Skip to main content
NCBI home page
ACS Omega logoLink to ACS Omega
. 2026 Oct 1;11(40):62107–62114. doi: 10.1021/acsomega.6c08401

A pH-Dependent Curcumin–Iminosugar Hybrid Promotes GCase Enhancement and Reactive Oxygen Species Reduction

Alessio Morano †, Camilla Matassini †, Francesca Cardona †,*, Damiano Tanini †, Silvia Falliano ‡, Amelia Morrone ‡,§, Rebecca Sodano ∥, Paolo Paoli ∥, Andrea Goti †, Francesca Clemente †,*
PMCID: PMC13670301  PMID: 42889562

Abstract

Gaucher disease and Parkinson’s disease are characterized by β-glucocerebrosidase (GCase) dysfunction and increased oxidative stress. Here, we report two multifunctional hybrids that combine an iminosugar-based pharmacological chaperone scaffold with curcumin- or ferulic acid-derived antioxidant motifs. The curcumin-iminosugar hybrid 2 exhibits pH-dependent GCase modulation, enhanced GCase activity under lysosomal conditions, enhanced enzyme activity in L444P Gaucher and wild-type fibroblasts, and reduced intracellular reactive oxygen species (ROS) levels. By integrating GCase enhancement and redox modulation within a single molecular framework, compound 2 represents a promising lead for Gaucher disease and GCase-related synucleinopathies.

graphic file with name ao6c08401_0006.webp

graphic file with name ao6c08401_0004.webp

Introduction

Curcumin (1), a natural polyphenol isolated from the rhizome of Curcuma longa, has attracted significant attention owing to its antioxidant and redox-modulating properties. Structurally, it consists of two guaiacol (o-methoxyphenol) moieties linked through a vinylogous β-diketone framework, a feature that enables the efficient neutralization of reactive oxygen and nitrogen species (ROS/RNS) and the modulation of endogenous antioxidant defenses. Recent studies have further highlighted its ability to activate cytoprotective signaling pathways in addition to direct radical scavenging activity, − supporting its therapeutic potential in disorders driven by oxidative stress, including neurodegenerative diseases, metabolic syndromes and cancer. −

In our field of interest, particularly in the context of Gaucher disease, increasing attention has been directed toward multitarget strategies, which are considered especially interesting due to their potential to concurrently address distinct pathogenic pathways. , Gaucher disease (GD) results from mutations in the GBA1 gene, which encodes β-glucocerebrosidase (GCase). These mutations lead to deficient enzyme activity, causing glucosylceramide accumulation, lysosomal dysfunction and elevated oxidative stress. Increased levels of inflammation and oxidative stress markers have been consistently reported in both experimental animal models and patients with GD. − Among small-molecule approaches aimed at restoring GCase activity, the development of pharmacological chaperones (PCs) has emerged as a particularly promising strategy. PCs bind selectively to misfolded defective GCase in the endoplasmic reticulum (ER), correcting its conformation and promoting correct trafficking to the lysosome. A typical class of PCs is represented by iminosugars, carbohydrate mimetics in which the endocyclic oxygen is replaced by a nitrogen atom. , This approach becomes even more relevant when considering the strong mechanistic link between GD and Parkinson disease (PD), since mutations in the GBA1 gene are among the major genetic risk factors for PD. − Moreover, it is now well established that a reduction in wild-type (WT) GCase activity is also observed in sporadic PD cases even in the absence of GBA1 mutations. , Decreased GCase functioning promotes α-synuclein accumulation, lysosomal impairment and increased oxidative stress, creating a pathogenic feedback loop. ,

Therefore, therapeutic strategies exclusively focused on targeting GCase activity may not be sufficient. While GCase activation may indirectly mitigate oxidative stress and α-synuclein accumulation, our goal was to develop multifunctional compounds that combine GCase enhancement with intrinsic antioxidant properties or direct modulation of α-synuclein, thereby addressing multiple interconnected pathological pathways simultaneously. In the present work, we aimed to develop multifunctional PCs capable of combining GCase stabilization with antioxidant activity. To this end, we designed hybrid 2 by conjugating a validated N-alkyl-3,4,5-trihydroxypiperidine PC scaffold, ,, a known GCase stabilizer, with curcumin, thereby coupling chaperone activity and redox modulation within a single molecular framework (Figure ). In parallel, we synthesized analogue 3 by conjugation with a ferulic acid moiety (Figure ). As a naturally occurring phenolic antioxidant, ferulic acid can be viewed as a structurally simplified “half-curcumin” surrogate that retains the key radical-scavenging features of curcumin while reducing molecular complexity. ,

1.

1

Open in a new tab

Structures of Curcumin (1) and new iminosugar curcumin 2 and iminosugar-ferulic acid 3 hybrids.

The (R,R)-3,4,5-trihydroxypiperidine was converted to azide 4 as described in the literature, enabling conjugation with a terminal alkyne-armed curcumin derivative 6 prepared as reported. The coupling was performed via copper-catalyzed azide–alkyne cycloaddition (CuAAC) using CuSO4/sodium ascorbate in THF/H2O (2:1) until complete conversion of the curcumin derivative (which occurred after 23 h at room temperature). After treatment with QuadraSil MP and purification by column chromatography, the hybrid 2 was obtained in 41% yield as a mixture of two tautomers (Scheme ). Alternatively, amine 5 was coupled with ferulic acid (7) under standard EDC/HOBt conditions in dry DMF. Hybrid 3 was isolated in 42% yield after 16 h at room temperature and purification by silica gel chromatography (Scheme ).

