Synthesis and activity evaluation of phenylurea derivatives as potent antitumor agents |
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Authors: | Dan-Qing Song Na-Na Du Yue-Ming Wang Wei-Ying He En-Zhu Jiang Shi-Xiang Cheng Yan-Xiang Wang Ying-Hong Li Yu-Ping Wang Xin Li Jian-Dong Jiang |
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Institution: | Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China |
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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 –CH2Br > –CHBrCH3; (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 IC50 values between 0.38 and 4.07 μM. 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. |
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