Benzoylurea Derivatives as a Novel Class of Antimitotic Agents: Synthesis, Anticancer Activity, and Structure-Activity Relationships.

[摘要]：Forty-six new compds. I (R1 = H, 2-Me, 4-MeO, 6-Br, 5-COOMe, etc.; R2 = CH2Br, CH2Cl, CH2I, CHBrMe, CHClMe) and II (X = O, S) were synthesized as 3-haloacylamino benzoylurea analogs and their anticancer activity has been studied. Structure-activity relationship (SAR) anal. indicated that (i) the configuration of the chiral center in I (R1 = H; R2 = CHBrMe) is not indispensable for the activity, (ii) the Ph ring is essential, and (iii) a substitution at the 6-position of the Ph ring with a halogen enhances the activity. Among the analogs, I (R1 = 6-F; R2 = CH2Br, CH2I) bearing 6-fluoro substituent 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 mM. I (R1 = 6-F; R2 = CH2I) inhibited human hepatocarcinoma by 86% in vol. in nude mice. The mechanism of action for this compd. is to inhibit microtubule assembly, followed by the M-phase arrest, bcl-2 inactivation, and then apoptosis.

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