Induction of apoptosis mediated by the inhibition of
ceramidases has been shown to enhance the efficacy of conventional
chemotherapy in several
cancer models. Among the inhibitors of
ceramidases reported in the literature, B-13 is considered as a lead compound having good in vitro potency towards
acid ceramidase. Furthermore, owing to the poor activity of B-13 on lysosoamal
acid ceramidase in living cells,
LCL-464 a modified derivative of B-13 containing a basic ω-amino group at the
fatty acid was reported to have higher potency towards lysosomal
acid ceramidase in living cells. In a search for more potent inhibitors of
ceramidases, we have designed a series of compounds with structural modifications of B-13 and
LCL-464. In this study, we show that the efficacy of B-13 in vitro as well as in intact cells can be enhanced by suitable modification of functional groups. Furthermore, a detailed SAR investigation on
LCL-464 analogues revealed novel promising inhibitors of aCDase and nCDase. In cell culture studies using the
breast cancer cell line MDA-MB-231, some of the newly developed compounds elevated endogenous
ceramide levels and in parallel, also induced apoptotic cell death. In summary, this study shows that structural modification of the known
ceramidase inhibitors B-13 and
LCL-464 generates more potent
ceramidase inhibitors that are active in intact cells and not only elevates the cellular
ceramide levels, but also enhances cell death.