Benzoylurea Derivatives as a Novel Class of Antimitotic Agents: Synthesis, Anticancer Activity, and Structure−Activity Relationships
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- 作者：Dan-Qing Song ; Yan Wang ; Lian-Zong Wu ; Peng Yang ; Yue-Ming Wang ; Li-Mei Gao ; Yan Li ; Jing-Rong Qu ; Yong-Hong Wang ; Ying-Hong Li ; Na-Na Du ; Yan-Xing Han ; Zhi-Ping Zhang ; Jian-Dong Jiang
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：June 12, 2008
- 年：2008
- 卷：51
- 期：11
- 页码：3094 - 3103
- 全文大小：436K
- 年卷期：v.51,no.11(June 12, 2008)
- ISSN：1520-4804
文摘
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 IC50 values between 0.01 and 0.30 µM. 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.