New more polar symmetrical bipyridinic compounds: new strategy for the inhibition of choline kinase α1

Author:

Castro-Navas Francisco Fermín1,Schiaffino-Ortega Santiago1,Carrasco-Jimenez María Paz2,Ríos-Marco Pablo2,Marco Carmen2,Espinosa Antonio1,Gallo Miguel Angel1,Mariotto Elena3,Basso Giuseppe3,Viola Giampietro3,Entrena-Guadix Antonio1,López-Cara Luisa Carlota1

Affiliation:

1. Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Campus de Cartuja, 18071, Granada, Spain

2. Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias, Campus Fuentenueva, 18071, Granada, Spain

3. Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, Padova, Italy

Abstract

Aim: Research of the antitumor properties of biscationic compounds has received significant attention over the last few years. Results: A novel family of 1,1′-([2,2′-bipyridine]-5,5′-diylbis(methylene))bis-substituted bromide (9a-k), containing two nitrogen atoms in the linker, considered as hypothetical hydrogen bond acceptors, were synthesized and evaluated as ChoK inhibitors and their antiproliferative activity against six cancer cell lines. Conclusion: The most promising compounds in this series are 1,1′-([2,2′-bipyridine]-5,5′-diylbis(methylene))bis(4-(methyl(phenyl)amino)-quinolinium bromide derivatives 9g-i (analogs to RSM932A), that significantly inhibit cancer cell growth at even submicromolar concentrations, especially against leukemia cells. Compounds 9g-i also inhibit the ChoKα1 with good or moderate values, as predicted by initial docking studies. In addition, the most active compound 9h remarkably induces apoptosis in two cell lines following the mitochondrial pathway.

Publisher

Future Science Ltd

Subject

Drug Discovery,Pharmacology,Molecular Medicine

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