N-Substituted Valiolamine Derivatives as Potent Inhibitors of Endoplasmic Reticulum α-Glucosidases I and II with Antiviral Activity

Karade, S.S.; Hill, Michelle L.; Kiappes, J. L.; Manne, R; Aakula, B; Zitzmann, Nicole; Warfield, Kelly L.; Treston, Anthony M.; Mariuzza, Roy A.

doi:10.1021/acs.jmedchem.1c01377

Cited by 52 publications

(50 citation statements)

References 41 publications

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“…The following crystal structures of the target enzymes were retrieved from the protein data bank ( (accessed on 1 June 2022)): AChE (PDB ID: 6O52) [ 23 ], BChE (PDB ID: 6EQP) [ 24 ], amylase (6TP0) [ 25 ], tyrosinase (6JU7) [ 26 ], glucosidase (7KBJ) [ 27 ], and two cancer targets: MMP-9 (4WZV) [ 28 ] and BCL-2 (6QGH) [ 29 ]. Missing hydrogen atoms were added at a physiological pH of 7.4, correct bond orders were assigned, and missing atoms were added using Biovia Discovery Studio (DS) (Accelrys Software Inc., San Diego, CA, USA, 2012).…”

Section: Methodsmentioning

confidence: 99%

An In-Depth Study on the Metabolite Profile and Biological Properties of Primula auriculata Extracts: A Fascinating Sparkle on the Way from Nature to Functional Applications

et al. 2022

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The biological activity of the aerial part and rhizomes of Primula auriculata were assessed for the first time. The biological activities (antioxidant properties, enzyme inhibition, and AGE inhibition) as well as the phenolic and flavonoid contents of the ethyl acetate, ethanol, hydro-ethanol and water extracts of P. auriculata aerial parts and rhizomes were determined. Cell viability assays and gelatin zymography were also performed for MMP-2/-9 to determine the molecular mechanisms of action. The gene expression for MMPs was described with RT-PCR. The levels of various proteins, including phospho-Nf-κB, BCL-2, BAX, p-53, and cyclin D1 as well as RAGE were measured using Western blot analysis. The hydro-ethanol extract of the aerial part possessed the highest phenolic (56.81 mg GAE/g) and flavonoid (63.92 mg RE/g) contents. In-depth profiling of the specialized metabolites by ultra-high-performance liquid chromatography—high-resolution mass spectrometry (UHPLC-HRMS) allowed for the identification and annotation of 65 compounds, including phenolic acids and glycosides, flavones, flavonols, chalcones, dihydrochalcones, and saponins. The hydro-ethanol extract of the aerial parts (132.65, 180.87, 172.46, and 108.37 mg TE/g, for the DPPH, ABTS, CUPRAC, and FRAP assays, respectively) and the ethanol extract of the rhizomes (415.06, 638.30, 477.77, and 301.02 mg TE/g, for the DPPH, ABTS, CUPRAC, and FRAP assays, respectively) exhibited the highest free radical scavenging and reducing activities. The ethanol and hydro-ethanol extracts of both the P. auriculata aerial part and rhizomes exhibited higher inhibitory activity against acetylcholinesterase, while the hydro-ethanol extracts (1.16 mmol ACAE/g, for both the aerial part and rhizomes extracts) were more active in the inhibition of α-glucosidase. After the treatment of an HT-29 colorectal cancer cell line with the extracts, the apoptosis mechanism was initiated, the integrity of the ECM was remodeled, and cell proliferation was also taken under control. In this way, Primula extracts were shown to be potential drug sources in the treatment of colorectal cancer. They were also detected as natural MMP inhibitors. The findings presented in the present study appraise the bioactivity of P. auriculata, an understudied species. Additional assessment is required to evaluate the cytotoxicity of P. auriculata as well as its activity in ex vivo systems.

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Section: Methodsmentioning

confidence: 99%

An In-Depth Study on the Metabolite Profile and Biological Properties of Primula auriculata Extracts: A Fascinating Sparkle on the Way from Nature to Functional Applications

et al. 2022

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“…The following crystal structures of the target enzymes were retrieved from the protein data bank ( (accessed on 1 June 2022)): AChE (PDB ID: 6O52) [ 57 ], BChE (PDB ID: 6EQP) [ 58 ], tyrosinase (PDB ID: 6QXD) [ 59 ], amylase (PDB ID: 2QMK) [ 60 ], and glucosidase (PDB ID: 7KBJ) [ 61 ]. In the absence of crystal structures of human tyrosinase and glucosidase, human sequences (UniProt IDs P14679 and P0DUB6, respectively) were used to build their homology models using these PDB structures as templates.…”

Section: Methodsmentioning

confidence: 99%

Phenolic Profile, Antioxidant and Enzyme Inhibitory Activities of Leaves from Two Cassia and Two Senna Species

