title: Synthesis and activity evaluation of benzoylurea derivatives as potential antiproliferative agents.
abstract: 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.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, 1# Tiantan Xili, Beijing 100050, China.
authors.forename: Dan-Qing
authors.initials: DQ
authors.lastname: Song
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Wang
authors.forename: Na-Na
authors.initials: NN
authors.lastname: Du
authors.forename: Wei-Ying
authors.initials: WY
authors.lastname: He
authors.forename: Ke-Liang
authors.initials: KL
authors.lastname: Chen
authors.forename: Gui-Fang
authors.initials: GF
authors.lastname: Wang
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.forename: Lian-Zong
authors.initials: LZ
authors.lastname: Wu
authors.forename: Xue-Bo
authors.initials: XB
authors.lastname: Zhang
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002264:Carboxylic Acids / Q000737:chemistry; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D008938:Mitosis; D008956:Models, Chemical; D008968:Molecular Conformation; D009369:Neoplasms / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D002264:Carboxylic Acids; D014508:Urea