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

被引：29

作者：

Bai, Aiping ^{[1
,2
]}

Szulc, Zdzislaw M. ^{[1
,2
]}

Bielawski, Jacek ^{[1
,2
]}

Pierce, Jason S. ^{[1
,2
]}

Rembiesa, Barbara ^{[1
,2
]}

Terzieva, Silva ^{[1
,2
]}

Mao, Cungui ^{[4
,5
]}

Xu, Ruijuan ^{[4
,5
]}

Wu, Bill ^{[1
]}

Clarke, Christopher J. ^{[4
,5
]}

Newcomb, Benjamin ^{[4
,5
]}

Liu, Xiang ^{[3
]}

Norris, James ^{[3
]}

Hannun, Yusuf A. ^{[4
,5
]}

Bielawska, Alicja ^{[1
,2
]}

机构：

[1] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA

[2] Med Univ S Carolina, Lipid Facil, Charleston, SC 29425 USA

[3] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA

[4] SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USA

[5] SUNY Stony Brook, Stony Brook Canc Ctr, Stony Brook, NY 11794 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2014年 / 22卷 / 24期

关键词：

B13; DMG-B13; prodrugs; Inhibitors; Acid ceramidase; Lysosomes; Cancer; TANDEM MASS-SPECTROMETRY; PROSTATE-CANCER CELLS; TUMOR-GROWTH; BIOACTIVE SPHINGOLIPIDS; PHOTODYNAMIC THERAPY; NEUTRAL CERAMIDASES; ANTICANCER AGENTS; AMINO-ACIDS; ANALOGS; RESISTANCE;

D O I：

10.1016/j.bmc.2014.10.025

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 center dot HCl) and LCL596 (1-O-DMG-B13 center dot HCl) and di-DMG-B13, LCL521 (1,3-O, O-DMGB13 center dot 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. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：6933 / 6944

页数：12

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