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

Aiping Bai; Zdzislaw M. Szulc; Jacek Bielawski; Jason S. Pierce; Barbara Rembiesa; Silva Terzieva; Cungui Mao; Ruijuan Xu; Bill Wu; Christopher J. Clarke; Benjamin Newcomb; Xiang Liu; James Norris; Yusuf A. Hannun; Alicja Bielawska

doi:10.1016/j.bmc.2014.10.025

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

Aiping Bai
, Zdzislaw M. Szulc
, Jacek Bielawski
, Jason S. Pierce
, Barbara Rembiesa
, Silva Terzieva
, Cungui Mao
, Ruijuan Xu
, Bill Wu
, Christopher J. Clarke
, Benjamin Newcomb
, Xiang Liu
, James Norris
, Yusuf A. Hannun
, Alicja Bielawska

Medical University of South Carolina
Stony Brook University

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

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/1 h) by DMG-B13 prodrugs was mainly from the inhibition of the lysosomal ACDase.

Original language	English
Pages (from-to)	6933-6944
Number of pages	12
Journal	Bioorganic and Medicinal Chemistry
Volume	22
Issue number	24
DOIs	https://doi.org/10.1016/j.bmc.2014.10.025
State	Published - Dec 15 2014

Keywords

Acid ceramidase
B13
Cancer
DMG-B13 prodrugs
Inhibitors
Lysosomes

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Bai, A., Szulc, Z. M., Bielawski, J., Pierce, J. S., Rembiesa, B., Terzieva, S., Mao, C., Xu, R., Wu, B., Clarke, C. J., Newcomb, B., Liu, X., Norris, J., Hannun, Y. A., & Bielawska, A. (2014). Targeting (cellular) lysosomal acid ceramidase by B13: Design, synthesis and evaluation of novel DMG-B13 ester prodrugs. Bioorganic and Medicinal Chemistry, 22(24), 6933-6944. https://doi.org/10.1016/j.bmc.2014.10.025

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

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/1 h) by DMG-B13 prodrugs was mainly from the inhibition of the lysosomal ACDase.",

keywords = "Acid ceramidase, B13, Cancer, DMG-B13 prodrugs, Inhibitors, Lysosomes",

author = "Aiping Bai and Szulc, \{Zdzislaw M.\} and Jacek Bielawski and Pierce, \{Jason S.\} and Barbara Rembiesa and Silva Terzieva and Cungui Mao and Ruijuan Xu and Bill Wu and Clarke, \{Christopher J.\} and Benjamin Newcomb and Xiang Liu and James Norris and Hannun, \{Yusuf A.\} and Alicja Bielawska",

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doi = "10.1016/j.bmc.2014.10.025",

language = "English",

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Bai, A, Szulc, ZM, Bielawski, J, Pierce, JS, Rembiesa, B, Terzieva, S, Mao, C, Xu, R, Wu, B, Clarke, CJ, Newcomb, B, Liu, X, Norris, J, Hannun, YA & Bielawska, A 2014, 'Targeting (cellular) lysosomal acid ceramidase by B13: Design, synthesis and evaluation of novel DMG-B13 ester prodrugs', Bioorganic and Medicinal Chemistry, vol. 22, no. 24, pp. 6933-6944. https://doi.org/10.1016/j.bmc.2014.10.025

TY - JOUR

T1 - Targeting (cellular) lysosomal acid ceramidase by B13

T2 - Design, synthesis and evaluation of novel DMG-B13 ester prodrugs

AU - Bai, Aiping

AU - Szulc, Zdzislaw M.

AU - Bielawski, Jacek

AU - Pierce, Jason S.

AU - Rembiesa, Barbara

AU - Terzieva, Silva

AU - Mao, Cungui

AU - Xu, Ruijuan

AU - Wu, Bill

AU - Clarke, Christopher J.

AU - Newcomb, Benjamin

AU - Liu, Xiang

AU - Norris, James

AU - Hannun, Yusuf A.

AU - Bielawska, Alicja

PY - 2014/12/15

Y1 - 2014/12/15

N2 - 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/1 h) by DMG-B13 prodrugs was mainly from the inhibition of the lysosomal ACDase.

AB - 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/1 h) by DMG-B13 prodrugs was mainly from the inhibition of the lysosomal ACDase.

KW - Acid ceramidase

KW - B13

KW - Cancer

KW - DMG-B13 prodrugs

KW - Inhibitors

KW - Lysosomes

UR - https://www.scopus.com/pages/publications/84913528658

U2 - 10.1016/j.bmc.2014.10.025

DO - 10.1016/j.bmc.2014.10.025

M3 - Article

C2 - 25456083

AN - SCOPUS:84913528658

SN - 0968-0896

VL - 22

SP - 6933

EP - 6944

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 24

ER -

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

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Keywords

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