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

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

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: yusuf.hannun@abumed.org.
  • 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: bielawsk@musc.edu.
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.

Figures
Products