Design, synthesis, and activity of caffeoyl pyrrolidine derivatives 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 100mg/kg, 6days/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.
Li
Ya-Lin
YL
Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Jinan, Shandong 250012, PR China.
Xu
Wen-Fang
WF
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002109:Caffeic Acids / Q000138:chemical synthesis / Q000494:pharmacology; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy / Q000473:pathology; D015195:Drug Design; D018093:Gelatinases / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000517:prevention & control / Q000556:secondary; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000517:prevention & control; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D002109:Caffeic Acids; D011759:Pyrrolidines; D018093:Gelatinases; C032519:pyrrolidine