Analogues of tamoxifen: the role of the basic side-chain. Applications of a whole-cell oestrogen-receptor binding assay to N-oxides and quaternary salts.
Derivatives of tamoxifen (1) and 4-hydroxy-2-methyltamoxifen (2) in which the basic side chain has been modified by N-oxidation or by quaternization have been investigated with respect to the effects on affinity for the oestrogen receptor and on cytostatic activity towards the MCF-7 cell line in vitro. In addition to the conventional cytosol assay for receptor binding affinity (RBA) a recently developed whole-cell assay was employed. N-oxidation (e.g. 2----3) produced no significant alteration in RBA value either in cytosol or in whole cells, nor in activity towards the MCF-7 line. Quaternization with methyl iodide (1----4, 2----6) or ethyl bromide (1----5, 2----7b: the cis isomer 7a also formed) did not alter receptor binding in the cytosol assay but almost abolished binding in the whole cell and cytostatic activity. The whole-cell RBA values for 2 (0.45) and 3 (0.5) were lower than those for 4-hydroxytamoxifen (2.9), suggested to be due to the lower oestrogenicity of the 2-methyl derivatives since activity against MCF-7 cells was unimpaired. The even lower values of whole-cell RBA (0.01-0.02) for the quaternary ethyl bromide derivatives 7a and 7b were ascribed to poor penetration into the cell since these compounds had minimal cytostatic activity.
Jarman
M
M
Drug Development Section, Institute of Cancer Research, Sutton, Surrey, UK.
Leung
O T
OT
Leclercq
G
G
Devleeschouwer
N
N
Stoessel
S
S
Coombes
R C
RC
Skilton
R A
RA
D000818:Animals; D001692:Biological Transport; D005260:Female; D006801:Humans; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D011960:Receptors, Estrogen; D013629:Tamoxifen