Targeting (cellular) lysosomal acid ceramidase by B13: design, synthesis and evaluation of novel DMG-B13 ester prodrugs

Bioorg Med Chem. 2014 Dec 15;22(24):6933-44. doi: 10.1016/j.bmc.2014.10.025. Epub 2014 Oct 22.

Abstract

Acid ceramidase (ACDase) is being recognized as a therapeutic target for cancer. B13 represents a moderate inhibitor of ACDase. The present study concentrates on the lysosomal targeting of B13 via its N,N-dimethylglycine (DMG) esters (DMG-B13 prodrugs). Novel analogs, the isomeric mono-DMG-B13, LCL522 (3-O-DMG-B13·HCl) and LCL596 (1-O-DMG-B13·HCl) and di-DMG-B13, LCL521 (1,3-O, O-DMG-B13·2HCl) conjugates, were designed and synthesized through N,N-dimethyl glycine (DMG) esterification of the hydroxyl groups of B13. In MCF7 cells, DMG-B13 prodrugs were efficiently metabolized to B13. The early inhibitory effect of DMG-B13 prodrugs on cellular ceramidases was ACDase specific by their lysosomal targeting. The corresponding dramatic decrease of cellular Sph (80-97% Control/1h) by DMG-B13 prodrugs was mainly from the inhibition of the lysosomal ACDase.

Keywords: Acid ceramidase; B13; Cancer; DMG-B13 prodrugs; Inhibitors; Lysosomes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acid Ceramidase / antagonists & inhibitors*
  • Acid Ceramidase / genetics
  • Acid Ceramidase / metabolism
  • Amides / chemistry*
  • Amides / metabolism
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Esters
  • HeLa Cells
  • Humans
  • Lysosomes / enzymology
  • MCF-7 Cells
  • Nitrobenzenes / chemistry*
  • Nitrobenzenes / metabolism
  • Prodrugs / chemical synthesis*
  • Prodrugs / chemistry
  • Prodrugs / metabolism
  • Propanolamines / chemistry*
  • Propanolamines / metabolism
  • Protein Binding

Substances

  • Amides
  • DMG-B13
  • Enzyme Inhibitors
  • Esters
  • N-(1-(4-nitrophenyl)-1,3-dihydroxyprop-2-yl)tetradecanamide
  • Nitrobenzenes
  • Prodrugs
  • Propanolamines
  • Acid Ceramidase