Exploring the effect of chirality on the therapeutic potential of N-alkyl-deoxyiminosugars: anti-inflammatory response to Pseudomonas aeruginosa infections for application in CF lung disease

Fenza, Maria De; D’Alonzo, Daniele; Esposito, Anna; Munari, Silvia; Loberto, Nicoletta; Santangelo, A; Lampronti, Ilaria; Tamanini, Anna; Rossi, Alice S.; Ranucci, Serena; Fino, Ida De; Bragonzi, Alessandra; Aureli, Massimo; Bassi, Rajiv; Tironi, Matteo; Lippi, Giuseppe; Gambari, Roberto; Cabrini, Giulio; Palumbo, Giovanni; Dechecchi, Maria Cristina; Guaragna, Annalisa

doi:10.1016/j.ejmech.2019.04.061

Cited by 16 publications

(55 citation statements)

References 45 publications

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“…A reduction of recruitment of neutrophils at a much lower dosage (40-fold) than that of D-NBDNJ [56] ( Figure 24A) and a strong inhibition of NLGase activity ( Figure 24B) were observed. These data, along with the high enzymatic selectivity associated with the use of L-iminosugars, highlight strong evidence of the therapeutic potential of N-alkyl L-iminosugars as anti-inflammatory agents in CF [179]. ) on the inflammatory response to P. aeruginosa in CF bronchial epithelial cells.…”

Section: Exploring the Role Of The Chirality In The Anti-inflamatory mentioning

confidence: 75%

“…The chirality of iminosugars demonstrated an important role in their pharmacological properties against carbohydrate-processing enzymes, including NLGase, especially in terms of enzymatic selectivity [45,96,177,178]. In this context, De Fenza et al explored the inhibition potential of L-glucoconfigured N-alkyl-deoxyiminosugars, ent- (4,14,16,91,92) (Figure 22) against NLGase, thereby studying the effect of chirality on the anti-inflammatory treatment of CF [179]. The synthesis of L-DNJ derivatives was achieved exploiting a de novo methodology [180][181][182] that relied on the use of a homologating agent 93 [183][184][185].…”

Section: Exploring the Role Of The Chirality In The Anti-inflamatory mentioning

confidence: 99%

“…l-iminosugars ent- (4,14,16,91,92) were found to act as NLGase inhibitors, although less efficient than their d-enantiomers, and were found to significantly reduce the inflammatory response induced by P. aeruginosa in CuFi cells (Figure 23), either alone or in synergistic combination with their d-enantiomers [179]. Notably, ent-(4) was not able to act as inhibitor for most glycosidases, showing enzymatic selectivity compared to its d-enantiomer [28].…”

Section: Exploring the Role Of The Chirality In The Anti-inflamatory mentioning

confidence: 99%

“…N-Alkylated D-and L-DNJ derivatives. This figure is reprinted from[179], with permission from Elsevier.…”

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confidence: 99%

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Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis

Esposito

D’Alonzo

Fenza

et al. 2020

IJMS

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Iminosugars are sugar analogues endowed with a high pharmacological potential. The wide range of biological activities exhibited by these glycomimetics associated with their excellent drug profile make them attractive therapeutic candidates for several medical interventions. The ability of iminosugars to act as inhibitors or enhancers of carbohydrate-processing enzymes suggests their potential use as therapeutics for the treatment of cystic fibrosis (CF). Herein we review the most relevant advances in the field, paying attention to both the chemical synthesis of the iminosugars and their biological evaluations, resulting from in vitro and in vivo assays. Starting from the example of the marketed drug NBDNJ (N-butyl deoxynojirimycin), a variety of iminosugars have exhibited the capacity to rescue the trafficking of F508del-CFTR (deletion of F508 residue in the CF transmembrane conductance regulator), either alone or in combination with other correctors. Interesting results have also been obtained when iminosugars were considered as anti-inflammatory agents in CF lung disease. The data herein reported demonstrate that iminosugars hold considerable potential to be applied for both therapeutic purposes.

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Section: Exploring the Role Of The Chirality In The Anti-inflamatory mentioning

confidence: 75%

Section: Exploring the Role Of The Chirality In The Anti-inflamatory mentioning

confidence: 99%

Section: Exploring the Role Of The Chirality In The Anti-inflamatory mentioning

confidence: 99%

“…N-Alkylated D-and L-DNJ derivatives. This figure is reprinted from[179], with permission from Elsevier.…”

mentioning

confidence: 99%

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Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis

Esposito

D’Alonzo

Fenza

et al. 2020

IJMS

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“…By contrast, a phase II clinical trial has already been carried out in patients with ulcerative colitis and demonstrated inhibition of ozone-induced airway inflammation in humans (Lazaar et al, 2011). Numerous other modulators of cytokines in the context of CF have been proposed, but only in vitro experiments have been performed (Lampronti et al, 2017;De Fenza et al, 2019). Cytokine modulation shows that cytokines have a significant role in limiting infections, although these approaches are confusing.…”

Section: Novel Anti-cytokines Approachesmentioning

confidence: 99%

Novel Anti-Inflammatory Approaches for Cystic Fibrosis Lung Disease: Identification of Molecular Targets and Design of Innovative Therapies

Mitri

Bardin

et al. 2020

Front. Pharmacol.

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Cystic fibrosis (CF) is the most common genetic disorder among Caucasians, estimated to affect more than 70,000 people in the world. Severe and persistent bronchial inflammation and chronic bacterial infection, along with airway mucus obstruction, are hallmarks of CF lung disease and participate in its progression. Anti-inflammatory therapies are, therefore, of particular interest for CF lung disease. Furthermore, a better understanding of the molecular mechanisms involved in airway infection and inflammation in CF has led to the development of new therapeutic approaches that are currently under evaluation by clinical trials. These new strategies dedicated to CF inflammation are designed to treat different dysregulated aspects such as oxidative stress, cytokine secretion, and the targeting of dysregulated pathways. In this review, we summarize the current understanding of the cellular and molecular mechanisms that contribute to abnormal lung inflammation in CF, as well as the new anti-inflammatory strategies proposed to CF patients by exploring novel molecular targets and novel drug approaches.

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A Stereoconvergent Tsuji–Trost Reaction in the Synthesis of Cyclohexenyl Nucleosides

Esposito

Giovanni

Fenza

et al. 2020

Chemistry A European J

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A highly regio‐ and stereoselective route to d‐ and l‐cyclohexenyl nucleosides has been devised, using the Tsuji–Trost reaction as the key step. Contrarily to the widely accepted mechanism (involving a net retention of configuration), the reaction proceeded in a highly stereoconvergent manner, providing cis nucleosides regardless of the relative configuration of the starting materials. DFT calculations confirmed the experimental data while suggesting the origin of the stereochemical reaction outcome.

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Exploring the effect of chirality on the therapeutic potential of N-alkyl-deoxyiminosugars: anti-inflammatory response to Pseudomonas aeruginosa infections for application in CF lung disease

Cited by 16 publications

References 45 publications

Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis

Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis

Novel Anti-Inflammatory Approaches for Cystic Fibrosis Lung Disease: Identification of Molecular Targets and Design of Innovative Therapies

A Stereoconvergent Tsuji–Trost Reaction in the Synthesis of Cyclohexenyl Nucleosides

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