Derivatives of tamoxifen. Dependence of antiestrogenicity on the 4-substituent.
A range of tamoxifen derivatives substituted in the 4-position of the 1-phenyl ring are described. The key steps in the synthesis of 4-iodo-, 4-bromo-, and 4-(methylthio)tamoxifen were reactions of 1,2-diarylbutanones with the (4-halogenophenyl)lithium or [4-(methylthio)phenyl]magnesium bromide. Oxidized precursors of 4-(methylthio)tamoxifen were used to prepare the methylsulfinyl and methylsulfonyl derivatives. Further derivatives (formyl, hydroxymethyl, oxirane, mercapto) were prepared from 4-bromotamoxifen via the 4-lithio derivative. Several of the derivatives (Br, I, SMe, SOMe, SO2Me, oxirane, CHO, CH2OH) displayed a higher affinity for estrogen receptors (ER) of calf uterine cytosol than did tamoxifen, but there was no relationship between affinity to ER and the ability to inhibit the growth of the MCF-7 breast cancer cell line in vitro.
McCague
R
R
Drug Development Section, Institute of Cancer Research, Sutton, Surrey, U.K.
Leclercq
G
G
Legros
N
N
Goodman
J
J
Blackburn
G M
GM
Jarman
M
M
Foster
A B
AB
D000818:Animals; D002417:Cattle; D055598:Chemical Phenomena; D002621:Chemistry; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004965:Estrogen Antagonists; D005260:Female; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D013629:Tamoxifen