Identification and biological evaluation of novel benzothiazole derivatives bearing a pyridine-semicarbazone moiety as apoptosis inducers activation of procaspase-3 to caspase-3.

Three series of compounds were designed, synthesized and evaluated for their anticancer activity against a procaspase-3 over-expression cancer cell line (U937) and a procaspase-3 no-expression cancer cell line (MCF-7) to rule out off-target effects. Biological evaluation led to the identification of a series of benzothiazole derivatives bearing a pyridine-semicarbazone moiety, and , with promising anticancer activity and remarkable selectivity. Further mechanism studies revealed that compounds and could induce apoptosis of cancer cells by activating procaspase-3 to caspase-3, and compound exhibited the strongest procaspase-3 activation activity. Structure-activity relationships (SARs) revealed that the presence of benzothiazole and an ,,-donor set is crucial for the anticancer activity and selectivity, and reducing the electron density of the ,,-donor set results in a dramatic decline in the anticancer activity and selectivity. Furthermore, toxicity evaluation (zebrafish) and metabolic stability studies (human, rat and mouse liver microsomes) were performed to provide reliable guidance for further PK/PD studies .