et al. 2022

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Several species within the genera Cassia or Senna have a treasure of traditional medicines worldwide and can be a promising source of bioactive molecules. The objective of the present study was to evaluate the phenolic content and antioxidant and enzyme inhibition activities of leaf methanolic extracts of C. fistula L., C. grandis L., S. alexandrina Mill., and S. italica Mill. The two Cassia spp. contained higher total polyphenolic content (42.23–49.75 mg GAE/g) than the two Senna spp., and C. fistula had significantly (p ˂ 0.05) the highest concentration. On the other hand, the Senna spp. showed higher total flavonoid content (41.47–59.24 mg rutin equivalent per g of extract) than that found in the two Cassia spp., and S. alexandrina significantly (p ˂ 0.05) accumulated the highest amount. HPLC–MS/MS analysis of 38 selected bioactive compounds showed that the majority of compounds were identified in the four species, but with sharp variations in their concentrations. C. fistula was dominated by epicatechin (8928.75 µg/g), C. grandis by kaempferol-3-glucoside (47,360.04 µg/g), while rutin was the major compound in S. italica (17,285.02 µg/g) and S. alexandrina (6381.85). The methanolic extracts of the two Cassia species exerted significantly (p ˂ 0.05) higher antiradical activity, metal reducing capacity, and total antioxidant activity than that recorded from the two Senna species’ methanolic extracts, and C. fistula displayed significantly (p ˂ 0.05) the highest values. C. grandis significantly (p ˂ 0.05) exhibited the highest metal chelating power. The results of the enzyme inhibition activity showed that the four species possessed anti-AChE activity, and the highest value, but not significantly (p ≥ 0.05) different from those obtained by the two Cassia spp., was exerted by S. alexandrina. The Cassia spp. exhibited significantly (p ˂ 0.05) higher anti-BChE and anti-Tyr properties than the Senna spp., and C. grandise revealed significantly (p ˂ 0.05) the highest values. C. grandise revealed significantly (p ˂ 0.05) the highest α- amylase inhibition, while the four species had more or less the same effect against the α-glucosidase enzyme. Multivariate analysis and in silico studies showed that many of the identified phenols may play key roles as antioxidant and enzyme inhibitory properties. Thus, these Cassia and Senna species could be a promising source of natural bioactive agents with beneficial effects for human health.

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“…The following crystal structures of the target enzymes were retrieved from the protein data bank ( , accessed on 1 June 2022): AChE (PDB ID: 6O52) [ 43 ], BChE (PDB ID: 6EQP) [ 44 ], tyrosinase (PDB ID: 6QXD) [ 45 ] amylase (PDB ID: 6TP0) [ 46 ], and glucosidase (PDB ID: 7KBJ) [ 47 ]. They were prepared at physiological pH of 7.4 using Biovia Discovery Studio (DS) (Dassault Systèmes Biovia Software Inc., San Diego, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Which Extraction Solvents and Methods Are More Effective in Terms of Chemical Composition and Biological Activity of Alcea fasciculiflora from Turkey?

et al. 2022

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The bioactive content, antioxidant properties, and enzyme inhibition properties of extracts of Alcea fasciculiflora from Turkey prepared with different solvents (water, methanol, ethyl acetate) and extraction methods (maceration, soxhlet, homogenizer assisted extraction, and ultrasound assisted extraction) were examined in this study. UHPLC-HRMS analysis detected or annotated a total of 50 compounds in A. fasciculiflora extracts, including 18 hydroxybenzoic and hydroxycinnamic acids, 7 Hexaric acids, 7 Coumarins, 15 Flavonoids, and 3 hydroxycinnamic acid amides. The extracts had phenolic and flavonoid levels ranging from 14.25 to 24.87 mg GAE/g and 1.68 to 25.26 mg RE/g, respectively, in the analysis. Both DPPH and ABTS tests revealed radical scavenging capabilities (between 2.63 and 35.33 mg TE/g and between 13.46 and 76.27 mg TE/g, respectively). The extracts had reducing properties (CUPRAC: 40.38–78 TE/g and FRAP: 17.51–42.58 TE/g). The extracts showed metal chelating activity (18.28–46.71 mg EDTAE/g) as well as total antioxidant capacity (phosphomolybdenum test) (0.90–2.12 mmol TE/g). DPPH, ABTS, FRAP, and metal chelating tests indicated the water extracts to be the best antioxidants, while the ethyl acetate extracts had the highest overall antioxidant capacity regardless of the extraction technique. Furthermore, anti-acetylcholinesterase activity was identified in all extracts (0.17–2.80 mg GALAE/g). The water extracts and the ultrasound-assisted ethyl acetate extract were inert against butyrylcholinesterase, but the other extracts showed anti-butyrylcholinesterase activity (1.17–5.80 mg GALAE/g). Tyrosine inhibitory action was identified in all extracts (1.79–58.93 mg KAE/g), with the most effective methanolic extracts. Only the ethyl acetate and methanolic extracts produced by maceration and homogenizer aided extraction showed glucosidase inhibition (0.11–1.11 mmol ACAE/g). These findings showed the overall bioactivity of the different extracts of A. fasciculiflora and provided an overview of the combination of solvent type and extraction method that could yield bioactive profile and pharmacological properties of interest and hence, could be a useful reference for future studies on this species.

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N-Substituted Valiolamine Derivatives as Potent Inhibitors of Endoplasmic Reticulum α-Glucosidases I and II with Antiviral Activity

Cited by 52 publications

References 41 publications

An In-Depth Study on the Metabolite Profile and Biological Properties of Primula auriculata Extracts: A Fascinating Sparkle on the Way from Nature to Functional Applications

An In-Depth Study on the Metabolite Profile and Biological Properties of Primula auriculata Extracts: A Fascinating Sparkle on the Way from Nature to Functional Applications

Phenolic Profile, Antioxidant and Enzyme Inhibitory Activities of Leaves from Two Cassia and Two Senna Species

Which Extraction Solvents and Methods Are More Effective in Terms of Chemical Composition and Biological Activity of Alcea fasciculiflora from Turkey?

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