Synthesis, antiproliferative activity, and mechanism of action of a series of 2-{[(2E)-3-phenylprop-2-enoyl]amino}benzamides

Several new 2-{[(2E)-3-phenylprop-2-enoyl]amino}benzamides 12a–s and 17t–v were synthesized by stirring in pyridine the (E)-3-(2-R1-3-R2-4-R3-phenyl)acrylic acid chlorides 11c–k and 11t–v with the appropriate anthranilamide derivatives 10a–c or the 5-iodoanthranilic acid 13. Some of the synthesized compounds were evaluated for their in vitro antiproliferative activity against the full NCI tumor cell line panel derived from nine clinically isolated cancer types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast). COMPARE analysis, effects on tubulin polymerization in cells and with purified tubulin, and effects on cell cycle distribution for 17t, the most active of the series, indicate that these new antiproliferative compounds act as antitubulin agents.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► A series of 2-{[(2E)-3-phenylprop-2-enoyl]amino}benzamides was synthesized. ► Synthesized compounds were evaluated by the NCI. ► They caused 50% growth inhibition at micromolar and submicromolar concentrations. ► COMPARE algorithm predicted an antimitotic activity directed against tubulin. ► The effects on tubulin polymerization and on cell cycle distribution confirmed the antitubulin activity.