Progress towards water-soluble triazole-based selective MMP-2 inhibitors

Benjamin Fabre; Kamila Filipiak; José María Zapico; Natalia Díaz; Rodrigo J. Carbajo; Anne K. Schott; María Paz Martínez-Alcázar; Dimas Suárez; Antonio Pineda-Lucena; Ana Ramos; Beatriz de Pascual-Teresa

doi:10.1039/C3OB41046C

Progress towards water-soluble triazole-based selective MMP-2 inhibitors†

Benjamin Fabre,^a Kamila Filipiak,^ab José María Zapico,^a Natalia Díaz,^c Rodrigo J. Carbajo,^d Anne K. Schott,^d María Paz Martínez-Alcázar,^a Dimas Suárez,^c Antonio Pineda-Lucena,^d Ana Ramos*^a and Beatriz de Pascual-Teresa*^a

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^a Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad CEU San Pablo, Urbanización Monteprincipe, 28668 Madrid, Spain
E-mail: bpaster@ceu.es, aramgon@ceu.es
Fax: (+34) 913510496
Tel: (+34) 913724724

^b Department of Molecular Biology, Faculty of Mathematics and Natural Sciences, The John Paul II Catholic University of Lublin, Lublin, Poland

^c Departamento de Química Física y Analítica, Universidad de Oviedo, C/Julián Clavería, 8. 33006 Oviedo, Asturias, Spain

^d Structural Biology Laboratory, Medicinal Chemistry Department, Centro de Investigación Príncipe Felipe, C/Eduardo Primo Yúfera 3, 46012 Valencia, Spain

Abstract

Water solubility is a key aspect that needs to be addressed to obtain drug-like compounds. In an effort to improve the water solubility of our recently reported nanomolar matrix metalloproteinase type 2 (MMP-2) inhibitors based on triazole-substituted hydroxamates, we synthesized a new series of α-sulfone, α-tetrahydropyran and α-piperidine, α-sulfone clicked hydroxamates and determined their inhibitory activities against both MMP-2 and MMP-9. The best results were found for 13e, a water-soluble compound that displays a low nanomolar activity against MMP-2 and is 26-fold less active against MMP-9. This finding allowed us to pursue in vitro permeability through the Caco-2 monolayer and opened the possibility of carrying out further preclinical investigations. Docking and MD simulations have been performed in order to rationalize the biological results. The inhibitory activity of this compound against a panel of ten MMPs was determined showing an interesting MMP-2/MMP-1, -8, and -14 selectivity profile. The cytotoxicity and anti-invasive activity of the compounds on highly metastatic human fibrosarcoma tumor cells (HT1080) were determined, showing, at 10 μM concentration, a decrease in cell invasiveness up to 80%.

Organic & Biomolecular Chemistry

Progress towards water-soluble triazole-based selective MMP-2 inhibitors†

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