Carbohydrate scaffolds in chemical genetic studies

Nicotra, Francesco; Cipolla, Laura; Ferla, Barbara La; Airoldi, Cristina; Zona, Cristiano; Orsato, Alexandre; Shaikh, Nasrin; Russo, Laura

doi:10.1016/j.jbiotec.2009.05.014

Cited by 15 publications

(6 citation statements)

References 43 publications

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“…38,43,45,46 In fact, NMR spectroscopy has provided most of the experimental data on the solution structure of carbohydrates, complex equilibriums and interconversions of sugar units, monitoring of chemical reactions involving carbohydrates, characterization of carbohydrate binding to other bioactive molecules and other processes of biological relevance. 38,43,[45][46][47][48] The method has been recognized as a valuable tool for the quality control and characterization of carbohydrate-containing drugs. 49 NMR-based approaches have been incorporated into the World Health Organization recommendations on the production and quality control of glycoconjugate vaccines.…”

Section: Introductionmentioning

confidence: 99%

Recent advances in computational predictions of NMR parameters for the structure elucidation of carbohydrates: methods and limitations

2013

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All living systems are comprised of four fundamental classes of macromolecules--nucleic acids, proteins, lipids, and carbohydrates (glycans). Glycans play a unique role of joining three principal hierarchical levels of the living world: (1) the molecular level (pathogenic agents and vaccine recognition by the immune system, metabolic pathways involving saccharides that provide cells with energy, and energy accumulation via photosynthesis); (2) the nanoscale level (cell membrane mechanics, structural support of biomolecules, and the glycosylation of macromolecules); (3) the microscale and macroscale levels (polymeric materials, such as cellulose, starch, glycogen, and biomass). NMR spectroscopy is the most powerful research approach for getting insight into the solution structure and function of carbohydrates at all hierarchical levels, from monosaccharides to oligo- and polysaccharides. Recent progress in computational procedures has opened up novel opportunities to reveal the structural information available in the NMR spectra of saccharides and to advance our understanding of the corresponding biochemical processes. The ability to predict the molecular geometry and NMR parameters is crucial for the elucidation of carbohydrate structures. In the present paper, we review the major NMR spectrum simulation techniques with regard to chemical shifts, coupling constants, relaxation rates and nuclear Overhauser effect prediction applied to the three levels of glycomics. Outstanding development in the related fields of genomics and proteomics has clearly shown that it is the advancement of research tools (automated spectrum analysis, structure elucidation, synthesis, sequencing and amplification) that drives the large challenges in modern science. Combining NMR spectroscopy and the computational analysis of structural information encoded in the NMR spectra reveals a way to the automated elucidation of the structure of carbohydrates.

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Section: Introductionmentioning

confidence: 99%

Recent advances in computational predictions of NMR parameters for the structure elucidation of carbohydrates: methods and limitations

2013

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“…This research stemmed from the idea that carbohydrate decoration of compounds having a firmly established pharmacological activity not only can modify pharmacokinetic or the pharmacodynamic properties but also can lead to products with new and unique biological functions [33][34][35][36][37][38][39] . The use of carbohydrates as scaffolds or a template for drug discovery has attracted considerable attention in recent years 40,41 . The modern emphasis on chiral synthesis of single-isomer drugs has further enhanced carbohydrate's utility 42 .…”

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confidence: 99%

Design and efficient synthesis of pyrazoline and isoxazole bridged indole C-glycoside hybrids as potential anticancer agents

