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Título:	Induction of cell killing and autophagy by amphiphilic pyrrolidine derivatives on human pancreatic cancer cells
Autor:	Bello, Claudia; Gajate, Consuelo CSIC ORCID ; Mollinedo, Faustino CSIC ORCID ; Vogel, Pierre
Palabras clave:	Amphiphilic Diol-derived pyrrolidine Anticancer Apoptosis Autophagy Edelfosine Pancreatic cancer
Fecha de publicación:	2-mar-2018
Editor:	Elsevier
Citación:	European Journal of Medicinal Chemistry 150:457e478 (2018)
Resumen:	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.
Descripción:	57 p.-9 fig.-2 tab.+Graph. Abst.+Suppl.mat. Bello, Claudia et al.
Versión del editor:	http://doi.org/10.1016/j.ejmech.2018.02.086
URI:	http://hdl.handle.net/10261/162835
DOI:	10.1016/j.ejmech.2018.02.086.
ISSN:	0223-5234
E-ISSN:	1768-3254
Aparece en las colecciones:	(CIB) Artículos

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Graphical abstract.pdf	Graph. Abst.	47,29 kB	Adobe PDF	Visualizar/Abrir
EJMC_Bello_mat. supl._2018.doc	Material suplementario	37,5 MB	Microsoft Word	Visualizar/Abrir
EJMC_Manuscript_Bello_2018 .pdf		662,57 kB	Adobe PDF	Visualizar/Abrir