901118-42-1Relevant articles and documents
Synthesis of novel antimitotic agents based on 2-amino-3-aroyl-5-(hetero) arylethynyl thiophene derivatives
Romagnoli, Romeo,Baraldi, Pier Giovanni,Cruz-Lopez, Olga,Tolomeo, Manlio,Cristina, Antonietta Di,Pipitone, Rosaria Maria,Grimaudo, Stefania,Balzarini, Jan,Brancale, Andrea,Hamel, Ernest
supporting information; scheme or table, p. 2746 - 2751 (2011/06/22)
Microtubules are dynamic structures that play a crucial role in cellular division and are recognized as an important target for cancer therapy. In search of new compounds with strong antiproliferative activity and simple molecular structure, a new series of 2-amino-3-(3′,4′,5′- trimethoxybenzoyl)-5-(hetero)aryl ethynyl thiophene derivatives was prepared by the Sonogashira coupling reaction of the corresponding 5-bromothiophenes with several (hetero)aryl acetylenes. When these compounds were analyzed in vitro for their inhibition of cell proliferation, the 2- and 3-thiophenyl acetylene derivatives were the most powerful compounds, both of which exerted cytostatic effects at submicromolar concentrations. In contrast, the presence of a more flexible ethyl chain between the (hetero)aryl and the 5-position of the thiophene ring resulted in significant reduction in activity relative to the 5-(hetero)aryl acetylene substituted derivatives. The effects of a selected series of compounds on cell cycle progression correlated well with their strong antiproliferative activity and inhibition of tubulin polymerization. We found that the antiproliferative effects of the most active compounds were associated with increase of the proportion of cells in the G2/M and sub-G 1 phases of the cell cycle.
Synthesis and biological evaluation of 2-amino-3-(3′,4′, 5′-trimethoxybenzoyl)-5-aryl thiophenes as a new class of potent antitubulin agents
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
, p. 3906 - 3915 (2007/10/03)
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 I, 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.
