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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

Synthetic route to the aCDase inhibitors DP24 a–c and DP25 a,c. Reagents and conditions: (i) triethylamine, r.t., 2–6 hrs; (ii) H2, Pd/C, methanol, r.t., 16 hrs; (iii) myristoyl chloride, pyridine, 4 hrs; (iv) tetradecyl isocyanate, acetonitrile/chloroform, r.t. 6 hrs.
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fig4: Synthetic route to the aCDase inhibitors DP24 a–c and DP25 a,c. Reagents and conditions: (i) triethylamine, r.t., 2–6 hrs; (ii) H2, Pd/C, methanol, r.t., 16 hrs; (iii) myristoyl chloride, pyridine, 4 hrs; (iv) tetradecyl isocyanate, acetonitrile/chloroform, r.t. 6 hrs.

Mentions: The retrosynthetic analysis revealed three variable moieties, an aromatic part (Ar), a nitrogen-bound substituent R2, and a nitrocomponent (O2N–CH2–R1). The simplest organic nitro component is nitromethane (R1 = H), leading to bases of type 3 (Figure 4). In our initial activity screening, the B-13 analogue DP24a displayed a remarkable inhibitory activity towards the recombinant human aCDase (Figure 5). In a more detailed study, the IC50 value was determined at 1.287 μM (Figure 6).


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

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

Synthetic route to the aCDase inhibitors DP24 a–c and DP25 a,c. Reagents and conditions: (i) triethylamine, r.t., 2–6 hrs; (ii) H2, Pd/C, methanol, r.t., 16 hrs; (iii) myristoyl chloride, pyridine, 4 hrs; (iv) tetradecyl isocyanate, acetonitrile/chloroform, r.t. 6 hrs.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: Synthetic route to the aCDase inhibitors DP24 a–c and DP25 a,c. Reagents and conditions: (i) triethylamine, r.t., 2–6 hrs; (ii) H2, Pd/C, methanol, r.t., 16 hrs; (iii) myristoyl chloride, pyridine, 4 hrs; (iv) tetradecyl isocyanate, acetonitrile/chloroform, r.t. 6 hrs.
Mentions: The retrosynthetic analysis revealed three variable moieties, an aromatic part (Ar), a nitrogen-bound substituent R2, and a nitrocomponent (O2N–CH2–R1). The simplest organic nitro component is nitromethane (R1 = H), leading to bases of type 3 (Figure 4). In our initial activity screening, the B-13 analogue DP24a displayed a remarkable inhibitory activity towards the recombinant human aCDase (Figure 5). In a more detailed study, the IC50 value was determined at 1.287 μM (Figure 6).

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