Aiping Bai1, Zdzislaw M Szulc1, Jacek Bielawski1, Jason S Pierce1, Barbara Rembiesa1, Silva Terzieva1, Cungui Mao2, Ruijuan Xu2, Bill Wu3, Christopher J Clarke2, Benjamin Newcomb2, Xiang Liu4, James Norris4, Yusuf A Hannun5, Alicja Bielawska6. 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.
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.
Acid ceramidase (n class="Gene">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.
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