Synthesis and Biological Evaluation of 2-Amino-3-(3‘,4‘,5‘-trimethoxybenzoyl)-5-aryl Thiophenes as a New Class of Potent Antitubulin Agents

• Published in: Journal of medicinal chemistry 2006-06, Vol.49 (13), p.3906-3915
• Main Authors: Romagnoli, Romeo, Baraldi, Pier Giovanni, Pavani, Maria Giovanna, Tabrizi, Mojgan Aghazadeh, Preti, Delia, Fruttarolo, Francesca, Piccagli, Laura, Jung, M. Katherine, Hamel, Ernest, Borgatti, Monica, Gambari, Roberto
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Benzoates - chemical synthesis; Benzoates - chemistry; Benzoates - pharmacology; Biological and medical sciences; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Colchicine - chemistry; Drug Screening Assays, Antitumor; General aspects; Humans; Medical sciences; Mice; Models, Molecular; Pharmacology. Drug treatments; Protein Binding; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; Tubulin - chemistry; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm060355e

A new series of compounds in which the 2-amino-5-chlorophenyl ring of phenstatin analogue 7 was replaced with a 2-amino-5-aryl thiophene was synthesized and evaluated for antiproliferative activity and for inhibition of tubulin polymerization and colchicine binding to tubulin. 2-Amino-3-(3‘,4‘,5‘-trimethoxybenzoyl)-5-phenyl thiophene (9f) as well as the p-fluoro-, p-methyl-, and p-methoxyphenyl substituted analogues (9i, j, and l, respectively) displayed high antiproliferative activities with IC50 values from 2.5 to 6.5 nM against the L1210 and K562 cell lines. Compounds 9i and j were more active than combretastatin A-4 as inhibitors of tubulin polymerization. Molecular docking simulations to the colchicine site of tubulin were performed to determine the possible binding mode of 9i. The results obtained demonstrated that antiproliferative activity correlated well with the inhibition of tubulin polymerization and the lengthening of the G2/M phase of the cell cycle. Moreover, a good correlation was found between these inhibitory effects and the induction of apoptosis in cells treated with the compounds.