title: Progress towards water-soluble triazole-based selective MMP-2 inhibitors.
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%.
authors.affiliation: Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad CEU San Pablo, Urbanización Monteprincipe, 28668 Madrid, Spain. bpaster@ceu.es aramgon@ceu.es.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Fabre
authors.forename: Kamila
authors.initials: K
authors.lastname: Filipiak
authors.forename: José María
authors.initials: JM
authors.lastname: Zapico
authors.forename: Natalia
authors.initials: N
authors.lastname: Díaz
authors.forename: Rodrigo J
authors.initials: RJ
authors.lastname: Carbajo
authors.forename: Anne K
authors.initials: AK
authors.lastname: Schott
authors.forename: María Paz
authors.initials: MP
authors.lastname: Martínez-Alcázar
authors.forename: Dimas
authors.initials: D
authors.lastname: Suárez
authors.forename: Antonio
authors.initials: A
authors.lastname: Pineda-Lucena
authors.forename: Ana
authors.initials: A
authors.lastname: Ramos
authors.forename: Beatriz
authors.initials: B
authors.lastname: de Pascual-Teresa
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011789:Quantum Theory; D012995:Solubility; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014867:Water / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors; D014230:Triazoles; D014867:Water; D020778:Matrix Metalloproteinase 2