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A series of new pentabromobenzylisothioureas [ZKK-1-ZKK-5; (ZKKs)] carrying additional substituents on nitrogen atoms has been synthesized. The ZKKs were found to induce apoptosis in HL-60 (human promyleocytic leukemia) and K-562 (human chronic erythromyeloblastoid leukemia) cell lines in a concentration-dependent manner at low micromolar concentrations. ZKK-3 [(N,N'-dimethyl-S-2,3,4,5,6-pentabromobenzyl)isothiouronium bromide] showed the highest proapoptotic activity in HL-60 cells, whereas ZKK-2 [N-methyl-S-(2,3,4,5,6-pentabromobenzyl)isothiouronium bromide] was most effective in this respect in K-562 cells. During the ZKKs-induced apoptosis, an 85 kDa fragment of cleaved PARP (caspase-3 and caspase-7 substrate) was detected in both cell lines tested. The studied compounds also decreased mitochondrial transmembrane potential in both these cell lines and caused the cells to accumulate in G(1) and at the G(1)/S border of the cell cycle in a concentration-dependent manner. These results show promise for their study as new compounds in the treatment of leukemia, after an appropriate preclinical toxicity profile.