Bello Claudia, Bai Jianfei, Zambron Bartosz K, Elías-Rodríguez Pilar, Gajate Consuelo, Robina Inmaculada, Caffa Irene, Cea Michele, Montecucco Fabrizio, Nencioni Alessio, Nahimana Aimable, Aubry Dominique, Breton Caroline, Duchosal Michel A, Mollinedo Faustino, Vogel Pierre
Laboratory of Glycochemistry and Asymmetric Synthesis, Swiss Federal Institute of Technology (EPFL), Batochime, CH-1015 Lausanne, Switzerland.
Laboratory of Glycochemistry and Asymmetric Synthesis, Swiss Federal Institute of Technology (EPFL), Batochime, CH-1015 Lausanne, Switzerland.
Eur J Med Chem. 2018 Apr 25;150:457-478. doi: 10.1016/j.ejmech.2018.02.086. Epub 2018 Mar 2.
We have synthesized a wide array of structurally related amphiphilic compounds, containing a functionalized pyrrolidine polar group coupled to different ether-linked hydrocarbon chains, to generate novel structures with antitumor activity. These newly synthesized amphiphilic pyrrolidine-derived compounds were classified in three different sub-libraries regarding the number of hydroxyl groups substituting the pyrrolidine moiety at C3 and C4. Pyrrolidine compounds with one or none hydroxyl groups showed a potent cell killing activity against pancreatic cancer cells, but they lacked selectivity for tumor cells. Pyrrolidine compounds with two hydroxyl groups induced cell death in a wide variety of pancreatic cancer cell lines, and they were somewhat less cytotoxic to normal non-tumor cells. Among these latter compounds, the diol-derived pyrrolidine 20 ((2R,3R,4S)-2-{(9Z)-hexadec-9-en-1-yloxy]methyl}pyrrolidine-3,4-diol) induced autophagy and a potent apoptotic response in pancreatic ductal adenocarcinoma cells, which was inhibited by Bcl-X overexpression and by caspase inhibition, in a way similar to that of the amphiphilic ether lipid edelfosine, with which it was compared. Pharmacological and genetic inhibition of autophagy potentiated 20-mediated apoptosis. These structure-activity relationship studies point out the importance of the diol polar group and aliphatic side chain of 20 in promoting apoptosis against pancreatic cancer cells in a rather controlled way, and some additional subtle modifications were found to be potential modulators of the cytotoxic activity.
我们合成了一系列结构相关的两亲性化合物，这些化合物含有与不同醚键连接的烃链偶联的功能化吡咯烷极性基团，以生成具有抗肿瘤活性的新结构。这些新合成的两亲性吡咯烷衍生化合物根据取代吡咯烷部分C3和C4位羟基的数量被分为三个不同的子库。具有一个或没有羟基的吡咯烷化合物对胰腺癌细胞显示出强大的细胞杀伤活性，但它们对肿瘤细胞缺乏选择性。具有两个羟基的吡咯烷化合物在多种胰腺癌细胞系中诱导细胞死亡，并且它们对正常非肿瘤细胞的细胞毒性略小。在这些后一类化合物中，二醇衍生的吡咯烷20（(2R,3R,4S)-2-{[(9Z)-十六碳-9-烯-1-氧基]甲基}吡咯烷-3,4-二醇）在胰腺导管腺癌细胞中诱导自噬和强烈的凋亡反应，这种反应被Bcl-X过表达和半胱天冬酶抑制所抑制，其方式与两亲性醚脂依地福新相似，并与之进行了比较。自噬的药理学和基因抑制增强了20介导的凋亡。这些构效关系研究指出了20的二醇极性基团和脂肪族侧链在以相当可控的方式促进对胰腺癌细胞的凋亡中的重要性，并且发现一些额外的细微修饰是细胞毒性活性的潜在调节剂。
