Design, synthesis, theoretical calculations and biological evaluation of new non-symmetrical choline kinase inhibitors

New non-symmetrical choline kinase inhibitors

“…18 The new series of non-symmetrical monocationic inhibitors was designed considering the hypothesis described for the initial series of non-symmetrical inhibitors. 14 The most active ChoK inhibitor of the series A (compound 14, n=1, n'=4, R 1 =R 2 = -CH 3 , IC 50 = 10.70 ± 0.40 μM) is constituted by an adenine moiety, a 1,4-diphenylbutane linker and a 4-(dimethylamino)pyridinium fragment. Docking studies indicated that it could bind simultaneously in both ATP and choline binding sites.…”

“…12 Recently, several families of 4,4-bis(pyridyl)-2,2'-bisoxazoles and theirs salts, structurally related to the ChoK inhibitor hemicolinium (HC-3) and its bispyridinium derivatives have shown good antiproliferative activity. 13 In a previous paper, 14 the design, synthesis and biological evaluation on some non-symmetrical mono-cationic compounds that inhibit choline kinase were described (Series A and B, Figure 1). These molecules are constituted by a cationic head: [4-(pyrrolidin-1-yl)pyridinium, R 1 + R 2 = (-CH 2 ) 4 -or 4-(dimethylamino)pyridinium, R 1 = R 2 = -CH 3 ]; a linker (benzene, biphenyl, 1,2-diphenylethane or 1,4-diphenylbutane); and, an adenine moiety connected to the linker through the N-9 (series A) or N-3 (series B) atom.…”

Determination of Potential Scaffolds for Human Choline Kinase α1 by Chemical Deconvolution Studies

“…We have previously described a new series of unsymmetrical monocationic compounds that showed moderate potency against CHOK in HepG2 cells. [5] These compounds all bear a 4-substituted pyridinium system and an adenine moiety, connected by linkers of different lengths. [5] The goal was to occupy both the ATP and the choline binding sites of the enzyme, as clearly demonstrated by the crystal structure of CHOKa1 in complexation with one of the compounds in this series (compound 1, PDB ID: 3ZM9).…”

“…[5] These compounds all bear a 4-substituted pyridinium system and an adenine moiety, connected by linkers of different lengths. [5] The goal was to occupy both the ATP and the choline binding sites of the enzyme, as clearly demonstrated by the crystal structure of CHOKa1 in complexation with one of the compounds in this series (compound 1, PDB ID: 3ZM9). [6] Whereas adenine occupies the ATP binding site, the pyridinium fragment, through its positive charge delocalised over the nitrogen atoms, mimics the positive charge present in choline or in HC-3 (Scheme 1).…”

Alterations of Choline Phospholipid Metabolism in Endometrial Cancer Are Caused by Choline Kinase Alpha Overexpression and a Hyperactivated Deacylation Pathway

“…Furthermore, overexpression of CHKA (6)(7)(8) and abundance of choline metabolites (13)(14)(15) have been shown to be prognostic in a number of cancers including prostate, breast, lung, and ovarian cancer. More recently inhibition of CHKA, both by shRNA and small-molecule inhibitors, has been shown to have both an antimitogenic and antiproliferative effects in vitro and in vivo (16)(17)(18)(19)(20)(21).…”