1. Synthesis of Iminosugar-Curcumin 2 and Iminosugar-Ferulic Acid 3 Hybrids.

1

Open in a new tab

Preliminary biological evaluation of the hybrids was performed by measuring their inhibitory activity against recombinant human GCase (rh-GCase) at pH 4.5 and 7.0, mimicking lysosomal and ER conditions, respectively. For comparison, iminosugar 8, previously identified as our reference GCase piperidine-type PC and curcumin (1; Supelco, 08511–10MG), were evaluated under identical experimental conditions (Table ). At pH 7.0, all compounds behaved as inhibitors of rh-GCase. Compounds 2 (IC50 = 12.0 ± 2.4 μM), 3 (IC50 = 20 ± 1 μM) and 8 (IC50 = 21.0 ± 3.3 μM) exhibited moderate inhibitory potency in the low micromolar range, whereas curcumin (1) was significantly less active (IC50 ≈ 500 μM) (Table ). These data indicate that the hybrids 2 and 3 retain the typical inhibitory profile of iminosugar-based scaffolds under neutral conditions, where binding to the enzyme in the ER is required to stabilize its folded conformation, a prerequisite to a potential PC mechanism. In contrast, a different behavior was observed at pH 4.5. Hybrid 2 induced a marked enhancement of enzyme activity, reaching up to 2.8 fold at 30 μM, suggesting an enhancer effect under lysosomal conditions. Curcumin (1) also promoted enzyme activation (∼2 fold), with a more modest effect, suggesting that the iminosugar-containing compound may provide a more effective enhancement of enzyme activity. In contrast, 3 and 8 displayed a weak enzyme inhibition (IC50 ∼500 μM and ∼2000 μM, respectively), reflecting a substantial loss of inhibitory potency compared to pH 7.0 (Table ). This pronounced pH-dependent behavior is a key requirement for effective PCs. Indeed, the use of inhibitory chaperones, that continue to bind and inhibit the lysosomal enzymes once they have reached the lysosomes, represents the main challenge for their clinical development. Remarkably, the compounds reported herein bind the enzyme strongly in the ER at neutral pH but lose affinity under acidic lysosomal conditions or even enhance catalytic activity. The observed loss of inhibition and, in the case of 1 and 2, enzyme activation at pH 4.5 therefore represents a highly favorable functional profile. To the best of our knowledge, although GCase activators have been described previously − and have recently been discussed in the context of the emerging landscape of small-molecule GCase modulators, none have been reported to display the pronounced pH-dependent switch from inhibition at neutral pH to activation under lysosomal acidic conditions observed for compounds 1 and 2. Kinetic studies were performed to investigate their mechanism of action, revealing distinct behaviors for compounds 1 and 2, likely arising from their different chemical architectures (see Supporting Information). Curcumin (1) increased GCase activity without affecting Km, consistent with a nonessential activator mechanism likely mediated by binding to a secondary site and inducing conformational changes that enhance catalysis. In contrast, hybrid 2, which combines a curcumin moiety with an N-alkylated 3,4,5-trihydroxypiperidine unit, increased both Km and Vmax, suggesting simultaneous engagement of an activation site and the active site. Notably, 2 showed stronger activation than 1 and greater inhibitory potency than 3,4,5-trihydroxypiperidine alone, supporting a cooperative interplay between the two pharmacophores. Although a contribution from pH-dependent differences in stability or solubility cannot be excluded, the distinct kinetic behavior of 2 compared with curcumin alone supports a direct contribution of the iminosugar moiety to GCase interaction. These findings highlight the potential of dual-binding molecules as GCase enhancers.

1. Summary of the Biological Evaluation of the Investigated Compounds: In Vitro GCase Interaction at pH 7.0 and 4.5, Expressed as IC50 Values for Inhibitory Activity or as Fold Enhancement Relative to the Control (in the Absence of Compounds), In Vitro Antioxidant Activity and Ex Vivo PC Activity in WT and GD Patient-Derived Fibroblasts (Nd: Not Determined).

graphic file with name ao6c08401_0003.webp

Open in a new tab

The chain-breaking antioxidant activity of the synthesized hybrid molecules was assessed using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical assay in ethanol. The time course of DPPH decolorization by an equimolar amount of the tested compounds allows determination of the percentage of DPPH inhibition (Table , see Supporting Information). The curcumin hybrid 2 and the feruloyl amide derivative 3 exhibited comparable radical scavenging properties in this assay, while curcumin (1) showed higher radical scavenging activity. The percentage of DPPH inhibition determined 10 min after the addition of the test compounds, widely considered a benchmark time point for assessing radical scavenging activity, was 70.3% for curcumin. On the other hand, compounds 2 and 3 exhibited DPPH inhibition values of 28% and 38%, respectively. For comparison purposes, the activity of 8 (not containing curcumin- or ferulic acid-related moieties) was also evaluated and, as expected, no radical scavenging activity was observed. All derivatives investigated herein exhibited lower antioxidant activity than di­(tert-butyl)­hydroxytoluene (BHT), employed as the positive control, which showed more than 95% inhibition of the DPPH radical.

To further evaluate the therapeutic potential of the compounds, experiments were conducted in patient-derived fibroblasts carrying either the N370S/RecNcil or the L444P/L444P GBA1 mutations, two of the most common variants associated with GD and GBA1-related PD. Cells were treated with increasing concentrations of each compound for 4 days and GCase activity was measured in intact cells. , As reported, the reference PCs Ambroxol (ABX) and Isofagomine (IFG) significantly increased GCase activity in N370S mutant fibroblasts but failed to rescue enzyme activity in L444P cells, , confirming the well-known mutation-dependent effect of PCs. Compounds 1-3 and 8 were evaluated under the same experimental conditions (see Supporting Information). Curcumin (1) and the feruloyl amide 3 did not show significant activity in either genotype (Table ). The N-octylpiperidine 8 demonstrated a consistent and dose-dependent increase in GCase activity in both genotypes, suggesting a broad activity profile that is not limited to specific mutations and confirming its excellent PC performance, even when evaluated with this intact-cell method (Table ). Interestingly, the curcumin-iminosugar hybrid 2, while being inactive in N370S mutated cells, produced a considerable increase in GCase activity in L444P fibroblasts at low concentrations (46% at 1 μM and 40% at 0.1 μM) (Table ). It is important to note that the L444P genotype represents one of the most severe neuropathic forms and is typically considered highly resistant to PC treatment. , Therefore, the ability of 2 to enhance GCase activity in this particularly refractory context is especially noteworthy. In contrast, curcumin (1) alone and the “half-curcumin” hybrid 3 did not show any significant PC effect under the tested conditions. This lack of activity suggests that the intact hybrid curcumin structure 2 is essential for effective GCase stabilization and restoration of enzyme function. To assess their potential relevance to sporadic PD, we evaluated the effects of 1 and 2 in wild-type human fibroblasts. As shown in Table , compounds 2 (at 1 and 10 μM), and 1 (at 10 μM), increased GCase activity by 33% and 44%, respectively (see Supporting Information), supporting their potential for further investigation in sporadic PD. Notably, a comparable enhancement of GCase activity (∼45%) has been reported for iminosugar-based chaperone 8 only at significantly higher concentrations (50 μM), highlighting the potency of 1 and 2. Having demonstrated potent PC activity, compound 2 was subsequently assessed for its ability to mitigate intracellular ROS accumulation. Remarkably, at the same concentration that showed significant PC activity, 2 achieved an approximate 20% decrease in ROS levels in L444P fibroblasts (see Supporting Information), demonstrating a clear antioxidant effect. This complementary action, simultaneously enhancing enzymatic performance while alleviating oxidative stress, further emphasizes the therapeutic promise of compound 2 as a multifunctional candidate for the treatment of GD and GBA1-related PD.

