title: Synthesis of bicyclic molecular scaffolds (BTAa): an investigation towards new selective MMP-12 inhibitors.
abstract: Starting from 3-aza-6,8-dioxa-bicyclo[3.2.1]octane scaffold (BTAa) a virtual library of molecules was generated and screened in silico against the crystal structure of the Human Macrophage Metalloelastase (MMP-12). The molecules obtaining high score were synthesized and the affinity for the catalytic domain of MMP-12 was experimentally proved by NMR experiments. A BTAa scaffold 20 having a N-hydroxyurea group in position 3 and a p-phenylbenzylcarboxy amide in position 7 showed a fair inhibition potency (IC50 = 149 microM) for MMP-12 and some selectivity towards five different MMPs. These results, taken together with the X-ray structure of the adduct between MMP-12, the inhibitor 20 and the acetohydroxamic acid (AHA), suggest that bicyclic scaffold derivatives may be exploited for the design of new selective matrix metalloproteinase inhibitors (MMPIs).
authors.affiliation: Department of Organic Chemistry U. Schiff, University of Florence, 50019 Sesto Fiorentino (FI), Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mannino
authors.forename: Marco
authors.initials: M
authors.lastname: Nievo
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Machetti
authors.forename: Athanasios
authors.initials: A
authors.lastname: Papakyriakou
authors.forename: Vito
authors.initials: V
authors.lastname: Calderone
authors.forename: Marco
authors.initials: M
authors.lastname: Fragai
authors.forename: Antonio
authors.initials: A
authors.lastname: Guarna
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002384:Catalysis; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D053508:Matrix Metalloproteinase 12 / Q000737:chemistry / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D013329:Structure-Activity Relationship
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D053508:Matrix Metalloproteinase 12