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 μM) 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).
Synthesis of Bicyclic Molecular Scaffolds (BTAa) for the Development of New Matrix Metalloproteinases Inhibitors / C. Mannino; M. Nievo; F. Machetti; A.Papakyriakou; V. Calderone; M. Fragai; A. Guarna. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 1464-3391. - STAMPA. - 14:(2006), pp. 7392-7403. [10.1016/j.bmc.2006.07.028]
Synthesis of Bicyclic Molecular Scaffolds (BTAa) for the Development of New Matrix Metalloproteinases Inhibitors
MACHETTI, FABRIZIO;CALDERONE, VITO;FRAGAI, MARCO;GUARNA, ANTONIO
2006
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 μM) 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).File | Dimensione | Formato | |
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