In summary, we developed two novel iminosugar-based hybrids incorporating antioxidant motifs and evaluated their potential as multifunctional modulators of GCase. Among them, the curcumin-derived hybrid 2 displayed a unique and highly favorable profile, combining pH-dependent GCase modulation, enzyme enhancement under lysosomal conditions, PC activity in L444P GD and in WT fibroblasts, and a significant reduction of intracellular ROS levels. These findings identify compound 2 as a promising dual-target lead for GD and GBA1-associated PD, supporting the development of multifunctional therapeutic strategies that simultaneously address enzyme dysfunction and oxidative stress.

Methods

General Procedures

Commercial reagents were used as received. All reactions were magnetically stirred and monitored by TLC on 0.25 mm silica gel plates (Merck F254) and column chromatography were carried out on Silica Gel 60 (32–63 μm). Yields refer to spectroscopically and analytically pure compounds unless otherwise stated. NMR spectra were recorded on a Varian Mercury-400, Varian INOVA-400 or Varian Gemini-200. The notations of multiplicity (s, d, t, q) in the 13C NMR spectra do not derive from a decoupled experiment but are deduced on the basis of signal attribution through 2D spectra. For practical reasons the assignment of H and C atoms in NMR characterizations reflects the numbering of chemical structures. Infrared spectra were recorded with a PerkinElmer Spectrum BX FT-IR System spectrophotometer. ESI full MS were recorded on a Thermo LTQ instrument by direct inlet; relative percentages are shown in brackets. Elemental analyses were performed with a PerkinElmer 2400 analyzer. Optical rotation measurements were performed with a JASCO DIP-370 polarimeter.

Compound 8 employed in the biological assays had previously been synthesized following the established laboratory procedure, while commercial curcumin (1) was obtained as an analytical standard (Curcumin, Supelco, 08511-10MG).

Synthesis of Compound 2

To a solution of curcumin derivative 6 (61 mg, 0.150 mmol) and piperidine 4 (59 mg, 0.195 mmol) in THF (3.6 mL) and H2O (1.8 mL), CuSO4·5H2O (7 mg, 0.0439 mmol) and Na Ascorbate (15 mg, 0.0757 mmol) were added. The reaction mixture was stirred in the dark for 23 h at room temperature, until a TLC control (PE/EtOAc 1:1) attested the disappearance of the starting material. The mixture was filtered through Celite and the solvent was removed under reduced pressure. The crude product was first treated with QuadraSil MP resin and then purified on silica gel by flash column chromatography in the dark (gradient of eluent from CH2Cl2/MeOH/NH4OH (6%) 10:1:0.1 to 5:1:0.1) to afford the product 2 as a mixture of tautomers (44 mg, 0.0622 mmol, 41%).

2: red solid mp 103.9–105.1 °C. Rf = 0.2 (CH2Cl2/MeOH/NH4OH (6%) 5:1:0.1). Mixture of tautomers (K + E): 1H NMR (400 MHz, CD3OD) δ ppm: 7.74–7.50 (m, 2H, Ar and conjugated double bonds, K + E), 7.47–7.30 (m, 1H, Ar and conjugated double bonds, K + E), 7.23–6.73 (m, 8H, Ar and conjugated double bonds, K + E), 5.50–5.42 (m, 1H, H-4′, K), 4.36–4.21 (m, 2H, CH 2 -N­(triazole)), 3.97–3.77 (m, 8H, OCH 3 , H-3, H-5; K + E), 3.47–3.39 (m, 1H, H-4, K + E), 3.12–3.01 (m, 2H, CH 2 -(triazole), E), 2.87–2.73 (m, 4H, Ha-6, Ha-2 K + E, CH 2 -(triazole) K), 2.48–2.27 (m, 3H, Hb-2, CH 2 -piperidine, K + E), 2.21–2.11 (m, 1H, Hb-6, K + E), 1.85–1.69 (m, 2H, CH 2 CH2–triazole, K + E), 1.53–1.37 (m, 2H, CH 2 CH2–piperidine, K + E), 1.32–1.11 (m, 10H, CH 2 , K + E). 13C NMR (100 MHz, CD3OD) δ ppm: 196.4, 194.4, 168.1, 151.8, 150.3, 149.5, 149.4, 149.4, 149.2, 148.8, 148.3, 147.0, 143.6, 140.5, 131.5, 128.9, 127.3, 125.3, 124.4, 124.3, 123.8, 123.5, 123.1, 120.8, 116.7, 116.7, 116.6, 116.6, 116.2, 113.9, 112.0, 111.7, 111.5, 81.0, 80.9, 75.0, 69.4, 68.8, 59.2, 57.9, 57.3, 56.5, 56.4, 51.3, 43.3, 40.4, 31.2, 31.8, 30.8, 30.7, 30.4, 30.4, 30.3, 29.9, 29.9, 28.4, 27.4, 27.4, 27.3, 25.6, 20.6. MS (ESI): m/z (%) = 707.33 (100) [M + H]+. C38H50N4O9 (706.36): calcd C, 64.57; H, 7.13; N, 7.93; found C, 64.56%; H, 7.19%; N, 7.66%.

