title: Design, synthesis, crystallization and biological evaluation of new symmetrical biscationic compounds as selective inhibitors of human Choline Kinase α1 (ChoKα1).
abstract: 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.
authors.affiliation: Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Campus de Cartuja, 18071 Granada (Spain).
authors.forename: Santiago
authors.initials: S
authors.lastname: Schiaffino-Ortega
authors.affiliation: Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Campus de Cartuja, 18071 Granada (Spain).
authors.forename: Eleonora
authors.initials: E
authors.lastname: Baglioni
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia Pediatrica, Università di Padova, Padua, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Mariotto
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia Pediatrica, Università di Padova, Padua, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bortolozzi
authors.affiliation: Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Campus de Cartuja, 18071 Granada (Spain).|Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, BIFI-IQFR (CSIC) Joint Unit, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D; Fundacion ARAID, Edificio Pignatelli 36 (Spain).
authors.forename: Lucía
authors.initials: L
authors.lastname: Serrán-Aguilera
authors.affiliation: Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias, Campus Fuentenueva, 18071 Granada (Spain).
authors.forename: Pablo
authors.initials: P
authors.lastname: Ríos-Marco
authors.affiliation: Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias, Campus Fuentenueva, 18071 Granada (Spain).
authors.forename: M Paz
authors.initials: MP
authors.lastname: Carrasco-Jimenez
authors.affiliation: Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Campus de Cartuja, 18071 Granada (Spain).
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gallo
authors.affiliation: Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, BIFI-IQFR (CSIC) Joint Unit, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D; Fundacion ARAID, Edificio Pignatelli 36 (Spain).
authors.forename: Ramon
authors.initials: R
authors.lastname: Hurtado-Guerrero
authors.affiliation: Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias, Campus Fuentenueva, 18071 Granada (Spain).
authors.forename: Carmen
authors.initials: C
authors.lastname: Marco
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia Pediatrica, Università di Padova, Padua, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia Pediatrica, Università di Padova, Padua, Italy.
authors.forename: Giampietro
authors.initials: G
authors.lastname: Viola
authors.affiliation: Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Campus de Cartuja, 18071 Granada (Spain).
authors.forename: Antonio
authors.initials: A
authors.lastname: Entrena
authors.affiliation: Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Campus de Cartuja, 18071 Granada (Spain).
authors.forename: Luisa Carlota
authors.initials: LC
authors.lastname: López-Cara
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry*; D001665:Binding Sites; D002073:Butanes / Q000737:chemistry; D002412:Cations; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002797:Choline Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D003460:Crystallization; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D062105:Molecular Docking Simulation; D009928:Organ Specificity; D011485:Protein Binding; D011726:Pyridinium Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D011806:Quinolinium Compounds / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: C507944:1,4-(4-4'-Bis-((4-(dimethylamine)pyridinium-1-yl) methyl)diphenyl)butane dibromide; D000970:Antineoplastic Agents; D002073:Butanes; D002412:Cations; D004791:Enzyme Inhibitors; D011726:Pyridinium Compounds; D011806:Quinolinium Compounds; C517212:CHKA protein, human; D002797:Choline Kinase