Cu(I)-Catalyzed Click Chemistry in Glycoscience and Their Diverse Applications

Chemical Reviews, Год журнала: 2021, Номер 121(13), С. 7638 - 7956

Опубликована: Июнь 24, 2021

Copper(I)-catalyzed 1,3-dipolar cycloaddition between organic azides and terminal alkynes, commonly known as CuAAC or click chemistry, has been identified one of the most successful, versatile, reliable, modular strategies for rapid regioselective construction 1,4-disubstituted 1,2,3-triazoles diversely functionalized molecules. Carbohydrates, an integral part living cells, have several fascinating features, including their structural diversity, biocompatibility, bioavailability, hydrophilicity, superior ADME properties with minimal toxicity, which support increased demand to explore them versatile scaffolds easy access diverse glycohybrids well-defined glycoconjugates complete chemical, biochemical, pharmacological investigations. This review highlights successful development chemistry in emerging areas glycoscience, synthesis triazole appended carbohydrate-containing molecular architectures (mainly glycohybrids, glycoconjugates, glycopolymers, glycopeptides, glycoproteins, glycolipids, glycoclusters, glycodendrimers through forming bio-orthogonal coupling protocols). It discusses widespread applications these glycoproducts enzyme inhibitors drug discovery development, sensing, gelation, chelation, glycosylation, catalysis. also covers impact provides future perspectives on its role various disciplines science technology.

Язык: Английский

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Recent insights about pyrrolidine core skeletons in pharmacology

Frontiers in Pharmacology, Год журнала: 2023, Номер 14

Опубликована: Сен. 6, 2023

To overcome numerous health disorders, heterocyclic structures of synthetic or natural origin are utilized, and notably, the emergence various side effects existing drugs used for treatment resistance disease-causing microorganisms renders ineffective. Therefore, discovery potential therapeutic agents that utilize different modes action is utmost significance to circumvent these constraints. Pyrrolidines, pyrrolidine-alkaloids, pyrrolidine-based hybrid molecules present in many products pharmacologically important agents. Their key roles pharmacotherapy make them a versatile scaffold designing developing novel biologically active compounds drug candidates. This review aims provide an overview recent advancements (especially during 2015-2023) exploration pyrrolidine derivatives, emphasizing their as fundamental components skeletal structure. In contrast previous reviews have predominantly focused on singular biological activity associated with molecules, this consolidates findings from investigations encompassing wide range activities (antimicrobial, antiviral, anticancer, anti-inflammatory, anticonvulsant, cholinesterase inhibition, carbonic anhydrase inhibition) exhibited by derivatives. study also anticipated serve valuable resource research development endeavors, offering significant insights guidance.

Язык: Английский

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GCase Enhancers: A Potential Therapeutic Option for Gaucher Disease and Other Neurological Disorders

Pharmaceuticals, Год журнала: 2022, Номер 15(7), С. 823 - 823

Опубликована: Июль 2, 2022

Pharmaceutical chaperones (PCs) are small compounds able to bind and stabilize misfolded proteins, allowing them recover their native folding thus biological activity. In particular, lysosomal storage disorders (LSDs), a class of metabolic due genetic mutations that result in enzymes, can strongly benefit from the use PCs facilitate translocation lysosomes. This results recovery catalytic No PC for GCase enzyme (lysosomal acid-β-glucosidase, or glucocerebrosidase) has reached market yet, despite importance this not only Gaucher disease, most common LSD, but also neurological disorders, such as Parkinson’s disease. review aims describe efforts made by scientific community last 7 years (since 2015) order identify new enzyme, which have been mainly identified among glycomimetic-based compounds.

Язык: Английский

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Multivalent pyrrolidines acting as pharmacological chaperones against Gaucher disease

Bioorganic Chemistry, Год журнала: 2024, Номер 146, С. 107295 - 107295

Опубликована: Март 16, 2024

Язык: Английский

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Discovery of human hexosaminidase inhibitors by in situ screening of a library of mono- and divalent pyrrolidine iminosugars

Bioorganic Chemistry, Год журнала: 2022, Номер 120, С. 105650 - 105650

Опубликована: Фев. 2, 2022

Two libraries of mono- and dimeric pyrrolidine iminosugars were synthesized by CuAAC (thio)urea-bond-forming reactions from the respective azido/aminohexylpyrrolidine iminosugar precursors. The resulting monomeric compounds screened for inhibition β-N-acetylglucosaminidase Jack beans, plant ortholog human lysosomal hexosaminidases. A selection best inhibitors these was then evaluated against β-N-acetylhexosaminidase B (hHexB) nucleocytoplasmic (hOGA). This evaluation identified a potent (nM) selective inhibitor hOGA (compound 7A) that showed 6770-fold higher affinity this enzyme than hHexB. corresponding derivative 9D) further remarkably improved selectivity in (2.7 × 104 times more over hHexB) potency (by one order magnitude). Docking studies performed to explain observed compound 7A.

