Hybrid molecules containing benzo[4,5]imidazo[1,2-d][1,2,4]thiadiazole and alpha-bromoacryloyl moieties as potent apoptosis inducers on human myeloid leukaemia cells

The synthesis and biol. activity of a series of hybrids I (n = 3, 6; X = NH, NMe, O, S) prepd. combining a benzo[4,5]imidazo[1,2-d][1,2,4]thiadiazole and different benzoheterocyclic -bromoacryloyl amides have been described and their structure-activity relationships discussed. All these hetero-bifunctional compds. were highly cytotoxic against the human myeloid leukemia cell lines HL-60 and U937 (IC50 0.24-1.72 M), significantly superior to that of both alkylating units alone. In human myeloid leukemia HL-60 cells we obsd. that these compds. suppress survival and proliferation by triggering morphol. changes and internucleosomal DNA fragmentation characteristic of apoptotic cell death. The apoptosis induced by these compds. is mediated by caspase-3 activation and is also assocd. to an early release of cytochrome c from the mitochondria