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.
Highlights
Choline kinase (ChoK) (EC 2.7.1.32) catalyzes the phosphorylation of choline by ATP in the presence of Mg2+ to yield phosphocholine (PCho) and ADP7,8
For compounds 1 and 2, we identified the adenine and 1-benzyl-4-(dimethylamino)pyridinium as the most efficient fragments of these molecules by the deconvolution approach based on the ChoKα 1/1 (PDB ID: 3ZM9)[30] and ChoKα 1/2 (PDB ID: 4BR3)[31] crystal structures, demonstrating that the adenine fragment occupies the ATP binding site and that the pyridinium fragment, through its positive charge delocalized over the nitrogen atom, mimics the positive charge present in choline or in HC-3
The synthesis of a novel family of 1,1′ -(((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methylene))-bispyridinium or –bisquinolinium bromide (10a-l) and their evaluation as inhibitors of choline kinase against a panel of cancer-cell lines are described
Summary
Choline kinase (ChoK) (EC 2.7.1.32) catalyzes the phosphorylation of choline by ATP in the presence of Mg2+ to yield phosphocholine (PCho) and ADP7,8. Choline kinase is overexpressed in many tumors such as breast, lung, bladder, colon, prostate, ovary, and liver carcinomas[14,15,16] and recently elevated enzymatic activity has been shown in T-lymphoma[17]. This increasing expression leads to abnormal choline metabolism, resulting in higher phosphocholine levels, which refer to a cholinic phenotype associated with oncogenesis and tumor progression[18]. For compounds 1 and 2, we identified the adenine and 1-benzyl-4-(dimethylamino)pyridinium as the most efficient fragments of these molecules by the deconvolution approach based on the ChoKα 1/1 (PDB ID: 3ZM9)[30] and ChoKα 1/2 (PDB ID: 4BR3)[31] crystal structures, demonstrating that the adenine fragment occupies the ATP binding site and that the pyridinium fragment, through its positive charge delocalized over the nitrogen atom, mimics the positive charge present in choline or in HC-3
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