Design, synthesis, and evaluation of novel galloyl pyrrolidine derivatives as potential anti-tumor agents

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 C4 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 (IC50 = 0.9 nM). The anti-metastasis model of mice bearing H22 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.

A series of novel C-2 substituted carbomethoxy (4–17) and hydroximic acid (18–20) derivatives of galloyl pyrrolidine were synthesized and evaluated for their in vitro inhibitory activities against gelatinase (MMP-2, -9) and in vivo anti-tumor activities.Figure optionsDownload as PowerPoint slide