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 derivative, reaction with urea and aminolytic deprotection to yield 3-aminobenzoylurea, followed by unconventional haloacetylation. Three key factors were found essential for antitumor activity: (i) the cytotoxic nature of the halogen: I > Br > Cl > F (ID90 0.014->10 microM); (ii) the position of the halogen: only the 3-position (meta) expressed relevant activity; and (iii) the presence of the urea group (1-position). The selectivity of the bromo and iodo compounds were higher than those of vinblastine and paclitaxel in terms of cytotoxicity (ID50 ratios in nonmalignant myocardial fibroblasts and CEM leukemia cells) and therapeutic indices (P338 leukemia bearing mice). Relevant mechanisms of bioactivity were mitotic arrest and apoptosis. Complete inhibition of microtubule assembly occurred in cell-free systems (at 2.8 versus 2.1 microM for vinblastine); in contrast to paclitaxel, the target compounds did not interfere with microtubule disassembly. The strong cancericidal and antimicrotubular activities of the bromine and iodine compounds justify further exploration of their potential in antineoplastic chemotherapy.
Jiang
J D
JD
Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Roboz
J
J
Weisz
I
I
Deng
L
L
Ma
L
L
Holland
J F
JF
Bekesi
J G
JG
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis
D000970:Antineoplastic Agents; D014508:Urea