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
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.
Department of Medicine and the Stony Brook Cancer Center at Stony Brook University, Stony Brook, NY 11794, USA.
Bioorg Med Chem. 2014 Dec 15;22(24):6933-44. doi: 10.1016/j.bmc.2014.10.025. Epub 2014 Oct 22.
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.
酸性神经酰胺酶（ACDase）正被视为癌症的治疗靶点。B13是一种中等强度的ACDase抑制剂。本研究聚焦于通过其N，N-二甲基甘氨酸（DMG）酯（DMG-B13前药）将B13靶向溶酶体。通过对B13羟基进行N，N-二甲基甘氨酸（DMG）酯化反应，设计并合成了新型类似物，即异构体单-DMG-B13、LCL522（3-O-DMG-B13·HCl）和LCL596（1-O-DMG-B13·HCl）以及双-DMG-B13、LCL521（1,3-O，O-DMG-B13·2HCl）缀合物。在MCF7细胞中，DMG-B13前药可有效代谢为B13。DMG-B13前药对细胞神经酰胺酶的早期抑制作用通过其溶酶体靶向作用具有ACDase特异性。DMG-B13前药使细胞内鞘氨醇（Sph）相应显著降低（对照组/1小时为80 - 97%），这主要源于对溶酶体ACDase的抑制。
