2. Academic Validation
  3. Induction of cell killing and autophagy by amphiphilic pyrrolidine derivatives on human pancreatic cancer cells

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.
Claudia Bello 1,  Jianfei Bai 2,  Bartosz K Zambron 2,  Pilar Elías-Rodríguez 3,  Consuelo Gajate 4,  Inmaculada Robina 3,  Irene Caffa 5,  Michele Cea 5,  Fabrizio Montecucco 5,  Alessio Nencioni 5,  Aimable Nahimana 6,  Dominique Aubry 6,  Caroline Breton 6,  Michel A Duchosal 6,  Faustino Mollinedo 7,  Pierre Vogel 2
Affiliations

Affiliations

  • 1 Laboratory of Glycochemistry and Asymmetric Synthesis, Swiss Federal Institute of Technology (EPFL), Batochime, CH-1015 Lausanne, Switzerland. Electronic address: claudia.bello@unifi.it.
  • 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: fmollin@cib.csic.es.
PMID: 29547833 DOI: 10.1016/j.ejmech.2018.02.086
Abstract

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.

Keywords

Amphiphilic; Anticancer; Apoptosis; Autophagy; Diol-derived pyrrolidine; Edelfosine; Pancreatic cancer.

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