Li Xun, Li Yalin, Xu Wenfang
College of Pharmacy, Shandong University, Ji'nan, PR China.
Bioorg Med Chem. 2006 Mar 1;14(5):1287-93. doi: 10.1016/j.bmc.2005.09.031. Epub 2005 Oct 4.
A series of novel galloyl pyrrolidine derivatives were synthesized as potential anti-tumor agents. Their inhibiting activities on gelatinase (MMP-2 and -9) were tested with succinylated gelatin as the substrate. Structure-activity analyses demonstrate that introduction of longer and more flexible side chains at the C(4) position of the pyrrolidine ring brings higher activity against gelatinase. Free phenol hydroxyl group is more favorable than the methylated one, which confirms the important role of the phenol hydroxyl group when inhibitors interact with gelatinase. In particular, (2S,4S)-4-(3-(3,4-dimethoxyphenyl)acrylamido)-N-hydroxy-1-(3,4,5- trimethoxybenzoyl)pyrrolidine-2-carboxamide (18) stood out as the most attractive compound (IC(50) = 0.9 nM). The anti-metastasis model of mice bearing H(22) tumor cells was used to evaluate their anti-tumor activities in vivo. The assay in vivo revealed that most of these inhibitors displayed favorable inhibitory activities (inhibitory rate >35%) and no significant toxic effects were observed. The inhibition for 62.37% of 19 indicates the strategy used to design MMP inhibitors (MMPIs) of galloyl pyrrolidine derivatives as potential anti-tumor agents is promising.
合成了一系列新型没食子酰基吡咯烷衍生物作为潜在的抗肿瘤药物。以琥珀酰化明胶为底物测试了它们对明胶酶（MMP - 2和 - 9）的抑制活性。构效分析表明，在吡咯烷环的C(4)位引入更长且更具柔性的侧链会带来更高的抗明胶酶活性。游离酚羟基比甲基化酚羟基更有利，这证实了抑制剂与明胶酶相互作用时酚羟基的重要作用。特别地，(2S,4S)-4-(3-(3,4 - 二甲氧基苯基)丙烯酰胺基)-N - 羟基 - 1-(3,4,5 - 三甲氧基苯甲酰基)吡咯烷 - 2 - 甲酰胺（18）作为最具吸引力的化合物脱颖而出（IC(50) = 0.9 nM）。利用荷H(22)肿瘤细胞小鼠的抗转移模型评估了它们在体内的抗肿瘤活性。体内试验表明，这些抑制剂中的大多数表现出良好的抑制活性（抑制率>35%），且未观察到明显的毒性作用。19号化合物62.37%的抑制率表明，将没食子酰基吡咯烷衍生物设计为潜在抗肿瘤药物的MMP抑制剂（MMPIs）的策略是有前景的。
