Effective inhibition of acid and neutral ceramidases by novel B-13 and LCL-464 analogues

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.

In this study we describe the design and synthesis of a series of modified B-13 and LCL-464 analogues with different substituents as inhibitors of recombinant acid and neutral ceramidases. We show that the inhibition potential of B-13 could be enhanced both in in vitro and in intact cells by suitable modification of functional groups. Furthermore, a detailed SAR investigation on LCL-464 analogues revealed some potent compounds for the inhibition of both aCDase and nCDase with the elevation of ceramide level.Figure optionsDownload as PowerPoint slide