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

Abstract

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.

• Authors: Xun Li, Yalin Li, Wenfang Xu
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 14 Issue 5 Pg. 1287-93 (Mar 01 2006) ISSN: 0968-0896 [Print] England
• PMID: 16213145 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Pyrrolidines
• Gelatinases

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology)
• Drug Design
• Gelatinases (antagonists & inhibitors)
• Inhibitory Concentration 50
• Mice
• Neoplasm Metastasis (drug therapy)
• Protein Binding
• Pyrrolidines (chemical synthesis, pharmacology)
• Structure-Activity Relationship
• Tumor Cells, Cultured