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Inhibition of Microtubule Assembly in Tumor Cells by 3-Bromoacetylamino Benzoylurea, a New Cancericidal Compound¹

Division of Neoplastic Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029

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 µg/ml (0.04–0.22 µM). 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.

¹ This work was supported by the T. J. Martell Memorial Foundation for Leukemia, Cancer and AIDS Research.

² To whom requests for reprints should be addressed, at Mount Sinai School of Medicine, Box 1131, One Gustave Levy Place, New York, NY 10029. Phone: (212) 241-8245; Fax: (212) 996-9801.

Received 10/ 1/97. Accepted 3/16/98.

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