Synthesis of Compound 3

To a solution of piperidine 5 (0.241 mmol, 66 mg) in dry DMF (3 mL), ferulic acid (7, 0.219 mmol, 43 mg), N-hydroxybenzotriazole (HOBt, 0.241 mmol, 33 mg), 1-ethyl-3-(3-(dimethylamino)­propyl)­carbodiimide hydrochloride (EDC·HCl, 0.241 mmol, 46 mg) and triethylamine (0.241 mmol, 34 μL) were added under nitrogen atmosphere. The reaction mixture was stirred in the dark at room temperature under nitrogen atmosphere for 16 h, until a TLC control (CH2Cl2/MeOH/NH4OH (6%) 5:1:0.1) attested the disappearance of the carboxylic acid. The crude product was purified on silica gel by flash column chromatography (washed with PE and then gradient of eluent from CH2Cl2/MeOH/NH4OH (6%) 10:1:0.1 to 5:1:0.1) to afford the product 3 (41 mg, 0.0910 mmol, 42%).

3: yellow solid mp 58.6–60.4 °C. Rf = 0.1 (CH2Cl2/MeOH/NH4OH (6%) 10:1:0.1). [α]D 24 = −13.2 (c = 0.5, MeOH). 1H NMR (400 MHz, CD3OD) δ ppm: 7.45 (d, J = 15.7 Hz, 1H, H-3′), 7.14 (d, J = 1.8 Hz, 1H, H-5′), 7.04 (dd, J = 8.2, 1.8 Hz, 1H, H-9′), 6.81 (d, J = 8.2 Hz, 1H, H-8′), 6.45 (d, J = 15.7 Hz, 1H, H-2′), 3.99–3.94 (m, 1H, H-3), 3.90 (s, 3H, OCH 3 ), 3.89−3.83 (m, 1H, H-5), 3.54–3.44 (m, 1H, H-4), 3.34–3.27 (m, 2H, CH 2 -NH), 2.97–2.83 (m, 2H, Ha-2, Ha-6), 2.63–2.44 (m, 3H, Hb-2, CH 2 -piperidine), 2.44–2.26 (m, 1H, Hb-6), 1.68–1.48 (m, 4H, CH 2 CH2–NH, CH 2 CH2–piperidine), 1.48–1.24 (m, 10H, CH 2 ). 13C NMR (100 MHz, CD3OD) δ ppm: 169.1 (s, CO), 149.8 (s, Cq), 149.3 (s, Cq), 141.9 (d, H-3′), 128.3 (s, Cq), 123.2 (d, H-9′), 118.8 (d, H-2′), 116.5 (d, H-8′), 111.6 (d, H-5′), 74.1 (d, C-4), 69.1 (d, C-5), 68.2 (d, C-3), 59.0 (t, CH2-piperidine), 57.1 (t, C-6), 56.8 (t, C-2), 56.4 (q, OCH 3 ), 40.5 (t, CH2–NH), 30.5 (t, CH2), 30.5 (t, CH2), 30.4 (t, CH2), 30.3 (t, CH2), 28.3 (t, CH2), 28.0 (t, CH2), 26.9 (t, CH2). MS (ESI): m/z (%) = 451.33 [M + H]+ (100), 473.25 (68) [M + Na]+, 922.92 (97) [2M+Na]+. C24H38N2O6 (450.27): calcd C, 63.98; H, 8.50; N, 6.22; found C, 63.91%; H, 8.83%; N, 6.24%.

Activity toward Human GCase

All experiments on biological materials were performed in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments.

Compounds 1, 2 and 3 were dissolved in DMSO and used immediately. For each replicate, freshly dissolved compound from the same synthesis batch was used. Compound 8 was dissolved in water.

All compounds were screened against recombinant human GCase (rh-GCase; Cerezyme) at pH 4.5 and 7.0, which mimic the lysosomal and endoplasmic reticulum environments, respectively.

Enzyme activity was measured in a flat-bottomed 96-well plate. Compound solution (3 μL), rh-GCase (7 μL), and substrate 4-methylumbelliferyl-β-d-glucoside (3.33 mM, 20 μL, Sigma-Aldrich) in citrate/phosphate buffer at pH 4.5 and 7.0 containing sodium taurocholate (0.3%) and Triton X-100 (0.15%) at 37 °C were incubated for 25 min. The reaction was stopped by the addition of sodium carbonate (200 μL; 0.5 M, pH 10.7) containing Triton X-100 (0.0025%), and the fluorescence of 4-methylumbelliferone released by β-glucosidase activity was measured in SpectraMax M2 microplate reader (λex = 365 nm, λem = 435 nm; Molecular Devices). GCase inhibition or enhancement is reported relative to the control (without compounds). For each compound a blank composed by a water, compound and substrate (called “compound blank”) was tested and compared with the experiment blank, composed by water and substrate. No “compound blank” differs from the experiment blank, demonstrating that the compounds do not interfere with the fluorescence of the hydrolyzed substrate. Data are presented as mean ± standard deviation (n = 3).

The IC50 values of inhibitors against rh-GCase were determined by measuring the initial hydrolysis rate with 4-methylumbelliferyl-β-d-glucoside (3.33 mM). For more details see Supporting Information.

Kinetic analysis of compounds 1 and 2: The action mechanism of compounds 1 and 2 was determined by studying the dependence of the main kinetic parameters (Km and Vmax) from the inhibitor concentration. Kinetic data were analyzed using the Lineweaver–Burk plots. For more details see Supporting Information.

2,2-Diphenyl-1-picrylhydrazyl (DPPH) Assay

The assay was performed according to a literature reported procedure. To 1.98 mL of a 200 μM DPPH solution in ethanol, 20 μL of a 20 mM ethanolic solution of compounds 1–3, 8 and dibutylhydroxytoluene (BHT) were added and rapidly mixed. The progress of the reaction was monitored by spectrophotometric analysis measuring the absorbance at 515 nm every 30 s for 10 min. For more details see Supporting Information.

Chaperoning Activity Assays on Gaucher-Derived Fibroblasts ,

Gaucher disease patients’ cells were obtained from the “Cell line and DNA Biobank from patients affected by Genetic Diseases” (Gaslini Hospital, Genova, Italy)Telethon Genetic Biobank Network). The cell passage number of fibroblasts is between 16 to 25.

