Targeting matrix metalloproteinases (MMPs) is a pursued strategy for treating several pathological conditions, such as multiple sclerosis and cancer. Herein, a series of novel tetrahydro-β-carboline derivatives with outstanding inhibitory activity toward MMPs are present. In particular, compounds 9 f, 9 g, 9 h and 9 i show sub-nanomolar IC50 values. Interestingly, compounds 9 g and 9 i also provide remarkable selectivity toward gelatinases; IC50 =0.15 nm for both toward MMP-2 and IC50 =0.63 and 0.58 nm, respectively, toward MMP-9. Molecular docking simulations, performed by employing quantum mechanics based partial charges, shed light on the rationale behind binding involving specific interactions with key residues of S1' and S3' domains. Taken together, these studies indicate that tetrahydro-β-carboline represents a promising scaffold for the design of novel inhibitors able to target MMPs and selectively bias gelatinases, over the desirable range of the pharmacokinetics spectrum.

Mangiatordi, G.f., Guzzo, T., Rossano, E.c., Trisciuzzi, D., Alberga, D., Fasciglione, G., et al. (2018). Design, Synthesis, and Biological Evaluation of Tetrahydro-β-carboline Derivatives as Selective Sub-Nanomolar Gelatinase Inhibitors. CHEMMEDCHEM, 13(13), 1343-1352 [10.1002/cmdc.201800237].

Design, Synthesis, and Biological Evaluation of Tetrahydro-β-carboline Derivatives as Selective Sub-Nanomolar Gelatinase Inhibitors

Fasciglione G.;Coletta M.;
2018-01-01

Abstract

Targeting matrix metalloproteinases (MMPs) is a pursued strategy for treating several pathological conditions, such as multiple sclerosis and cancer. Herein, a series of novel tetrahydro-β-carboline derivatives with outstanding inhibitory activity toward MMPs are present. In particular, compounds 9 f, 9 g, 9 h and 9 i show sub-nanomolar IC50 values. Interestingly, compounds 9 g and 9 i also provide remarkable selectivity toward gelatinases; IC50 =0.15 nm for both toward MMP-2 and IC50 =0.63 and 0.58 nm, respectively, toward MMP-9. Molecular docking simulations, performed by employing quantum mechanics based partial charges, shed light on the rationale behind binding involving specific interactions with key residues of S1' and S3' domains. Taken together, these studies indicate that tetrahydro-β-carboline represents a promising scaffold for the design of novel inhibitors able to target MMPs and selectively bias gelatinases, over the desirable range of the pharmacokinetics spectrum.
2018
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/10 - BIOCHIMICA
English
Con Impact Factor ISI
gelatinases; metalloproteinases; molecular docking; selectivity; β-carbolines; Carbolines; Drug Design; Enzyme Assays; Gelatinases; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Molecular Docking Simulation; Stereoisomerism
Mangiatordi, G.f., Guzzo, T., Rossano, E.c., Trisciuzzi, D., Alberga, D., Fasciglione, G., et al. (2018). Design, Synthesis, and Biological Evaluation of Tetrahydro-β-carboline Derivatives as Selective Sub-Nanomolar Gelatinase Inhibitors. CHEMMEDCHEM, 13(13), 1343-1352 [10.1002/cmdc.201800237].
Mangiatordi, Gf; Guzzo, T; Rossano, Ec; Trisciuzzi, D; Alberga, D; Fasciglione, G; Coletta, M; Topai, A; Nicolotti, O
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/229017
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