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2-Alkoxycarbonyl-3-arylamino-5-substituted thiophenes as a novel class of antimicrotubule agents: Design, synthesis, cell growth and tubulin polymerization inhibition.

Abstract：

:Microtubules are recognized as crucial components of the mitotic spindle during cell division, and, for this reason, the microtubule system is an attractive target for the development of anticancer agents. Continuing our search strategy for novel tubulin targeting-compounds, a new series of 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)-5-aryl/heteroarylthiophene derivatives was designed, synthesized and demonstrated to act as tubulin polymerization inhibitors at the colchicine site. A structure-activity relationship study on the phenyl at the 5-position of the thiophene ring was performed by introducing a variety of substituents containing electron-releasing and electron-withdrawing groups, with the 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold being the minimum structural requirement for activity. Of the tested compounds, derivatives 4a, 4c, 4i and 4k possessed the highest overall potency and displayed high antiproliferative activities at submicromolar concentrations, with IC50 values ranging from 0.13 to 0.84 μM against four different cancer cell lines. Three agents (4a, 4c and 4i) in the present series had similar effects, and these were comparable to those of the reference compound combretastatin A-4 (CA-4) as inhibitors of tubulin assembly. The antitubulin effects correlated with the cytostatic activities and indicate that these compounds inhibit cell growth through inhibition of tubulin polymerization by binding at the colchicine site. Compound 4c, containing the 2'-thienyl ring at the 5-position of the 2-methoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold, exhibited substantial antiproliferative activity with a mean IC50 value of 140 nM, inhibited tubulin polymerization with an IC50 value of 1.2 μM, similar to that of CA-4 (IC50: 1.1 μM), and induced apoptosis in HeLa cells.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Romagnoli R,Kimatrai Salvador M,Schiaffino Ortega S,Baraldi PG,Oliva P,Baraldi S,Lopez-Cara LC,Brancale A,Ferla S,Hamel E,Balzarini J,Liekens S,Mattiuzzo E,Basso G,Viola G

doi

10.1016/j.ejmech.2017.11.096

subject

Has Abstract

pub_date

2018-01-01 00:00:00

pages

683-698

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(17)30999-6

journal_volume

143

pub_type

杂志文章

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2-Alkoxycarbonyl-3-arylamino-5-substituted thiophenes as a novel class of antimicrotubule agents: Design, synthesis, cell growth and tubulin polymerization inhibition.