Kumari

Mishra

Narayana

et al. 2020

Sci Rep

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C-glycosides are important class of molecules exhibit diverse biological activities and present as structural motif in many natural products. Two series of new pyrazoline and isoxazole bridged indole C-glycoside molecular hybrids (n = 36) were efficiently synthesized starting from diverse indole 3-carboxaldehydes derived α, β-unsaturated ketone derivatives of β-D-glucosyl-propan-2-one, β-D-galactosyl-propan-2-one and β-D-mannosyl-propan-2-one, reacting with hydrazine hydrate and hydroxyl amine hydrochloride in shorter reaction time (15 min) under microwave assisted condition. Anticancer activity of these newly synthesized pyrazoline and isoxazole bridged indoles C-glycoside hybrids were determined in details through cellular assays against MCF-7, MDA-MB-453 and MDA-MB-231 cancer cell lines. The selected library members displayed low micromolar (IC 50 = 0.67-4.67 µM) and selective toxicity against breast cancer cell line (MCF-7). Whereas these compounds were nontoxic towards normal cell line (MCF-10A). Mechanistic studies showed that, active compounds inhibit COX-2 enzyme, which was also supported by molecular docking studies. These findings are expected to provide new leads towards anticancer drug discovery.C-Glycosides are stable surrogates of O-glycosides and are often used as investigative tool in chemical biology and medicinal chemistry, in particular C-glycoside analogues are often used as substrate mimics for different enzymes involved in the carbohydrate metabolism 1-10 . The use of glycomimetic in the design of inhibitors has proven to be a successful approach and now constitutes one of the most attractive ways to develop new generations of effective and selective inhibitors 11 . α, β-unsaturated ketone is a central core for many significant biological compounds 12,13 . According to literature α, β-unsaturated ketone derivatives from natural and synthetic analogues exhibit diverse pharmacological activities such as anti-tuberculosis, anti-inflammatory, anticancer, antineoplastic, antibacterial, antifungal, antimalarial, antiviral, antiallergic, estrogenic 12 and COX-2 inhibitor 13 .Pyrazoline derivatives are important biologically active heterocyclic compounds. These derivatives are the subject of many research studies due to their widespread potential biological activities such as anticancer, antioxidant, antibacterial activities 14 and COX-2 inhibitor 15 . The most prominent compounds containing pyrazoline nucleus are ampyrone, phenazone and propyphenzone. Isoxazole heterocycle is well known for its medicinal relevance 16,17 . There are isoxazole nucleus containing drug molecules currently available in market, such as acetylsulfisoxazole, cycloserine, sulfisoxazole, and zonisamide etc. These drugs possess antimicrobial 18 , antioxidant 19,20 tuberculostatic 21 neurotoxic 22 , antiepileptic activities 23,24 and COX-2 inhibitor 25 . The comparable activities are also observed in other isoxazole derivatives, captivates researcher to search for newer bioactive compounds of using this as pharmacophore. α, β-...

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“…However, it would be difficult to knock out all 33 A. thaliana XTHs simultaneously, and a totally XET-deficient plant might well be embryo-lethal and thus useless for investigating the range of XET’s roles in planta . In principle, an alternative strategy that circumvents this obstacle is ‘chemical genetics’: treating plant cells with specific, non-phytotoxic, enzyme inhibitors ( Nagahashi et al, 1990; Gruner et al, 2002; Hicks and Raikhel, 2012; Nicotra et al, 2009; Winchester and Fleet, 1992 ). Xenobiotics that target the active site common to all XTHs could potentially be applied at any desired stage of development, and the consequences of a sudden block in XET action observed.…”

Section: Introductionmentioning

confidence: 99%

Discovery of small molecule inhibitors of xyloglucan endotransglucosylase (XET) activity by high-throughput screening

et al. 2015

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Graphical abstractXenobiotics that inhibit the cell-wall-remodelling enzyme activity, xyloglucan endotransglucosylase (XET), would be a valuable tool in ‘chemical genetics’ for elucidating its biological roles. By screening 4216 small molecules in a dot-blot assay on paper-immobilised xyloglucan, we discovered 45 compounds that inhibited or promoted XET activity. The most effective inhibitors were singlet oxygen generators.

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Carbohydrate scaffolds in chemical genetic studies

Cited by 15 publications

References 43 publications

Recent advances in computational predictions of NMR parameters for the structure elucidation of carbohydrates: methods and limitations

Recent advances in computational predictions of NMR parameters for the structure elucidation of carbohydrates: methods and limitations

Design and efficient synthesis of pyrazoline and isoxazole bridged indole C-glycoside hybrids as potential anticancer agents

Discovery of small molecule inhibitors of xyloglucan endotransglucosylase (XET) activity by high-throughput screening

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