Synthesis and bioevaluation of ω-N-amino analogs of B13
Synthesis and bioevaluation of ω-N-amino analogs of B13
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DOI：
10.1016/j.bmc.2009.01.057
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发表时间：
2009-03-01
影响因子：
3.5
通讯作者：
Bielawska, Alicja
中科院分区：
文献类型：
--
作者：
Bai, Aiping;Szulc, Zdzislaw M.;Bielawska, Alicja
设计、合成和测试了B13的新型欧米伽-N-氨基类似物(E类)，作为酸性神经酰胺酶(ACDase)的抑制剂和潜在的抗癌剂[Szulc，Z.M.；Mayroo，N.；Bai，A.；Bielawski，J.；Liu，X.；Norris，J.S.；Hannun，Y.A.；Bielawska，A.Bioorg]。地中海医院。化学。[2008，16,1015].有代表性的类似物LCL464，(1R，2R)-2-N-(12‘-N，N-二甲氨基十二烷基氨基)-1-(4’-硝基苯基)-1，3-丙二醇在体外对ACDase活性有抑制作用，与B13相似，但高于LCL204.LCL464在细胞水平上引起该酶的早期抑制，与神经鞘氨醇的减少和C-14-和C-16-神经酰胺的特异性增加相对应。LCL464不诱导溶酶体失稳或ACDase的降解，显示在广泛的不同癌细胞系中表现出固有的抗癌活性的细胞死亡增加，并通过激活执行半胱氨酸天冬氨酸酶诱导细胞凋亡。LCL464是一种通过抑制ACDase发挥作用的新型结构先导化疗药物。(C)2009爱思唯尔有限公司。保留所有权利。
Novel omega-N-amino analogs of B13 (Class E) were designed, synthesized and tested as inhibitors of acid ceramidase (ACDase) and potential anticancer agents deprived of unwanted lysosomal destabilization and ACDase proteolytic degradation properties of LCL204 [Szulc, Z. M.; Mayroo, N.; Bai, A.; Bielawski, J.; Liu, X.; Norris, J. S.; Hannun, Y. A.; Bielawska, A. Bioorg. Med. Chem. 2008, 16, 1015].Representative analog LCL464, (1R,2R)-2-N-(12'-N,N-dimethylaminododecanoyl amino)-1-(4 ''-nitrophenyl)-1,3- propandiol, inhibited ACDase activity in vitro, with a similar potency as B13 but higher than LCL204. LCL464 caused an early inhibition of this enzyme at a cellular level corresponding to decrease of sphingosine and specific increase of C-14- and C-16-ceramide. LCL464 did not induce lysosomal destabilization nor degradation of ACDase, showed increased cell death demonstrating inherent anticancer activity in a wide range of different cancer cell lines, and induction of apoptosis via executioner caspases activation. LCL464 represents a novel structural lead as chemotherapeutic agent acting via the inhibition of ACDase. (C) 2009 Elsevier Ltd. All rights reserved.