Dual targeting of PTP1B and glucosidases with new bifunctional iminosugar inhibitors to address type 2 diabetes

Ferhati, Xhenti; Matassini, Camilla; Fabbrini, Maria Giulia; Goti, Andrea; Morrone, Amelia; Cardona, Francesca; Vargas, Ângelo; Paoli, Paolo

doi:10.1016/j.bioorg.2019.03.053

Cited by 33 publications

(20 citation statements)

References 66 publications

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“…The above results are broadly in line with those reported by Guisot et al, who conceived to evaluate a library of DNJ derivatives 17-23 ( Figure 6), in which triazole-bearing alkyl chains were introduced to link an adamantane moiety to the iminosugar core [98]. This project stands on the intriguing therapeutic potential of AMP-DNM (16) [99][100][101][102], even though it must be noted that, to the best of our knowledge, the latter has never been tested as a CFTR corrector. The above results are broadly in line with those reported by Guisot et al, who conceived to evaluate a library of DNJ derivatives 17-23 ( Figure 6), in which triazole-bearing alkyl chains were introduced to link an adamantane moiety to the iminosugar core [98].…”

Section: N-alkyl Dnj Derivatives: Studying the Role Of Lipophilicity supporting

confidence: 88%

“…The first recognized property of iminosugars was their ability to act as glycosidase [5,7] and glycosyltransferase inhibitors [9,10], essentially acting in a competitive manner and exerting their activity mainly as antivirals (HIV-1, HSV, BVDV, HCV) [11,12] and antidiabetics [13][14][15][16]. Furthermore, they were also found to inhibit other classes of enzymes, such as metalloproteinases [17], sugar nucleotide mutase or nucleoside-processing enzymes [18][19][20].…”

Section: Iminosugars: Powerful Glycomimeticsmentioning

confidence: 99%

“…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%

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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: N-alkyl Dnj Derivatives: Studying the Role Of Lipophilicity supporting

confidence: 88%

Section: Iminosugars: Powerful Glycomimeticsmentioning

confidence: 99%

Section: Exploring the Role Of The Chirality In The Anti-inflamatory 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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“…As an alternative deprotection procedure, the cycloadduct 11 was treated with a BCl 3 solution in dry CH 2 Cl 2 at room temperature 16 h and the crude reaction mixture was directly reacted with an excess of acetic anhydride in pyridine, affording the peracetylated compound 15 in 95 % yield over two steps. In analogy with the peculiar reactivity of BCl 3 towards the N‐O bonds in nitrones, in N ‐hydroxypyrrolidines and in nitro compounds, the N‐O bond of isoxazolidine 11 was not cleaved with this reagent.…”

Section: Resultsmentioning

confidence: 95%

Studies for the Multimerization of DAB‐1‐Based Iminosugars through Iteration of the Nitrone Cycloaddition/Ring‐Opening/Allylation Sequence

et al. 2019

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Multivalent iminosugars have gained the attention of the research community in the last ten years. We report herein the proof of principle for an original synthetic strategy to build multivalent iminosugars based on the natural DAB‐1 moiety as the bioactive epitope. The synthesis relies on the iteration of three selective and high‐yielding steps (1,3‐dipolar cycloaddition to nitrone 1, N‐O bond cleavage of the adduct and selective N‐ and/or O‐allylation), and allows the preparation of different topologies of the final DAB‐1 clusters.

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“…In contrast, construction of monocyclic pyrrolidine iminosugars with only four chiral centres are easier to accomplish. The pyrrolidine core of the corresponding iminosugar frequently appears to be the HexNAcase pharmacophore [37][38][39], as the pyrrolidine sections are responsible for mimicking the transition-state of enzyme reaction [40]. Among these monocyclic iminosugars, a series of pyrrolidines containing acetamide groups which are essential for their β-HexNAcase inhibitions were reported (Figure 2), among which considerable examples were accomplished before the isolation of pochonicine (1) [41,42].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Pyrrolidine Monocyclic Analogues of Pochonicine and Its Stereoisomers: Pursuit of Simplified Structures and Potent β-N-Acetylhexosaminidase Inhibition

et al. 2020

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Ten pairs of pyrrolidine analogues of pochonicine and its stereoisomers have been synthesized from four enantiomeric pairs of polyhydroxylated cyclic nitrones. Among the ten N-acetylamino pyrrolidine analogues, only compounds with 2,5-dideoxy-2,5-imino-d-mannitol (DMDP) and pochonicine (1) configurations showed potent inhibition of β-N-acetylhexosaminidases (β-HexNAcases); while 1-amino analogues lost almost all their inhibitions towards the tested enzymes. The assay results reveal the importance of the N-acetylamino group and the possible right configurations of pyrrolidine ring required for this type of inhibitors.

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Dual targeting of PTP1B and glucosidases with new bifunctional iminosugar inhibitors to address type 2 diabetes

Cited by 33 publications

References 66 publications

Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis

Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis

Studies for the Multimerization of DAB‐1‐Based Iminosugars through Iteration of the Nitrone Cycloaddition/Ring‐Opening/Allylation Sequence

Synthesis of Pyrrolidine Monocyclic Analogues of Pochonicine and Its Stereoisomers: Pursuit of Simplified Structures and Potent β-N-Acetylhexosaminidase Inhibition

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