We have synthesized a new compound,
3-bromoacetylamino benzoylurea (3-BAABU), which showed strong cancericidal activity by inducing irreversible mitotic arrest and subsequently apoptosis in human T cell leukemic cells (CEM), human biphenotypic leukemic cells (SP), a human
prostate cancer cell line (PC-3), murine
melanoma cells (B-16), and murine
lymphoma/
leukemia cells (EL4) in vitro with an ID50 in the range of 0.013-0.07 microg/ml (0.04-0.22 microM). Treatment of
tumor cells for 12-24 h with
3-BAABU resulted in mitotic arrest at prometaphase/metaphase/anaphase, with separation and dispersion of chromosomes and with the absence of mitotic spindle apparatus in cytoplasm. Treatment with
3-BAABU had no cytotoxic and mitotic blocking effect in normal human lymphocytes, proliferating fibroblast cells (3T3), or proliferating myocardial cells (MOT). Cell cycle analyses showed that most treated leukemic cells accumulated at M phase 12 h
after treatment. By the end of 48 h of treatment, the cells underwent apoptosis with DNA fragmentation.
3-BAABU inhibited the assembly of microtubules from
tubulin but did not interfere with the disassembly of microtubules. The presence and the position of
bromine and
urea groups on the benzoic ring are the determining factors for its inhibition of microtubule assembly. Replacing
bromine with
chlorine yielded much less mitotic blocking activity and increased the ID50 40-fold. Substitution of the
urea group with ethyl
ester abrogated the activity of blocking mitosis but induced apoptosis. Moving the bromoacetylamino group from the 3-position to the 4-position removed blocking activity for mitosis but induced
necrosis. These results suggest that
3-BAABU possesses a unique and functional structure and is a potential agent for
cancer chemotherapy.