Ceramide-like synthetic amides that inhibit cerebroside galactosidase

Abstract

Amides resembling ceramide (fatty acyl sphingosine) were synthesized and tested for their effects on rat brain cerebrosidase (galactosyl ceramide β-galactosidase). The best inhibitor was N-decanoyl dl-erythro-3-phenyl-2-aminopropanediol, which exhibited a Ki, of 0.4 mm. A Lineweaver-Burk plot indicated that the amide acted as a noncompetitive inhibitor, presumably by attachment to a site other than the substrate-active site. Preincubation did not affect the degree of inhibition, and inhibition was independent of incubation duration; these observations suggest that the inhibitor does not combine with the enzyme irreversibly. Structural variations produced decreased inhibitory activity: loss of one of the hydroxyl groups, replacement of the aromatic side chain with an aliphatic or substituted phenyl group, or isomeric inversion of the 3-hydroxyl group. It appears that the best activity is obtained with a substance most closely resembling natural ceramide. The cerebrosidases of rat spleen, kidney, and liver are also inhibited by the same amide.

Keywords

• N-decanoyl 3-phenyl-2-aminopropane-1,3-diol and homologs
• N-decanoyl 3-phenyl-2-amino-propan-3-ol and homologs
• N-decanoyl 3-phenyl-2-amino-propan-1-ol and homologs
• N-decanoyl 3-(p-nitrophenyl)-2-amino-propane-1,3-diol
• N-decanoyl 3-(m-nitrophenyl)-2-amino-propane-1,3-diol
• N-decanoyl 3-(p-biphenyl)-2-amino-propane-1,3-diol