QSAR of 1,1′-(1,2-ethylenebisbenzyl)bis(4-substitutedpyridinium) dibromides as choline kinase inhibitors: a different approach for antiproliferative drug design

Campos, Joaquı́n M.; Núñez, Marı́a del Carmen; Rodríguez, V. Bravo; Gallo, Miguel Á.; Espinosa, Antonio

doi:10.1016/s0960-894x(00)00080-9

Cited by 31 publications

(21 citation statements)

References 12 publications

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“…In an effort to develop new anti-cancer therapies, numerous compounds have been synthesized and tested as ChoK inhibitors (20, 25–27). Most of these compounds are derivatives of hemicholinium-3 (HC-3), a known competitive inhibitor of ChoK with a structural homology to choline (Fig.…”

Section: Introductionmentioning

confidence: 99%

Crystal Structures of Human Choline Kinase Isoforms in Complex with Hemicholinium-3

Hong

Allali-Hassani

Tempel

et al. 2010

Journal of Biological Chemistry

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Human choline kinase (ChoK) catalyzes the first reaction in phosphatidylcholine biosynthesis and exists as ChoKα (α1 and α2) and ChoKβ isoforms. Recent studies suggest that ChoK is implicated in tumorigenesis and emerging as an attractive target for anticancer chemotherapy. To extend our understanding of the molecular mechanism of ChoK inhibition, we have determined the high resolution x-ray structures of the ChoKα1 and ChoKβ isoforms in complex with hemicholinium-3 (HC-3), a known inhibitor of ChoK. In both structures, HC-3 bound at the conserved hydrophobic groove on the C-terminal lobe. One of the HC-3 oxazinium rings complexed with ChoKα1 occupied the choline-binding pocket, providing a structural explanation for its inhibitory action. Interestingly, the HC-3 molecule co-crystallized with ChoKβ was phosphorylated in the choline binding site. This phosphorylation, albeit occurring at a very slow rate, was confirmed experimentally by mass spectroscopy and radioactive assays. Detailed kinetic studies revealed that HC-3 is a much more potent inhibitor for ChoKα isoforms (α1 and α2) compared with ChoKβ. Mutational studies based on the structures of both inhibitor-bound ChoK complexes demonstrated that Leu-401 of ChoKα2 (equivalent to Leu-419 of ChoKα1), or the corresponding residue Phe-352 of ChoKβ, which is one of the hydrophobic residues neighboring the active site, influences the plasticity of the HC-3-binding groove, thereby playing a key role in HC-3 sensitivity and phosphorylation.

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Section: Introductionmentioning

confidence: 99%

Crystal Structures of Human Choline Kinase Isoforms in Complex with Hemicholinium-3

Hong

Allali-Hassani

Tempel

et al. 2010

Journal of Biological Chemistry

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“…β-Carboline is a key pharmacophore present in a large number of natural tricyclic alkaloids, which can be found in numerous plants and animals, exhibiting potent biological activities [1,2,3,4,5,6,7,8,9,10]. As a key member of the β-carboline family, its structural variant tricyclic β-carbolinone (9 H -pyrido[3,4- b ]indol-1(2 H )-one derivative or β-carbolin-1-one, Figure 1) has served as an important intermediate for the preparation of complex alkaloids [11,12,13,14,15,16,17,18,19] and has been found to possess potent bioactivities. The natural and synthetic β-carbolinones are reported to have pharmacological effects in several aspects, such as the anticancer activity against colon and lung cancers, central nervous system activity in mammals, and also as the biological control agent for receptor research on bio-enzyme inhibitors, such as the inhibition of HLE (Human leukocyte elastase) [20,21,22,23].…”

Section: Introductionmentioning

confidence: 99%

A Facile Synthesis of 3-Substituted 9H-Pyrido[3,4-b]indol-1(2H)-one Derivatives from 3-Substituted β-Carbolines

et al. 2010

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A mild and efficient two-step synthesis of 3-substituted β-carbolinone derivatives from 3-substituted β-carboline in good yields is described. A possible reaction mechanism for the formation of the skeleton of β-carbolin-1-one is proposed. The structures of these compounds were established by IR, 1H-NMR, 13C-NMR, mass spectrometry and elemental analysis, as well as X-ray crystallographic analysis of 4-2 and 6-2.

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“…Thus, the last 6-7 years have witnessed a frantic activity in the synthesis and analysis of a range of ChoK inhibitors [6][7][8][9][10][11][12][13]. Most of these inhibitors are synthesized by taking the basic skeleton of choline uptake inhibitor, hemicholinium (HC-3, II) (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, II structure has taken as a template to propose new analogues with devoid of side effects, and attempts to obtain new chemical entities through computational methods [19]. By replacing the hemiketal ring of II with different groups like, pyridinium (III), quinolinium (IV) and isoquinolinium (V) rings various derivatives have been generated in last five years [6][7][8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Potential choline kinase inhibitors: A molecular modeling study of bis-quinolinium compounds

Srivani

Sastry

2009

Journal of Molecular Graphics and Modelling

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QSAR of 1,1′-(1,2-ethylenebisbenzyl)bis(4-substitutedpyridinium) dibromides as choline kinase inhibitors: a different approach for antiproliferative drug design

Cited by 31 publications

References 12 publications

Crystal Structures of Human Choline Kinase Isoforms in Complex with Hemicholinium-3

Crystal Structures of Human Choline Kinase Isoforms in Complex with Hemicholinium-3

A Facile Synthesis of 3-Substituted 9H-Pyrido[3,4-b]indol-1(2H)-one Derivatives from 3-Substituted β-Carbolines

Potential choline kinase inhibitors: A molecular modeling study of bis-quinolinium compounds

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