To determine the GCase activity in intact cells, 3000–4000 cells were plated into 96-well black plate with clear bottom in D-MEM, 10% FBS at 37 °C under 5% CO2, either with or without the tested compounds in a dose-dependent manner at several concentrations. After 24 h of attachment, the medium was replaced with a fresh medium containing new compounds or Isofagomine (IFG) or Ambroxol (ABX) (as a control, they reached clinical trials for GD or/and GD/PD treatment). The cells were incubated for 4 days with the medium for DMSO-treated cells or compound-treated cells. The final concentration of DMSO was <0.5% which had no cytotoxicity. The enzyme activity assay was performed after removing the medium supplemented with compounds. The monolayers were washed with Dulbecco’s PBS solution (Gibco, pH 7.4). PBS (16 μL) and acetate buffer (0.2 M, 16 μL, pH 4.0) were added to each well. The reaction was started by the addition of 4-methylumbelliferyl β-d-glucoside (4 mM, 25 μL, Sigma) to each well, followed by incubation at 37 °C for 2 h. The reaction was stopped by lysing the cells with glycine buffer (0.2 M, 200 μL, pH 10.8). The fluorescence was also measured by the release of 4-methylumbelliferone with an excitation wavelength of 355 nm and an emission wavelength of 460 nm (SpectraMax M5, Molecular Devices). The fluorescence of untreated cells was compared with those treated with compounds. For the initial screening, treatments were evaluated in two independent biological experiments (n = 2), with untreated controls and compound-treated conditions analyzed in eight and five technical replicates, respectively. Selected compounds and concentrations were subsequently evaluated in three additional independent experiments, resulting in a total of five independent biological replicates (n = 5) for these conditions. Technical replicates from each independent experiment were averaged to obtain a single value for each biological replicate and were not considered as independent observations for statistical analysis. Under these experimental conditions, the activity of nonlysosomal β-glucosidase was shown to be negligible (typically around 5%) at pH 4. This was confirmed by J. W. Kelly and coworkers using conduritol B epoxide (CBE), an irreversible inhibitor that specifically targets lysosomal GCase but does not affect nonlysosomal β-glucosidase. As expected, the CBE-insensitive activity was minimal, indicating that the observed GCase activity largely originated from the lysosomal enzyme.

Statistical Analysis: Statistical significance was evaluated using Student’s t test. A p-value lower than 0.05 was considered to be statistically significant. The single (*), double (**), triple (***) and quadruple (****) asterisks refer to p-values lower than 0.05, 0.01, 0.001 and 0.0001, respectively. Statistical analysis was performed using the GraphPad Prism 8.

Flow Cytometric Analysis of ROS Levels in Cells Treated with Compound 2

Fibroblasts derived from GD patients bearing L444P/L444P were seeded in P60 culture dishes and maintained at 37 °C in a controlled atmosphere with 5% CO2. Once cells reached confluence, the growth medium was replaced with fresh medium containing either 1 μM of compound 2 or vehicle, and cells were incubated for an additional 24 h at 37 °C. After incubation, the medium was removed, and cells were washed with PBS, trypsinized, and collected into 15 mL conical Falcon tubes. Cells were centrifuged (5 min at 1000 rpm), then washed with 1X wash buffer provided in the ROS-ID Total ROS/Superoxide Detection Kit (Enzo Life Sciences, Enzo Biochem, Inc., 21 Executive Blvd., Farmingdale, NY 11735). The resulting cell pellet was resuspended in 500 μL of ROS detection solution included in the kit and incubated at 37 °C for 30 min. Finally, cells were centrifuged and resuspended in 120 μL of PBS prior to analysis by flow cytometry (FACSCanto II, BD Biosciences).

Pharmacological Chaperoning Activity in Wild-Type Fibroblasts

Wild-type fibroblasts were obtained from the “Cell Line and DNA Biobank from Patients Affected by Genetic Diseases” at Gaslini Hospital (Genoa, Italy). Cells (1.35–1.50 × 105) were seeded in T25 culture flasks containing DMEM supplemented with 10% fetal bovine serum, 1% penicillin/streptomycin, and 1% glutamine, and incubated for 24 h at 37 °C in a humidified atmosphere with 5% CO2. The culture medium was then replaced with fresh medium containing the tested compounds 1 and 2, and cells were incubated for an additional 4 days. Following treatment, the medium was removed, and cells were washed with PBS and detached using trypsin. Cell pellets were collected, washed four times with PBS, frozen, and lysed by sonication in water. Total protein concentration in fibroblasts homogenates was determined using the Micro BCA Protein Assay Kit (Sigma–Aldrich), following the manufacturer’s instructions. GCase activity was measured in flat-bottom 96-well microplates in triplicates. The reaction mixture consisted of fibroblast homogenate (10 μL, 3 μg protein/μL), and 4-methylumbelliferyl-β-d-glucoside (20 μL, 3.33 mM; Sigma–Aldrich) dissolved in citrate/phosphate buffer (0.1/0.2 M, pH 5.8) containing sodium taurocholate (0.3%) and Triton X-100 (0.15%). Samples were incubated at 37 °C for 1 h. The reaction was terminated by adding 200 μL of sodium carbonate solution (0.5 M, pH 10.7) containing Triton X-100 (0.0025%). The fluorescence of the released 4-methylumbelliferone, generated by β-glucosidase activity, was measured using a SpectraMax M2 microplate reader (Molecular Devices) at excitation and emission wavelengths of 365 and 435 nm, respectively. Data are reported as mean ± SD from two technical replicates (n = 2).

Supplementary Material

ao6c08401_si_001.pdf (1.2MB, pdf)

Acknowledgments

F. Clemente thanks further support by Fondazione Telethon ETS and Associazione Italiana Gaucher (grant GSA22P001). F. Clemente and F. Cardona thank #NEXTGENERATIONEU (NGEU) funded by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), projects “A multiscale integrated approach to the study of the nervous system in health and disease” (MNESYS Grant PE0000006). Financial support provided by MUR-Dipartimenti di Eccellenza 2023–2027 (DICUS 2.0) to the Department of Chemistry “Ugo Schiff” of the University of Florence is acknowledged. This work was partially funded under the NRRP, M4C2 investment of MUR funded by #NEXTGENERATIONEU (NGEU) (Bando PRIN 2022, Project code 2022N9E847; project: MULTIFUN. CUP: B53D23015580006). Access to the DICUS-University of Florence instrumentation (see the Methods section) is acknowledged. A. Morrone gratefully thanks the AMMeC ONLUS for their continuing support.

