Bignon E, Pons M, Crastes de Paulet A C, Doré J C, Gilbert J, Abecassis J, Miquel J F, Ojasoo T, Raynaud J P
INSERM U58, Montpellier, France.
J Med Chem. 1989 Sep;32(9):2092-103. doi: 10.1021/jm00129a013.
In a study of a series of 26 triphenylacrylonitrile derivatives (TPEs), we investigated the influence of several possibly interrelated factors on the proliferation of human breast cancer cell lines. (1) Chemical substituents: the test compounds were for the most part para-hydroxylated with increasingly bulky hydrophobic and/or basic side chains [isopropyloxy or (diethylamino)ethoxy] or standard reference compounds. (2) Relative binding affinities (RBAs): they competed diversely for [3H]estradiol (E2) binding to calf uterus cytosol and little, if at all, for binding to the [3H]tamoxifen-labeled antiestrogen binding site (AEBS) in lower speed supernatant. A multiparametric comparison of RBAs recorded for calf, rat, and mouse uterus cytosol estrogen receptor (ER) revealed a possible influence of species-specific receptor conformation and/or environment on binding. (3) Estrogen/antiestrogen potency: their stimulation and inhibition of the proliferation of the ER-positive human breast cancer cell line (MCF7) was measured. Compounds with only hydroxy substituents stimulated proliferation more markedly than methylated derivatives and had a maximum effect at 10(-11)-10(-6) M. Stimulation was related to the RBA for ER. Compounds with isopropyloxy or (diethylamino)ethoxy side chains only weakly stimulated MCF7 cell growth and more powerfully antagonized E2-promoted growth. The extent of inhibition depended upon the bulk of the side chain and could be reversed by 10(-7) M E2. Within the same concentration ranges, the test compounds were without effect on the BT20 ER-negative cell line. (4) Cytostatic and/or cytolytic activity: most compounds could arrest the proliferation of both MCF7 and BT20 cells at concentrations above 3 x 10(-6) M. This activity was thus independent of ER. Nevertheless, those compounds with a charged hydrophobic side chain, which were the most powerful antagonists of E2-promoted cell growth, were also the most cytotoxic. The overall results for all molecules on all parameters were submitted to a multivariate analysis (correspondence analysis) which revealed the progressive influence of increasing substitution by hydroxy and more bulky groups on the generation of antagonist activity and cytotoxicity.
在一项对一系列26种三苯基丙烯腈衍生物（TPEs）的研究中，我们调查了几个可能相互关联的因素对人乳腺癌细胞系增殖的影响。（1）化学取代基：测试化合物大多为对羟基化，带有体积逐渐增大的疏水和/或碱性侧链[异丙氧基或（二乙氨基）乙氧基]或标准参考化合物。（2）相对结合亲和力（RBA）：它们对[³H]雌二醇（E₂）与小牛子宫胞质溶胶的结合有不同程度的竞争，而对低速上清液中[³H]他莫昔芬标记的抗雌激素结合位点（AEBS）的结合几乎没有竞争（如果有竞争的话也很微弱）。对小牛、大鼠和小鼠子宫胞质溶胶雌激素受体（ER）记录的RBA进行多参数比较，揭示了物种特异性受体构象和/或环境对结合可能产生的影响。（3）雌激素/抗雌激素效力：测量了它们对雌激素受体阳性人乳腺癌细胞系（MCF7）增殖的刺激和抑制作用。仅带有羟基取代基的化合物比甲基化衍生物更明显地刺激增殖，并且在10⁻¹¹ - 10⁻⁶ M时具有最大效应。刺激作用与ER的RBA相关。带有异丙氧基或（二乙氨基）乙氧基侧链的化合物仅微弱地刺激MCF7细胞生长，并且更有效地拮抗E₂促进的生长。抑制程度取决于侧链的大小，并且可以被10⁻⁷ M E₂逆转。在相同浓度范围内，测试化合物对BT20雌激素受体阴性细胞系没有影响。（4）细胞抑制和/或细胞溶解活性：大多数化合物在浓度高于3×10⁻⁶ M时可以阻止MCF7和BT20细胞的增殖。因此，这种活性与ER无关。然而，那些带有带电荷疏水侧链的化合物，它们是E₂促进细胞生长的最有力拮抗剂，也是最具细胞毒性的。对所有分子在所有参数上的总体结果进行了多变量分析（对应分析），该分析揭示了羟基和更大体积基团取代增加对拮抗剂活性和细胞毒性产生的渐进影响。
