title: Synthesis and activity evaluation of phenylurea derivatives as potent antitumor agents.
abstract: We have discovered several tubulin-active compounds in our previous studies. In the establishment of a compound library of small molecule weight tubulin ligands, 14 new N-3-haloacylaminophenyl-N'-(alkyl/aryl) urea analogs were designed and synthesized. The structure-activity relationship (SAR) analysis revealed that (i) the order of anticancer potency for the 3-haloacylamino chain was following -CH(2)Br>-CHBrCH(3); (ii) the N'-substituent moiety was not essential for the anticancer activity, and a proper alkyl substitution might enhance the anticancer activity. Among these analogs, the compounds 16j bearing bromoacetyl at the N'-end exhibited a potent activity against eight human tumor cell lines, including CEM (leukemia), Daudi (lymphoma), MCF-7 (breast cancer), Bel-7402 (hepatoma), DU-145 (prostate cancer), DND-1A (melanoma), LOVO (colon cancer) and MIA Paca (pancreatic cancer), with the IC(50) values between 0.38 and 4.07 microM. Interestingly, compound 16j killed cancer cells with a mechanism independent of the tubulin-based mechanism, indicating a significant change of the action mode after the structure modification.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
authors.forename: Dan-Qing
authors.initials: DQ
authors.lastname: Song
authors.forename: Na-Na
authors.initials: NN
authors.lastname: Du
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Wang
authors.forename: Wei-Ying
authors.initials: WY
authors.lastname: He
authors.forename: En-Zhu
authors.initials: EZ
authors.lastname: Jiang
authors.forename: Shi-Xiang
authors.initials: SX
authors.lastname: Cheng
authors.forename: Yan-Xiang
authors.initials: YX
authors.lastname: Wang
authors.forename: Ying-Hong
authors.initials: YH
authors.lastname: Li
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D015394:Molecular Structure; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds