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.
Aiping Bai  1 ,  Zdzislaw M Szulc  1 ,  Jacek Bielawski  1 ,  Jason S Pierce  1 ,  Barbara Rembiesa  1 ,  Silva Terzieva  1 ,  Cungui Mao  2 ,  Ruijuan Xu  2 ,  Bill Wu  3 ,  Christopher J Clarke  2 ,  Benjamin Newcomb  2 ,  Xiang Liu  4 ,  James Norris  4 ,  Yusuf A Hannun  5 ,  Alicja Bielawska  6
Affiliations
  • 1. Department of Biochemistry & Molecular Biology, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425, USA; Lipidomics Facility, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425, USA.
  • 2. Department of Medicine and the Stony Brook Cancer Center at Stony Brook University, Stony Brook, NY 11794, USA.
  • 3. Department of Biochemistry & Molecular Biology, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425, USA.
  • 4. Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425, USA.
  • 5. Department of Medicine and the Stony Brook Cancer Center at Stony Brook University, Stony Brook, NY 11794, USA. Electronic address: [email protected].
  • 6. Department of Biochemistry & Molecular Biology, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425, USA; Lipidomics Facility, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425, USA. Electronic address: [email protected].
PMID: 25456083 DOI: 10.1016/j.bmc.2014.10.025
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.
Products