Symmetrical bis-quinolinium compounds: new human choline kinase inhibitors with antiproliferative activity against the HT-29 cell line.
Studies have been aimed at the establishment of structure-activity relationships that define choline kinase inhibitory and antiproliferative activities of 40 bisquinolinium compounds. These derivatives have electron-releasing groups at position 4 of the quinolinium ring. It is found that the enzymatic inhibition is closely related to the size of the linker, the 3,3'-biphenyl moiety being the most suitable. On the other hand, the antiproliferative activity against the HT-29 cancer cell line is less influenced by the linker type and by substituent R(4). The corresponding QSAR equation was obtained for the whole set of compounds for the antiproliferative activity, the electronic parameter sigma(R) of R(4), the molar refractivity of R(8), and the lipophilic parameters clog P and pi(linker). The most potent antiproliferative agent so far described is 40 for which an IC(50) = 0.45 microM was predicted by the QSAR equation, while its experimental value is IC(50) = 0.20 microM.
Sánchez-Martín
Rosario
R
Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, c/ Campus de Cartuja s/n, 18071 Granada, Spain.
Campos
Joaquín M
JM
Conejo-García
Ana
A
Cruz-López
Olga
O
Báñez-Coronel
Mónica
M
Rodríguez-González
Agustín
A
Gallo
Miguel A
MA
Lacal
Juan C
JC
Espinosa
Antonio
A
D001713:Biphenyl Compounds / Q000737:chemistry; D002797:Choline Kinase / Q000037:antagonists & inhibitors*; D019073:HT29 Cells; D006801:Humans; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011806:Quinolinium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C500850:1,1'-(ethylenebis(benzene-1,4-diylmethylene))bis(7-chloro-4-(pyrrolidino)quinolinium); D001713:Biphenyl Compounds; D011804:Quinolines; D011806:Quinolinium Compounds; D002797:Choline Kinase