(E)-4-Aryl-4-oxo-2-butenoic acid amides, chalcone–aroylacrylic acid chimeras: Design, antiproliferative activity and inhibition of tubulin polymerization

Antiproliferative activity of twenty-nine (E)-4-aryl-4-oxo-2-butenoic acid amides against three human tumor cell lines (HeLa, FemX, and K562) is reported. Compounds showed antiproliferative activity in one-digit micromolar to submicromolar concentrations. The most active derivatives toward all the cell lines tested bear alkyl substituents on the aroyl moiety of the molecules. Fourteen compounds showed tubulin assembly inhibition at concentrations <20 μM. The most potent inhibitor of tubulin assembly was unsubstituted compound 1, with IC50 = 2.9 μM. Compound 23 had an oral LD50in vivo of 45 mg/kg in mice. Cell cycle analysis on K562 cells showed that compounds 1, 2 and 23 caused accumulation of cells in the G2/M phase, but inhibition of microtubule polymerization is not the principal mode of action of the compounds. Nevertheless, they may be useful leads for the design of a new class of antitubulin agents.

Graphical abstractAroylacrylic acid amides exert antiproliferative activity in low micromolar to submicromolar concentrations. Unsubstituted compound and compounds bearing small substituents on aroyl phenyl ring inhibit tubulin polymerization in low micromolar concentrations.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Novel aroylacrylic acid amides were reported. ► Compounds have shown significant antiproliferative activity. ► Unsubstituted compound was the most potent tubulin polymerization inhibitor. ► Cell cycle analysis revealed at least two different mechanisms of action.