Synthesis and structure–activity relationship analysis of caffeic acid amides as selective matrix metalloproteinase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 5; pp. 1206 - 1211
• Main Authors: Shi, Zhi-Hao, Li, Nian-Guang, Shi, Qian-Ping, Tang, Hao, Tang, Yu-Ping, Li, Wei, Yin, Lian, Yang, Jian-Ping, Duan, Jin-Ao
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.03.2013; Elsevier
• Subjects: amides; Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Caffeic acid; Caffeic Acids - chemical synthesis; Caffeic Acids - chemistry; Caffeic Acids - pharmacology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Humans; Life Sciences & Biomedicine; Matrix metalloproteinase; Matrix Metalloproteinase Inhibitors - chemical synthesis; Matrix Metalloproteinase Inhibitors - chemistry; Matrix Metalloproteinase Inhibitors - pharmacology; metalloproteinases; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Structure-Activity Relationship; structure-activity relationships; Tumor; Tumor; Matrix metalloproteinase; Caffeic acid; Structure–activity relationship; METASTASIS; SPECIFICITY; ANALOGS; INTERSTITIAL COLLAGENASE; CATALYTIC DOMAIN; AMIDATION; CLEAVAGE; PHENETHYL ESTER; Structure-activity relationship; DERIVATIVES; EXTRACT
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.01.027

Four series of acid amides were synthesized, preliminary structure–activity relationship analysis indicated that caffeic acid amides with electron-donating groups at para-position of amino phenyl group showed better inhibitory activities and selectivity than those with electron-withdrawing groups, and the presence of adjacent dihydroxy in the caffeoyl group was very important for the MMP-2 and MMP-9 inhibitory activities. Four series of acid amides were synthesized, and through measurement using a fluorogenic substrate assay with human recombinant MMP-1, MMP-2 and MMP-9, compound 3f showed considerable inhibitory activities against MMP-2, MMP-9 and the best selectivity over MMP-1. Preliminary structure–activity relationship analysis indicated that caffeic acid amides with electron-donating groups at para-position of amino phenyl group showed better inhibitory activities and selectivity than those with electron-withdrawing groups, and the presence of adjacent dihydroxy in the caffeoyl group was very important for the MMP-2 and MMP-9 inhibitory activities.