title: Benzoylurea derivatives as a novel class of antimitotic agents: synthesis, anticancer activity, and structure-activity relationships.
abstract: Forty-six new compounds were synthesized on the basis of our knowledge of the 3-haloacylamino benzoylurea (HBU) series. Structure-activity relationship (SAR) analysis indicates that (i) the configuration of the chiral center in 1 (JIMB01) is not indispensable for the activity, (ii) the phenyl ring is essential, and (iii) a substitution at the 6-position of the phenyl ring with a halogen enhances the activity. Among the analogues, 11e and 14b bearing 6-fluoro substitution showed potent activities against nine human tumor cell lines, including CEM (leukemia), Daudi (lymphoma), MCF-7 (breast cancer), Bel-7402 (hepatoma), DU-145 (prostate cancer), PC-3 (prostate cancer), DND-1A(melanoma), LOVO (colon cancer), and MIA Paca (pancreatic cancer) with IC 50 values between 0.01 and 0.30 microM. 14b inhibited human hepatocarcinoma by 86% in volume in nude mice. The mechanism of 14b is to inhibit microtubule assembly, followed by the M-phase arrest, bcl-2 inactivation, and then apoptosis. We consider 14b promising for further anticancer investigation.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Dan-Qing
authors.initials: DQ
authors.lastname: Song
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Lian-Zong
authors.initials: LZ
authors.lastname: Wu
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Wang
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Gao
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Jing-Rong
authors.initials: JR
authors.lastname: Qu
authors.forename: Yong-Hong
authors.initials: YH
authors.lastname: Wang
authors.forename: Ying-Hong
authors.initials: YH
authors.lastname: Li
authors.forename: Na-Na
authors.initials: NN
authors.lastname: Du
authors.forename: Yan-Xing
authors.initials: YX
authors.lastname: Han
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Zhang
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
mesh_terms: D000083:Acetanilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C530301:6-fluoro-3-(iodoacetamido)benzoylurea; D000083:Acetanilides; D050256:Antimitotic Agents; D014508:Urea