Glossary

Abbreviations

ROS

reactive oxygen species

RNS

reactive nitrogen species

GD

Gaucher disease

GCase

β-glucocerebrosidase

PCs

pharmacological chaperones

ER

endoplasmic reticulum

PD

Parkinson’s disease

WT

wild-type

rh-GCase

recombinant human GCase

CuAAC

copper-catalyzed azide–alkyne cycloaddition

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.6c08401.

  • The NMR spectra of compound 8 and the newly synthesized hybrids 2 and 3, as well as the raw data from the biological (in vitro and ex vivo) studies (PDF)

A. Morano carried out the syntheses and characterization of compounds; F. Clemente designed and carried out the biological experiments and performed data curation and analysis; F. Clemente and F. Cardona contributed to conceptualization, investigation, validation, data curation, and writing – original draft preparation and supervised the chemical part; R.S. carried out the flow cytometric analysis of ROS levels in cells; P.P. supervised the kinetic analysis and flow cytometric analysis of ROS levels in cells and contributed to writing – review and editing; S.F. performed cell culture and maintenance. A. Morrone supervised the biological experiments and contributed to writing – review and editing; D.T. carried out the antioxidant analysis in vitro and contributed to writing – review and editing; C.M. and A.G. supervised the chemical part and contributed to writing – review and editing. All authors have approved the final version of the manuscript.

The authors declare no competing financial interest.

References

  1. Sökmen M., Khan M. A.. The Antioxidant Activity of Some Curcuminoids and Chalcones. Inflammopharmacology. 2016;24:81–86. doi: 10.1007/s10787-016-0264-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Lin X., Bai D., Wei Z., Zhang Y., Huang Y., Deng H., Huang X.. Curcumin Attenuates Oxidative Stress in RAW264.7 Cells by Increasing the Activity of Antioxidant Enzymes and Activating the Nrf2-Keap1 Pathway. PLoS One. 2019;14:e0216711. doi: 10.1371/journal.pone.0216711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Wolnicka-Glubisz A., Wisniewska-Becker A.. Dual Action of Curcumin as an Anti- and Pro-Oxidant from a Biophysical Perspective. Antioxidants. 2023;12:1725. doi: 10.3390/antiox12091725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cui J., Li H., Zhang T., Lin F., Chen M., Zhang G., Feng Z.. Research Progress on the Mechanism of Curcumin Anti-Oxidative Stress Based on Signaling Pathway. Front. Pharmacol. 2025;16:1548073. doi: 10.3389/fphar.2025.1548073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Avendaño-Briseño K. A., Escutia-Martínez J., Hernández-Cruz E. Y., Pedraza-Chaverri J.. Antioxidant Effect of Curcumin and Its Impact on Mitochondria: Evidence from Biological Models. J. Xenobiot. 2025;15:139. doi: 10.3390/jox15050139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Sohn S.-I., Priya A., Balasubramaniam B., Muthuramalingam P., Sivasankar C., Selvaraj A., Valliammai A., Jothi R., Pandian S.. Biomedical Applications and Bioavailability of CurcuminAn Updated Overview. Pharmaceutics. 2021;13:2102. doi: 10.3390/pharmaceutics13122102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Genchi G., Lauria G., Catalano A., Carocci A., Sinicropi M. S.. Neuroprotective Effects of Curcumin in Neurodegenerative Diseases. Foods. 2024;13:1774. doi: 10.3390/foods13111774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Moldoveanu C.-A., Tomoaia-Cotisel M., Sevastre-Berghian A., Tomoaia G., Mocanu A., Pal-Racz C., Toma V.-A., Roman I., Ujica M.-A., Pop L.-C.. A Review on Current Aspects of Curcumin-Based Effects in Relation to Neurodegenerative, Neuroinflammatory and Cerebrovascular Diseases. Molecules. 2025;30:43. doi: 10.3390/molecules30010043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cheng M., Ding F., Li L., Dai C., Sun X., Xu J., Chen F., Li M., Li X.. Exploring the Role of Curcumin in Mitigating Oxidative Stress to Alleviate Lipid Metabolism Disorders. Front. Pharmacol. 2025;16:1517174. doi: 10.3389/fphar.2025.1517174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Lehoczki A., Fekete M., Jarecsny T., Zábó V., Szappanos Á., Csípő T., Lipécz Á., Major D., Fazekas-Pongor V., Varga P., Varga J. T.. The Neuroprotective Role of Curcumin: From Molecular Pathways to Clinical TranslationA Narrative Review. Nutrients. 2025;17:2884. doi: 10.3390/nu17172884. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Luo M., Xiao H.. Curcumin, Resveratrol, and Other Polyphenols in Regulating Redox Imbalance in Inflammatory Bowel Disease. Curr. Opin. Physiol. 2026;47:100890. doi: 10.1016/j.cophys.2025.100890. [DOI] [Google Scholar]
  12. Bolognesi M. L., Cavalli A.. Multitarget Drug Discovery and Polypharmacology. ChemMedChem. 2016;11:1190–1192. doi: 10.1002/cmdc.201600161. [DOI] [PubMed] [Google Scholar]
  13. Ramsay R. R., Popovic-Nikolic M. R., Nikolic K., Uliassi E., Bolognesi M. L.. A Perspective on Multi-Target Drug Discovery and Design for Complex Diseases. Clin. Transl. Med. 2018;7:3. doi: 10.1186/s40169-017-0181-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Grabowski, G. A. Advances in Gaucher Disease: Basic and Clinical Perspectives; Future Medicine Ltd.: London, U.K., 2013. [Google Scholar]
  15. Méndez-Cobián D. A., Guzmán-Silahua S., García-Hernández D., Conde-Sánchez J., Castaneda-Borrayo Y., Duey K. L., Zavala-Cerna M. G., Rubio-Jurado B., Nava-Zavala A. H.. An Overview of Gaucher Disease. Diagnostics. 2024;14:2840. doi: 10.3390/diagnostics14242840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Mozafari H., Khatami S., Kiani A., Rahimi Z., Vaisi-Raygani A., Afsharnaderi A., Alaei M. R.. Oxidative Stress Parameters, Trace Elements, and Lipid Profile in Iranian Patients with Gaucher Disease. Biol. Trace Elem. Res. 2020;193:130–137. doi: 10.1007/s12011-019-01709-3. [DOI] [PubMed] [Google Scholar]
  17. Kartha R. V., Terluk M. R., Brown R., Travis A., Mishra U. R., Rudser K., Lau H., Jarnes J. R., Cloyd J. C., Weinreb N. J.. Patients with Gaucher Disease Display Systemic Oxidative Stress Dependent on Therapy Status. Mol. Genet Metab. Rep. 2020;25:100667. doi: 10.1016/j.ymgmr.2020.100667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Sahasrabudhe S. A., Terluk M. R., Rudser K. D., Cloyd J. C., Kartha R. V.. Biological Variation in Peripheral Inflammation and Oxidative Stress Biomarkers in Individuals with Gaucher Disease. Int. J. Mol. Sci. 2022;23:9189–9203. doi: 10.3390/ijms23169189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Roh J., Subramanian S., Weinreb N. J., Kartha R. V.. Gaucher DiseaseMore than Just a Rare Lipid Storage Disease. J. Mol. Med. 2022;100:499–518. doi: 10.1007/s00109-021-02174-z. [DOI] [PubMed] [Google Scholar]
  20. Boddupalli C. S., Nair S., Belinsky G., Gans J., Teeple E., Nguyen T.-H., Mehta S., Guo L., Kramer M. L., Ruan J.. et al. Neuroinflammation in Neuronopathic Gaucher Disease: Role of Microglia and NK Cells, Biomarkers, and Response to Substrate Reduction Therapy. eLife. 2022;11:e79830. doi: 10.7554/eLife.79830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Cabasso O., Kuppuramalingam A., Lelieveld L., Van der Lienden M., Boot R. G., Aerts J. M. F. G., Horowitz M.. Animal Models for the Study of Gaucher Disease. Int. J. Mol. Sci. 2023;24:16035. doi: 10.3390/ijms242216035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Boyd R. E., Lee G., Rybczynski P., Benjamin E. R., Khanna R., Wustman B. A., Valenzano K. J.. Pharmacological Chaperones as Therapeutics for Lysosomal Storage Diseases. J. Med. Chem. 2013;56:2705–2725. doi: 10.1021/jm301557k. [DOI] [PubMed] [Google Scholar]
  23. Sánchez-Fernández E. M., García Fernández J. M., Ortiz Mellet C.. Glycomimetic-Based Pharmacological Chaperones for Lysosomal Storage Disorders: Lessons from Gaucher, GM1-Gangliosidosis and Fabry Diseases. Chem. Commun. 2016;52:5497–5515. doi: 10.1039/C6CC01564F. [DOI] [PubMed] [Google Scholar]
  24. Martínez-Bailén M., Clemente F., Matassini C., Cardona F.. GCase Enhancers: A Potential Therapeutic Option for Gaucher Disease and Other Neurological Disorders. Pharmaceuticals. 2022;15:823. doi: 10.3390/ph15070823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Smith L., Schapira A. H. V.. GBA Variants and Parkinson Disease: Mechanisms and Treatments. Cells. 2022;11:1261. doi: 10.3390/cells11081261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Koros C., Bougea A., Alefanti I., Simitsi A. M., Papagiannakis N., Pachi I., Sfikas E., Antonelou R., Stefanis L.. A Global Perspective of GBA1-Related Parkinson’s Disease: A Narrative Review. Genes. 2024;15:1605. doi: 10.3390/genes15121605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Li Q., Bi Z., Liang W., Yin S., Li H., Liang Z., Wu M., Quan J., Li C.. Effects of Glucocerebrosidase Gene Variations on the Risk of Parkinson’s Disease Dementia: A Meta-Analysis. Front. Aging Neurosci. 2025;17:1671760. doi: 10.3389/fnagi.2025.1671760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Gegg M. E., Menozzi E., Schapira A. H. V.. Glucocerebrosidase-Associated Parkinson Disease: Pathogenic Mechanisms and Potential Drug Treatments. Neurobiol. Dis. 2022;166:105663. doi: 10.1016/j.nbd.2022.105663. [DOI] [PubMed] [Google Scholar]
