Design, synthesis, and activity of caffeoyl pyrrolidine derivatives as potential gelatinase inhibitors

• Published in: Bioorganic & medicinal chemistry 2004-10, Vol.12 (19), p.5171-5180
• Main Authors: Li, Ya-Lin, Xu, Wen-Fang
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Biological and medical sciences; Caffeic Acids - chemical synthesis; Caffeic Acids - pharmacology; Caffonyl pyrrolidine derivatives; Carcinoma, Ehrlich Tumor - drug therapy; Carcinoma, Ehrlich Tumor - pathology; Drug Design; Gelatinases - antagonists & inhibitors; General aspects; IC 50; Lung Neoplasms - drug therapy; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Male; Medical sciences; Mice; Mice, Inbred Strains; MMPs inhibitors; Neoplasm Metastasis - drug therapy; Neoplasm Metastasis - prevention & control; Pharmacology. Drug treatments; Protein Binding; Pyrrolidines - chemical synthesis; Pyrrolidines - pharmacology; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2004.07.025

A group of caffeoyl pyrrolidine derivatives has been developed to act as potential gelatinase inhibitors. The synthesis and biological evaluation of caffonyl pyrrolidine derivatives as MMPs inhibitors are reported in this paper. Inhibiting activities of synthesized compounds on gelatinase (MMP-2 and -9) were tested by using succinylated gelatin as substrate. Structure–activity relationship results from these tested compounds demonstrated that longer and more flexible side chain linked to the pyrrolidine ring at C 4 produced higher activity at gelatinase. Furthermore, aromatic heterocycle and sulfamide in the same position could enhance the activities. Compounds with free phenol hydroxyl group showed higher activity compared to methylated derivatives (or counterparts), which confirms the importance of phenol hydroxyl functionality in the interaction with gelatinase. The anti-metastasis model of mice bearing H 22 tumor cell was used to evaluate their in vivo inhibiting activities. All tested compounds were orally administered at a dose of 50 or 100 mg/kg, 6 days/week for two weeks. The test results demonstrated that most of these inhibitors showed significant anti-cancer activities (inhibitory rate > 35%) and were devoid of toxic effects. Compound 29 showed the highest inhibitory rate at 69.25%, indicating that it might be a promising lead compound.