Design, synthesis, crystallization and biological evaluation of new symmetrical biscationic compounds as selective inhibitors of human Choline Kinase a1 (ChoKa1)

Schiaffino-Ortega, S. ; Baglioni, E. ; Mariotto, E. ; Bortolozzi, R. ; Serrán-Aguilera, L. ; Riós-Marco, P. ; Carrasco-Jimenez, M. ; Gallo, M.A. ; Hurtado-Guerrero, R. (Universidad de Zaragoza) ; Marco, C. ; Basso, G. ; Viola, G. ; Entrena, A. ; López-Cara, L.C.

Resumen: 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 (ChoKa1) with IC 50 of 1.0 and 0.92 Î 1/4M, 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 GI 50 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 ChoKa1 with compound 10a reveals that this compound binds to the choline-binding site and mimics HC-3 binding mode as never before.

Idioma: Inglés

DOI: 10.1038/srep23793

Año: 2016

Publicado en: SCIENTIFIC REPORTS 6 (2016), 23793 [17 pp]
ISSN: 2045-2322

Factor impacto JCR: 4.259 (2016)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 10 / 63 = 0.159 (2016) - Q1 - T1

Factor impacto SCIMAGO: 1.691 - Multidisciplinary (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/B89
Financiación: info:eu-repo/grantAgreement/EC/FP7/283570/EU/Transnational access and enhancement of integrated Biological Structure determination at synchrotron X-ray radiation facilities/BIOSTRUCT-X
Financiación: info:eu-repo/grantAgreement/ES/MICINN/BFU2010-19504
Financiación: info:eu-repo/grantAgreement/ES/MICINN/CTQ2013-44367-C2-2-P
Financiación: info:eu-repo/grantAgreement/ES/MICINN/SAF2009-11955

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)