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

Retrosynthetic analysis of the B-13/D-MAPP scaffold.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3066644&req=5

fig3: Retrosynthetic analysis of the B-13/D-MAPP scaffold.

Mentions: The molecular basis of the ceramidase inhibition by D-MAPP and B-13 is still unknown. Accordingly, the possibilities for a rationallydriven synthesis of improved inhibitors are limited. Small libraries of compounds with systematically altered functional groups or stereochemistry can provide information about structural requirements for binding to ceramidases. Preceding the investigation of the structure-activity relationship (SAR) for B13-inhibiting acid ceramidase, we did a retrosynthetic analysis of the B-13/D-MAPP scaffold. It is known that the base of D-MAPP, norephedrine, can easily be obtained by nitroaldol reaction (“Henry reaction”) of nitroethane with benzaldehyde and subsequent reduction (see retrosynthetic analysis in Figure 3).


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

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

Retrosynthetic analysis of the B-13/D-MAPP scaffold.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Retrosynthetic analysis of the B-13/D-MAPP scaffold.
Mentions: The molecular basis of the ceramidase inhibition by D-MAPP and B-13 is still unknown. Accordingly, the possibilities for a rationallydriven synthesis of improved inhibitors are limited. Small libraries of compounds with systematically altered functional groups or stereochemistry can provide information about structural requirements for binding to ceramidases. Preceding the investigation of the structure-activity relationship (SAR) for B13-inhibiting acid ceramidase, we did a retrosynthetic analysis of the B-13/D-MAPP scaffold. It is known that the base of D-MAPP, norephedrine, can easily be obtained by nitroaldol reaction (“Henry reaction”) of nitroethane with benzaldehyde and subsequent reduction (see retrosynthetic analysis in Figure 3).

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