Design, synthesis, crystallization and biological evaluation of new symmetrical biscationic compounds as selective inhibitors of human Choline Kinase α1 (ChoKα1) Schiaffino Ortega, Santiago Baglioni, Eleonora Serrán Aguilera, Lucía Ríos Marco, Pablo Carrasco Jiménez, María Paz Gallo Mezo, Miguel Ángel Marco De La Calle, Carmen Entrena Guadix, Antonio López Cara, Luisa Carlota The authors gratefully acknowledge the ‘Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía’ (Excellence Research Project: P07-CTS-03210), the ‘Diputación General de Aragón (B89)’ and the ‘Ministerio de Ciencia e Innovación’ (SAF2009-11955, BFU2010-19504 and CTQ2013-44367-C2-2-P) for the financial support, the award of grants from ‘Ministerio de Educación’ to P.R.-M. and S.S.-E. is gratefully acknowledged, and the ‘Centro de Servicios de Informática of the University of Granada (Spain) for the use of their computers and scientific software. G.V.,R.B., R.M. and G.B. We thanks also the Fondazione Cariparo by the “Progetto Ricerca Pediatrica”. We thank synchrotron radiation sources ALBA (Barcelona), and in particular the beamline XALOC. The research leading to these results has also received funding from the FP7 (2007–2013) under BIOSTRUCTX-7687. A novel family of compounds derivative of 1,1′-(((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methylene))-bispyridinium or –bisquinolinium bromide (10a-l) containing a pair of oxygen atoms in the spacer of the linker between the biscationic moieties, were synthesized and evaluated as inhibitors of choline kinase against a panel of cancer-cell lines. The most promising compounds in this series were 1,1′-(((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methylene))bis(4-(dimethylamino)pyridinium) bromide (10a) and 1,1′-(((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methylene))-bis(7-chloro-4-(pyrrolidin-1-yl)quinolinium) bromide (10l), which inhibit human choline kinase (ChoKα1) with IC50 of 1.0 and 0.92 μM, respectively, in a range similar to that of the previously reported biscationic compounds MN58b and RSM932A. Our compounds show greater antiproliferative activities than do the reference compounds, with unprecedented values of GI50 in the nanomolar range for several of the cancer-cell lines assayed, and more importantly they present low toxicity in non-tumoral cell lines, suggesting a cancer-cell-selective antiproliferative activity. Docking studies predict that the compounds interact with the choline-binding site in agreement with the binding mode of most previously reported biscationic compounds. Moreover, the crystal structure of ChoKα1 with compound 10a reveals that this compound binds to the choline-binding site and mimics HC-3 binding mode as never before. 2024-04-30T10:15:35Z 2024-04-30T10:15:35Z 2016-03-31 journal article Schiaffino-Ortega, S., Baglioni, E., Mariotto, E. et al. Design, synthesis, crystallization and biological evaluation of new symmetrical biscationic compounds as selective inhibitors of human Choline Kinase α1 (ChoKα1). Sci Rep 6, 23793 (2016). https://doi.org/10.1038/srep23793 https://hdl.handle.net/10481/91277 10.1038/srep23793 eng http://creativecommons.org/licenses/by-nc-nd/3.0/ open access Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License Springer Nature