Язык: Английский

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Exploring Multivalent Architectures for Binding and Stabilization of N-Acetylgalactosamine 6-Sulfatase

Molecules, Год журнала: 2025, Номер 30(10), С. 2222 - 2222

Опубликована: Май 20, 2025

Morquio A syndrome is a lysosomal disorder caused by the deficiency of enzyme N-acetylgalactosamine 6-sulfatase (GALNS, EC 3.1.6.4). Currently, replacement therapy (ERT) used to treat through infusion recombinant VIMIZIM® (elosulfase alfa, BioMarin). Unfortunately, exhibits low conformational stability in vivo. promising approach address this issue coadministration human GALNS (rhGALNS) with pharmacological chaperone (PC), molecule that selectively binds misfolded protein, stabilizes its conformation, and assists restoration impaired function. We report work synthesis library multivalent glycomimetics exploiting copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between several dendrimeric scaffolds armed terminal alkynes azido ending iminosugars different structures (pyrrolidines, piperidines, pyrrolizidines) or simple carbohydrates as bioactive units. The biological evaluation identified pyrrolidine-based nonavalent dendrimers 1 36 most compounds, able both bind native IC50 micromolar range act stabilizers toward rhGALNS thermal denaturation study, thus identifying compounds for combined PC/ERT therapy.

Язык: Английский

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3,4,5‐Trihydroxypiperidine Based Multivalent Glucocerebrosidase (GCase) Enhancers

ChemBioChem, Год журнала: 2022, Номер 23(11)

Опубликована: Март 24, 2022

The synthesis of five new multivalent derivatives a trihydroxypiperidine iminosugar was accomplished through copper catalyzed alkyne-azide cycloaddition (CuAAC) reaction an azido ending piperidine and several propargylated scaffolds. resulting architectures were assayed as inhibitors lysosomal GCase, the defective enzyme in Gaucher disease. compounds resulted much more potent than parent monovalent reference compound, thus showing good effect. Biological investigation these pharmacological chaperones revealed that trivalent derivative (12) gives 2-fold recovery GCase activity on patient fibroblasts bearing L444P/L444P mutations responsible for neuropathies. Additionally, thermal denaturation experiment showed its ability to impart stability recombinant used therapy.

Язык: Английский

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

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2020, Номер 36(1), С. 138 - 146

Опубликована: Ноя. 23, 2020

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 catalytic anionic site (CAS); a hydrocarbon tether variable lengths, and fragment derived from 2-phenylethanol promoting interactions peripheral (PAS). Title compounds exhibited good selectivity towards BuChE, strongly depending substitution pattern length tether. The lead were found to be strong mixed BuChE (IC50 = 1.8 1.9 µM). presumptive binding mode compound was analysed using molecular docking simulations, revealing H-bond subsite (His438) CAS (Trp82 Glu197) van der Waals PAS (Thr284, Pro285, Asn289). They also lacked significant antiproliferative activity against tumour non-tumour cells at 100 µM, making them promising new agents tackling Alzheimer's disease through cholinergic approach.

Язык: Английский

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Phosphorus Dendrimers for Metal‐Free Ligation: Design of Multivalent Pharmacological Chaperones against Gaucher Disease

Chemistry - A European Journal, Год журнала: 2023, Номер 29(53)

Опубликована: Июнь 14, 2023

The first phosphorus dendrimers built on a cyclotriphosphazene core and decorated with six or twelve monofluorocyclooctyne units were prepared. A simple stirring allowed the grafting of N-hexyl deoxynojirimycin inhitopes onto their surface by copper-free strain promoted alkyne-azide cycloaddition click reaction. synthesized iminosugars clusters tested as multivalent inhibitors biologically relevant enzymes β-glucocerebrosidase acid α-glucosidase, involved in Gaucher Pompe lysosomal storage diseases, respectively. For both enzymes, all compounds more potent than reference deoxynojirimycin. Remarkably, final dodecavalent compound proved to be one best described date. These cyclotriphosphazene-based then evaluated pharmacological chaperones against disease. Not only did these constructs cross cell membranes but they also able increase activity cells. Notably, 1.4-fold enzyme enhancement at concentration low 100 nM. new monofluorocyclooctyne-presenting may further find numerous applications synthesis objects for biological purposes.

Язык: Английский

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Design and synthesis of novel benzimidazole-iminosugars linked a substituted phenyl group and their inhibitory activities against β-glucosidase

Bioorganic Chemistry, Год журнала: 2022, Номер 127, С. 106016 - 106016

Опубликована: Июль 9, 2022

Язык: Английский

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