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/1h) by DMG-B13 prodrugs was mainly from the inhibition of the lysosomal ACDase.
authors.affiliation: 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.
authors.forename: Aiping
authors.initials: A
authors.lastname: Bai
authors.affiliation: 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.
authors.forename: Zdzislaw M
authors.initials: ZM
authors.lastname: Szulc
authors.affiliation: 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.
authors.forename: Jacek
authors.initials: J
authors.lastname: Bielawski
authors.affiliation: 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.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Pierce
authors.affiliation: 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.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rembiesa
authors.affiliation: 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.
authors.forename: Silva
authors.initials: S
authors.lastname: Terzieva
authors.affiliation: Department of Medicine and the Stony Brook Cancer Center at Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Cungui
authors.initials: C
authors.lastname: Mao
authors.affiliation: Department of Medicine and the Stony Brook Cancer Center at Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Ruijuan
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Biochemistry & Molecular Biology, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425, USA.
authors.forename: Bill
authors.initials: B
authors.lastname: Wu
authors.affiliation: Department of Medicine and the Stony Brook Cancer Center at Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Clarke
authors.affiliation: Department of Medicine and the Stony Brook Cancer Center at Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Newcomb
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425, USA.
authors.forename: James
authors.initials: J
authors.lastname: Norris
authors.affiliation: Department of Medicine and the Stony Brook Cancer Center at Stony Brook University, Stony Brook, NY 11794, USA. Electronic address: yusuf.hannun@abumed.org.
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.affiliation: 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.
authors.forename: Alicja
authors.initials: A
authors.lastname: Bielawska
mesh_terms: D055573:Acid Ceramidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000577:Amides / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D004952:Esters; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000201:enzymology; D061986:MCF-7 Cells; D009578:Nitrobenzenes / Q000737:chemistry* / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011412:Propanolamines / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding
chemical_list: D000577:Amides; C000599918:DMG-B13; D004791:Enzyme Inhibitors; D004952:Esters; C421619:N-(1-(4-nitrophenyl)-1,3-dihydroxyprop-2-yl)tetradecanamide; D009578:Nitrobenzenes; D011355:Prodrugs; D011412:Propanolamines; D055573:Acid Ceramidase
keywords: Acid ceramidase; B13; Cancer; DMG-B13 prodrugs; Inhibitors; Lysosomes