Limits...
Potent inhibition of Acid ceramidase by novel B-13 analogues.

Proksch D, Klein JJ, Arenz C - J Lipids (2010)

Bottom Line: However, introduction of weakly basic groups at the ω-position of the fatty acid moiety of B-13 led to a significant reduction of potency towards acid ceramidase from cellular extracts.Herein, we report a novel B-13-derived scaffold for more effective inhibitors of acid ceramidase.Furthermore, we provide hints for an introduction of basic functional groups at an alternative site of the B-13 scaffold that do not interfere with acid ceramidase inhibition in vitro.

View Article: PubMed Central - PubMed

Affiliation: Institut für Chemie, Humboldt Universität zu Berlin, Brook-Taylor-Str 2, 12489 Berlin, Germany.

ABSTRACT
The lipid-signalling molecule ceramide is known to induce apoptosis in a variety of cell types. Inhibition of the lysosomal acid ceramidase can increase cellular ceramide levels and thus induce apoptosis. Indeed, inhibitors of acid ceramidase have been reported to induce cell death and to display potentiating effects to classical radio- or chemo therapy in a number of in vitro and in vivo cancer models. The most potent in vitro inhibitor of acid ceramidase, B-13, recently revealed to be virtually inactive towards lysosomal acid ceramidase in living cells. In contrast, a number of weakly basic B-13 analogues have been shown to accumulate in the acidic compartments of living cells and to efficiently inhibit lysosomal acid ceramidase. However, introduction of weakly basic groups at the ω-position of the fatty acid moiety of B-13 led to a significant reduction of potency towards acid ceramidase from cellular extracts. Herein, we report a novel B-13-derived scaffold for more effective inhibitors of acid ceramidase. Furthermore, we provide hints for an introduction of basic functional groups at an alternative site of the B-13 scaffold that do not interfere with acid ceramidase inhibition in vitro.

No MeSH data available.


Related in: MedlinePlus

Some of the basic analogues of D-MAPP and B-13 developed by Gatt et al. (LCL 204, LCL 385) and by Bielawska et al. (LCL 464).
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3066644&req=5

fig2: Some of the basic analogues of D-MAPP and B-13 developed by Gatt et al. (LCL 204, LCL 385) and by Bielawska et al. (LCL 464).

Mentions: Because of their potential as anticancer drugs, several novel ceramidase inhibitors have been developed recently. From a collection of NOE analogues, two compounds not only inhibited aCDase in cell culture (IC50 ~ 15 μM), but at the same time exhibited cytotoxicity to A549 cells (IC50 ~ 40 μM) [29, 30]. The screening of these potential CDase inhibitors has been facilitated by a fluorescent ceramidase probe allowing for high-throughput screening of CDase inhibitors in vitro and in cell culture [31]. In an effort to improve the activity of B-13 and D-MAPP in vitro and in cell culture, Bielawska and colleagues recently conducted several very detailed and interesting studies. In an attempt to develop aCDase inhibitors that accumulate in lysosomes, B-13 and D-MAPP analogues carrying basic functional groups have been evaluated (Figure 2) [32–34]. Several of these compounds were synthesized before in the group of Shimon Gatt [35, 36].


Potent inhibition of Acid ceramidase by novel B-13 analogues.

Proksch D, Klein JJ, Arenz C - J Lipids (2010)

Some of the basic analogues of D-MAPP and B-13 developed by Gatt et al. (LCL 204, LCL 385) and by Bielawska et al. (LCL 464).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3066644&req=5

fig2: Some of the basic analogues of D-MAPP and B-13 developed by Gatt et al. (LCL 204, LCL 385) and by Bielawska et al. (LCL 464).
Mentions: Because of their potential as anticancer drugs, several novel ceramidase inhibitors have been developed recently. From a collection of NOE analogues, two compounds not only inhibited aCDase in cell culture (IC50 ~ 15 μM), but at the same time exhibited cytotoxicity to A549 cells (IC50 ~ 40 μM) [29, 30]. The screening of these potential CDase inhibitors has been facilitated by a fluorescent ceramidase probe allowing for high-throughput screening of CDase inhibitors in vitro and in cell culture [31]. In an effort to improve the activity of B-13 and D-MAPP in vitro and in cell culture, Bielawska and colleagues recently conducted several very detailed and interesting studies. In an attempt to develop aCDase inhibitors that accumulate in lysosomes, B-13 and D-MAPP analogues carrying basic functional groups have been evaluated (Figure 2) [32–34]. Several of these compounds were synthesized before in the group of Shimon Gatt [35, 36].

Bottom Line: However, introduction of weakly basic groups at the ω-position of the fatty acid moiety of B-13 led to a significant reduction of potency towards acid ceramidase from cellular extracts.Herein, we report a novel B-13-derived scaffold for more effective inhibitors of acid ceramidase.Furthermore, we provide hints for an introduction of basic functional groups at an alternative site of the B-13 scaffold that do not interfere with acid ceramidase inhibition in vitro.

View Article: PubMed Central - PubMed

Affiliation: Institut für Chemie, Humboldt Universität zu Berlin, Brook-Taylor-Str 2, 12489 Berlin, Germany.

ABSTRACT
The lipid-signalling molecule ceramide is known to induce apoptosis in a variety of cell types. Inhibition of the lysosomal acid ceramidase can increase cellular ceramide levels and thus induce apoptosis. Indeed, inhibitors of acid ceramidase have been reported to induce cell death and to display potentiating effects to classical radio- or chemo therapy in a number of in vitro and in vivo cancer models. The most potent in vitro inhibitor of acid ceramidase, B-13, recently revealed to be virtually inactive towards lysosomal acid ceramidase in living cells. In contrast, a number of weakly basic B-13 analogues have been shown to accumulate in the acidic compartments of living cells and to efficiently inhibit lysosomal acid ceramidase. However, introduction of weakly basic groups at the ω-position of the fatty acid moiety of B-13 led to a significant reduction of potency towards acid ceramidase from cellular extracts. Herein, we report a novel B-13-derived scaffold for more effective inhibitors of acid ceramidase. Furthermore, we provide hints for an introduction of basic functional groups at an alternative site of the B-13 scaffold that do not interfere with acid ceramidase inhibition in vitro.

No MeSH data available.


Related in: MedlinePlus