SYNTHESIS, CANCERICIDAL AND ANTIMICROTUBULE ACTIVITIES OF 3-(HALOACETAMIDO)-BENZOYLUREAS

The four title compounds (not hitherto reported) were synthesized from 3-aminobenzoic acid through its trifluoroacetic acid-acid chloride de rivative, reaction with urea and aminolytic deprotection to yield 3-am inobenzoylurea, followed by unconventional haloacetylation. Three key factors were found essential for antitumor activity: (i) the cytotoxic nature of the halogen: I > Pr > Cl > F (ID90 0.014-->10 mu M); (ii) t he position of the halogen: only the 3-position (meta) expressed relev ant activity; and (iii) the presence of the urea group (l-position). T he selectivity of the bromo and iodo compounds were higher than those of vinblastine and paclitaxel in terms of cytotoxicity (ID, ratios in nonmalignant myocardial fibroblasts and CEM leukemia cells) and therap eutic indices (P338 leukemia bearing mice). Relevant mechanisms of bio activity were mitotic arrest and apoptosis. Complete inhibition of mic rotubule assembly occurred in cell-free systems (at 2.8 versus 2.1 mu M for vinblastine); in contrast to paclitaxel, the target compounds di d not interfere with microtubule disassembly. The strong cancericidal and antimicrotubular activities of the bromine and iodine compounds ju stify further exploration of their potential in antineoplastic chemoth erapy.