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

作者：Mangiatordi Giuseppe Felice; Guzzo Tatiana; Rossano Eugenio Claudio; Trisciuzzi Daniela; Alberga Domenico; Fasciglione Giovanni; Coletta Massimiliano; Topai Alessandra^*; Nicolotti Orazio^*

来源：ChemMedChem, 2018, 13(13): 1343-1352.

DOI：10.1002/cmdc.201800237

• metalloproteinases
• gelatinases
• -carbolines
• molecular docking
• selectivity

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--carboline derivatives with outstanding inhibitory activity toward MMPs are present. In particular, compounds 9f, 9g, 9h and 9i show sub-nanomolar IC50 values. Interestingly, compounds 9g and 9i also provide remarkable selectivity toward gelatinases; IC50=0.15nm for both toward MMP-2 and IC50=0.63 and 0.58nm, 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--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.

• 出版日期2018-7-6