical observations, ophthalmic examinations, body weights and body weight gains or feed consumption, clinical chemistry and pathological changes compared to control. The mutagenicity as evaluated by Ames assay, in vitro chromosomal aberration test and in vivo micronucleus assay did not reveal any potential of Q-Actin to induce genotoxicity. The results showed that Q-Actin is well tolerated in general toxicity studies and did not induce mutagenicity. The no-observed-adverse-effect level (NOAEL) of the standardized aqueous cucumber extract (Q-Actin) is considered to be ≥1000 mg/kg bw/day, followed by repeated administration for90 days.

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“…The installation of various functionalities via N-and/or O-alkylation has been shown to impart improved biological profiles and potencies to iminosugars (Š está k et al, 2018;Prichard et al, 2018;Simone et al, 2012;Sayce et al, 2016, Woodhouse et al, 2008Johnson & Houston, 2002). Diminishing the number of synthetic steps to the iminosugar building blocks that are precursors to their alkylated congeners is advantageous.…”

Section: Chemical Contextmentioning

confidence: 99%

Crystal structure of 6-azido-6-deoxy-1,2-O-isopropylidene-α-D-glucofuranose

et al. 2020

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Short syntheses to high Fsp 3 index natural-product analogues such as iminosugars are of paramount importance in the investigation of their biological activities and reducing the use of protecting groups is an advantageous synthetic strategy. An isopropylidene group was employed towards the synthesis of seven-membered ring iminosugars and the title compound, C9H15N3O5, was crystallized as an intermediate, in which the THF ring is twisted and the dioxolane ring adopts an envelope conformation: the dihedral angle between the rings is 67.50 (13)°. In the crystal, the hydroxyl groups participate in O—H...(O,O) and O—H...N hydrogen-bonding interactions, which generate chains of molecules propagating parallel to the a-axis direction. There is a notable non-classical C—H...O hydrogen bond, which cross-links the [100] chains into (001) sheets.

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Biological activities of 3,4,5‐trihydroxypiperidines and their N‐ and O‐derivatives

Cited by 31 publications

References 63 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

Safety assessment of a standardized cucumber extract (Q-Actin™): Oral repeat-dose toxicity and mutagenicity studies

Crystal structure of 6-azido-6-deoxy-1,2-O-isopropylidene-α-D-glucofuranose

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