  29. Chatterjee D., Krainc D.. Mechanisms of Glucocerebrosidase Dysfunction in Parkinson’s Disease. J. Mol. Biol. 2023;435:168023. doi: 10.1016/j.jmb.2023.168023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kuo S. H., Tasset I., Cheng M. M., Diaz A., Pan M. K., Lieberman O. J., Hutten S. J., Alcalay R. N., Kim S., Ximénez-Embún P.. et al. Mutant Glucocerebrosidase Impairs α-Synuclein Degradation by Blockade of Chaperone-Mediated Autophagy. Sci. Adv. 2022;8:eabm6393. doi: 10.1126/sciadv.abm6393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Hertz E., Chen Y., Sidransky E.. Gaucher Disease Provides a Unique Window into Parkinson Disease Pathogenesis. Nat. Rev. Neurol. 2024;20:526–540. doi: 10.1038/s41582-024-00999-z. [DOI] [PubMed] [Google Scholar]
  32. Pratesi D., Clemente F., Matassini C., Falliano S., Morrone A., Sodano R., Paoli P., Goti A., Fernández-Bolaños J. G., López Ó.. et al. Selenoureido-N-alkyl-3,4,5-trihydroxypiperidines: Probing Their Dual-Target Role in Gaucher Disease. Bioorg. Med. Chem. 2026;132:118453. doi: 10.1016/j.bmc.2025.118453. [DOI] [PubMed] [Google Scholar]
  33. Tagliaferro G., Davighi M. G., Clemente F., Turchi F., Schiavina M., Matassini C., Goti A., Morrone A., Pierattelli R., Cardona F., Felli I.. Evidence of α-Synuclein/Glucocerebrosidase Dual Targeting by Iminosugar Derivatives: New Insights for Addressing Parkinson’s Disease. ACS Chem. Neurosci. 2025;16:1251–1257. doi: 10.1021/acschemneuro.4c00618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Vanni C., Clemente F., Paoli P., Morrone A., Matassini C., Goti A., Cardona F.. 3,4,5-Trihydroxypiperidine-Based Multivalent Glucocerebrosidase (GCase) Enhancers. ChemBioChem. 2022;23:e202200077. doi: 10.1002/cbic.202200077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Buco F., Clemente F., Morrone A., Vanni C., Moya S. E., Cardona F., Goti A., Marradi M., Matassini C.. Multivalent GCase Enhancers: Synthesis and Evaluation of Glyco-Gold Nanoparticles Decorated with Trihydroxypiperidine Iminosugars. Bioconjugate Chem. 2025;36:92–103. doi: 10.1021/acs.bioconjchem.4c00496. [DOI] [PubMed] [Google Scholar]
  36. Purushothaman J. R., Rizwanullah M.. Ferulic Acid: A Comprehensive Review. Cureus. 2024;16:e68063. doi: 10.7759/cureus.68063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Zheng M., Liu Y., Zhang G., Yang Z., Xu W., Chen Q.. The Antioxidant Properties, Metabolism, Application and Mechanism of Ferulic Acid in Medicine, Food, Cosmetics, Livestock and Poultry. Antioxidants. 2024;13:853. doi: 10.3390/antiox13070853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Seghetti F., Di Martino R. M. C., Catanzaro E., Bisi A., Gobbi S., Rampa A., Canonico B., Montanari M., Krysko D. V., Papa S., Fimognari C., Belluti F.. Curcumin-1,2,3-Triazole Conjugation for Targeting the Cancer Apoptosis Machinery. Molecules. 2020;25:3066. doi: 10.3390/molecules25133066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Parmeggiani C., Catarzi S., Matassini C., D’adamio G., Morrone A., Goti A., Paoli P., Cardona F.. Human Acid β-Glucosidase Inhibition by Carbohydrate-Derived Iminosugars: Towards New Pharmacological Chaperones for Gaucher Disease. ChemBioChem. 2015;16:2054–2064. doi: 10.1002/cbic.201500292. [DOI] [PubMed] [Google Scholar]
  40. Skerlj, R. T. ; Lansbury, P. T. ; Bourque, E. M. J. ; Good, A. C. . Methods of Treatment and Combination Therapies Using GCase Activator Heterobicyclic and Related Compounds; WO 2017192841 A1. 2017.
  41. Zheng J., Chen L., Skinner O. S., Ysselstein D., Remis J., Lansbury P., Skerlj R., Mrosek M., Heunisch U., Krapp S., Charrow J., Schwake M., Kelleher N. L., Silverman R. B., Krainc D.. β-Glucocerebrosidase Modulators Promote Dimerization of β-Glucocerebrosidase and Reveal an Allosteric Binding Site. J. Am. Chem. Soc. 2018;140:5914–5924. doi: 10.1021/jacs.7b13003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Zheng J., Jeon S., Jiang W., Burbulla L. F., Ysselstein D., Oevel K., Krainc D., Silverman R. B.. Conversion of Quinazoline Modulators from Inhibitors to Activators of β-Glucocerebrosidase. J. Med. Chem. 2019;62:1218–1230. doi: 10.1021/acs.jmedchem.8b01294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Schulze M.-S. E. D., Scholz D., Jnoff E., Hall A., Melin J., Sands Z. A., Rodriguez E., Andre V. M.. Identification of β-Glucocerebrosidase Activators for Glucosylceramide Hydrolysis. ChemMedChem. 2024;19:e202300548. doi: 10.1002/cmdc.202300548. [DOI] [PubMed] [Google Scholar]
  44. Henderson M. J., Chen T. C., Glasstetter L. M., Chen Y., Marugan J. J., Sidransky E.. The Race to Salvage Glucocerebrosidase: Understanding Small-Molecule Therapies for GBA1-Associated Parkinsonism. Mov. Disord. 2026;41:596–602. doi: 10.1002/mds.70168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Tanini D., Lupori B., Malevolti G., Ambrosi M., Nostro P. L., Capperucci A.. Direct biocatalysed synthesis of first sulfur-, selenium- and tellurium- containing l-ascorbyl hybrid derivatives with radical trapping and GPx-like properties. Chem. Commun. 2019;55:5705–5708. doi: 10.1039/C9CC02427A. [DOI] [PubMed] [Google Scholar]
  46. Stirnemann J., Belmatoug N., Camou F., Serratrice C., Froissart R., Caillaud C., Levade T., Astudillo L., Serratrice J., Brassier A., Rose C., Billette de Villemeur T., Berger M. G.. A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. Int. J. Mol. Sci. 2017;18:441. doi: 10.3390/ijms18020441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Li H.-Y., Chen W.-A., Lin H.-Y., Tsai C.-W., Chiu Y.-T., Yun W.-Y., Lee N.-C., Chien Y.-H., Hwu W.-L., Cheng W.-C.. A Practical Synthesis of Nitrone-Derived C5a-Functionalized Isofagomines as Protein Stabilizers to Treat Gaucher Disease. Commun. Chem. 2024;7:91. doi: 10.1038/s42004-024-01164-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Sawkar A. R., Cheng W.-C., Beutler E., Wong C.-H., Balch W. E., Kelly J. W.. Chemical Chaperones Increase the Cellular Activity of N370S β-Glucosidase: A Therapeutic Strategy for Gaucher Disease. Proc. Natl. Acad. Sci. U. S. A. 2002;99:15428–15433. doi: 10.1073/pnas.192582899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Zhang L., Li L., Higaki K., Nanba E., Suzuki Y., Ohno K.. The Chaperone Activity and Toxicity of Ambroxol on Gaucher Cells and Normal Mice. Brain Dev. 2013;35:317–322. doi: 10.1016/j.braindev.2012.05.008. [DOI] [PubMed] [Google Scholar]
  50. Clemente F., Matassini C., Faggi C., Giachetti S., Cresti C., Morrone A., Paoli P., Goti A., Martínez-Bailén M., Cardona F.. Glucocerebrosidase (GCase) Activity Modulation by 2-Alkyl Trihydroxypiperidines: Inhibition and Pharmacological Chaperoning. Bioorg. Chem. 2020;98:103740. doi: 10.1016/j.bioorg.2020.103740. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ao6c08401_si_001.pdf (1.2MB, pdf)

Articles from ACS Omega are provided here courtesy of American Chemical Society

RESOURCES