Induction of cell killing and autophagy by amphiphilic pyrrolidine derivatives on human pancreatic cancer cells
- Eur J Med Chem. 2018 Apr 25:150:457-478. doi: 10.1016/j.ejmech.2018.02.086.
- 1. Laboratory of Glycochemistry and Asymmetric Synthesis, Swiss Federal Institute of Technology (EPFL), Batochime, CH-1015 Lausanne, Switzerland. Electronic address: [email protected].
- 2. Laboratory of Glycochemistry and Asymmetric Synthesis, Swiss Federal Institute of Technology (EPFL), Batochime, CH-1015 Lausanne, Switzerland.
- 3. Departamento de Química Orgánica, Universidad de Sevilla, E-41012, Seville, Spain.
- 4. Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), E-28040 Madrid, Spain.
- 5. Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy.
- 6. Service and Central Laboratory of Hematology, University Hospital (CHUV), CH 1011 Lausanne, Switzerland.
- 7. Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), E-28040 Madrid, Spain. Electronic address: [email protected].
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-XL 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.