关键词: 基质金属蛋白酶抑制剂, 丁二酰氧肟酸, 伊洛马司他, 抑制活性

Abstract: Matrix metalloproteinases(MMPs) are a family of zinc-dependent proteolytic enzymes. The overexpression of these proteinases is associated with a number of pathological processes.Thus, matrix metalloprotease inhibitors(MMPIs) are expected to be useful for the treatment of these disorders. Fifteen novel α-halogen substituted succinate-based hydroxamic acid analoges were designed and synthesized as MMPIs. Introducing halogen to the α-position of hydroxamic acid is expected to potentialize compounds' inhibitory activity and lipophilicify. All of new compounds' inhibitory activities against MMP-2 and MMP-9 were tested in vitro. Among these compounds, four of them exhibited similar inhibitory activities against MMP-2 and five of them showed similar inhibitory activities against MMP-9 comparing, respectively, with positive control, Ilomastat. The activity results indicate the following SAR: (1) It seems that introducing halogen doesn't have significant effect on inhibitory activity. (2) Configuration of the new chiral centre arising from introducing halogen perhaps has nothing to do with the inhibitory activity. (3) Compouds possessing hydrophilic groups as the R₂ substituents appeared to have improved potency as compared to those with hydrophobic groups as the R₂ substituents. (4) Planar fused-ring aryl groups as the R₃ substituents perhaps facilitate improving compounds' inhibitory activity.

Key words: Matrix metalloproteinase inhibitors, Succinate-based hydroxamic acids, Ilomastat, Inhibitory activity