Synthesis and activity evaluation of benzoylurea derivatives as potential antiproliferative agents

3-Haloacylamino benzoylureas (3-HBUs) consist of a new family of tubulin ligands that kill cancer cells through mitotic arrest. In exploring the structure–activity relationship (SAR), 17 analogues defined through variations of formylurea at the 1-position of the aromatic ring were synthesized. SAR analysis revealed that (i) the p–π conjugation between the aromatic ring and formylurea was essential; (ii) suitable aryl substitutions at the N′-end increased anticancer activity with a mechanism different from that of parent compounds; and (iii) introduction of pyridyl at the N′-end provided an opportunity of making soluble salts to improve bioavailability. Among the analogues, 16c bearing 3,4,5-trimethoxyphenyl and 16g bearing 2-pyridyl at the N′-end showed an enhanced activity and were active in hepatoma cells that were resistant to tubulin ligands including the parent compounds. Furthermore, 16c and 16g killed cancer cells with a mechanism independent of mitotic arrest, indicating a change of action mode.

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