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

[Display omitted] 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...

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Published in:Bioorganic & medicinal chemistry 2014-12, Vol.22 (24), p.6933-6944
Main Authors: Bai, Aiping, Szulc, Zdzislaw M., Bielawski, Jacek, Pierce, Jason S., Rembiesa, Barbara, Terzieva, Silva, Mao, Cungui, Xu, Ruijuan, Wu, Bill, Clarke, Christopher J., Newcomb, Benjamin, Liu, Xiang, Norris, James, Hannun, Yusuf A., Bielawska, Alicja
Format: Article
Language:English
Subjects:
Acid ceramidase
Acid Ceramidase - antagonists & inhibitors
Acid Ceramidase - genetics
Acid Ceramidase - metabolism
Amides - chemistry
Amides - metabolism
B13
Cancer
DMG-B13 prodrugs
Drug Design
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - metabolism
Esters
HeLa Cells
Humans
Inhibitors
Lysosomes
Lysosomes - enzymology
MCF-7 Cells
Nitrobenzenes - chemistry
Nitrobenzenes - metabolism
Prodrugs - chemical synthesis
Prodrugs - chemistry
Prodrugs - metabolism
Propanolamines - chemistry
Propanolamines - metabolism
Protein Binding
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Summary:[Display omitted] 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2014.10.025