Synthesis and activity evaluation of benzoylurea derivatives as potential antiproliferative agents
- Bioorg Med Chem Lett. 2009 Feb 1;19(3):755-8. doi: 10.1016/j.bmcl.2008.12.020.
- 1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, 1# Tiantan Xili, Beijing 100050, China.
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-pi 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.