McCague R, Leclercq G, Legros N, Goodman J, Blackburn G M, Jarman M, Foster A B
Drug Development Section, Institute of Cancer Research, Sutton, Surrey, U.K.
J Med Chem. 1989 Dec;32(12):2527-33. doi: 10.1021/jm00132a006.
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.
本文描述了一系列在1-苯基环的4-位上被取代的他莫昔芬衍生物。4-碘-、4-溴-和4-(甲硫基)他莫昔芬合成中的关键步骤是1,2-二芳基丁酮与(4-卤代苯基)锂或[4-(甲硫基)苯基]溴化镁的反应。4-(甲硫基)他莫昔芬的氧化前体用于制备甲亚砜基和甲磺酰基衍生物。进一步的衍生物(甲酰基、羟甲基、环氧乙烷、巯基)由4-溴他莫昔芬通过4-锂代衍生物制备。几种衍生物(Br、I、SMe、SOMe、SO2Me、环氧乙烷、CHO、CH2OH)对小牛子宫胞质溶胶的雌激素受体(ER)的亲和力高于他莫昔芬，但对ER的亲和力与体外抑制MCF-7乳腺癌细胞系生长的能力之间没有关系。
