Loss of antagonistic activity of tamoxifen by replacement of one N-methyl of its side chain by fluorinated residues.
Efforts to limit the metabolic alteration of the aminoalkyl side chain of tamoxifen by fluorination largely decrease its ER-mediated antagonistic properties in MCF-7 cells (i.e., ability to inhibit growth, to stabilize ER, and to modulate ERE and AP-1 transcriptional activity). This loss is associated with an enhancement of agonistic activity. Loss of interaction between Asp 351 and the nitrogen atom of tamoxifen provoked by the fluorination of its side chain may explain this property.
Agouridas
Vangelis
V
Institut Lavoisier, UMR CNRS 8180, Université de Versailles, 45 avenue des Etats-Unis, 78035 Versailles cedex, France.
Laïos
Ioanna
I
Cleeren
Anny
A
Kizilian
Elyane
E
Magnier
Emmanuel
E
Blazejewski
Jean-Claude
JC
Leclercq
Guy
G
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004965:Estrogen Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005461:Fluorine / Q000737:chemistry*; D006801:Humans; D008745:Methylation; D015394:Molecular Structure; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D018808:Transcription Factor AP-1; D013629:Tamoxifen; D005461:Fluorine