α-卤代丁二酰氧肟酸类基质金属蛋白酶抑制剂的合成及活性评价  

Synthesis and Activity Evaluation of α-Halogen Substituted Succinate-based Hydroxamic Acids as Matrix Metalloproteases Inhibitors

作　　者：韩寒[1] 梁远军[1] 魏晓莉[1] 许笑宇[1] 刘克良[1] 

机构地区：[1]军事医学科学院毒物药物研究所,北京100850

出　　处：《高等学校化学学报》2009年第1期72-77,共6页Chemical Journal of Chinese Universities

摘　　要：基质金属蛋白酶(MMPs)是一族Zn2+依赖的蛋白水解酶.该族酶的过度表达与多种病理过程密切相关,因此其抑制剂可用于这些疾病的治疗.本文设计合成了15个α-卤代丁二酰氧肟酸类新型基质金属蛋白酶抑制剂,经核磁共振氢谱和质谱进行了结构表征,并以伊洛马司他(Ilomastat)为阳性对照,分别测定了它们对基质金属蛋白酶MMP-2和MMP-9的体外抑制活性.结果显示,4个化合物对MMP-2的抑制活性与阳性对照相当;5个化合物对MMP-9的抑制活性与对照药相当.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 a-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 RE 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.

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 

分 类 号：O622.2[理学—有机化学]