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

Autor: Ferhati X; Department of Chemistry 'Ugo Schiff', University of Firenze, via della Lastruccia 3-13, Sesto Fiorentino, (FI), Italy., Matassini C; Department of Chemistry 'Ugo Schiff', University of Firenze, via della Lastruccia 3-13, Sesto Fiorentino, (FI), Italy., Fabbrini MG; Department of Chemistry 'Ugo Schiff', University of Firenze, via della Lastruccia 3-13, Sesto Fiorentino, (FI), Italy., Goti A; Department of Chemistry 'Ugo Schiff', University of Firenze, via della Lastruccia 3-13, Sesto Fiorentino, (FI), Italy; Associated with Consorzio Interuniversitario Nazionale di ricerca in Metodologie e Processi Innovativi di Sintesi (CINMPIS), Italy., Morrone A; Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital, and Department of Neurosciences, Pharmacology and Child Health. University of Florence, Viale Pieraccini n. 24, 50139 Firenze, Italy., Cardona F; Department of Chemistry 'Ugo Schiff', University of Firenze, via della Lastruccia 3-13, Sesto Fiorentino, (FI), Italy; Associated with Consorzio Interuniversitario Nazionale di ricerca in Metodologie e Processi Innovativi di Sintesi (CINMPIS), Italy. Electronic address: francesca.cardona@unifi.it., Moreno-Vargas AJ; Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, n/Prof. García González 1, E-41012 Sevilla, Spain., Paoli P; Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy. Electronic address: paolo.paoli@unifi.it.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2019 Jun; Vol. 87, pp. 534-549. Date of Electronic Publication: 2019 Mar 22.
DOI: 10.1016/j.bioorg.2019.03.053
Abstrakt: The diffusion of type 2 diabetes (T2D) throughout the world represents one of the most important health problems of this century. Patients suffering from this disease can currently be treated with numerous oral anti-hyperglycaemic drugs, but none is capable of reproducing the physiological action of insulin and, in several cases, they induce severe side effects. Developing new anti-diabetic drugs remains one of the most urgent challenges of the pharmaceutical industry. Multi-target drugs could offer new therapeutic opportunities for the treatment of T2D, and the reported data on type 2 diabetic mice models indicate that these drugs could be more effective and have fewer side effects than mono-target drugs. α-Glucosidases and Protein Tyrosine Phosphatase 1B (PTP1B) are considered important targets for the treatment of T2D: the first digest oligo- and disaccharides in the gut, while the latter regulates the insulin-signaling pathway. With the aim of generating new drugs able to target both enzymes, we synthesized a series of bifunctional compounds bearing both a nitro aromatic group and an iminosugar moiety. The results of tests carried out both in vitro and in a cell-based model, show that these bifunctional compounds maintain activity on both target enzymes and, more importantly, show a good insulin-mimetic activity, increasing phosphorylation levels of Akt in the absence of insulin stimulation. These compounds could be used to develop a new generation of anti-hyperglycemic drugs useful for the treatment of patients affected by T2D.
(Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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