Pyrazole carboxamides and carboxylic acids as protein kinase inhibitors in aberrant eukaryotic signal transduction: induction of growth arrest in MCF-7 cancer cells.
Densely functionalised pyrazole carboxamides and carboxylic acids were synthesised in an expedient manner through saponification and transamidation, respectively, of ester-functionalised pyrazoles. This synthetic protocol allowed for three diversifying steps in which appendages on the pyrazole scaffold were adjusted to optimise inhibition of protein kinases. Thirty-five analogues were tested in CK2, AKT1, PKA, PKCalpha, and SAPK2a (p38) kinase inhibition bioassays. Blocking of these kinases may lead to effective therapies for treating inflammatory diseases and cancer. In order to investigate potential biological activity, MCF-7 human breast cancer cells were incubated with the most promising derivatives. Two analogues caused changes in MCF-7 cell growth, one of them through cell cycle arrest demonstrated by cell cycle analysis.
Department of Natural Sciences, Faculty of Life Sciences, University of Copenhagen, Thorvaldsensvej 40, 1871, Frederiksberg, Denmark.
Tobias
T
Persson
Christina W
CW
Yde
Jakob E
JE
Rasmussen
Tine L
TL
Rasmussen
Barbara
B
Guerra
Olaf-Georg
OG
Issinger
John
J
Nielsen
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects*
D000577:Amides; D002264:Carboxylic Acids; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C031280:pyrazole; D011494:Protein Kinases; C494918:AKT1 protein, human; D047390:Casein Kinase II; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha; D048308:Mitogen-Activated Protein Kinase 14