Magarian R A, Avor K S, Overacre L B, Kunchandy J, Paxton T R
Medicinal Chemistry/Pharmacodynamics Department, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City 73190, USA.
Anticancer Drug Des. 1995 Jun;10(4):311-31.
In an effort to prepare effective non-steroidal antiestrogens without intrinsic estrogenicity and with greater antagonism than those of the triarylethylenes (tamoxifen; TAM) four N-substituted (Z)-1,1-dichloro-2-[4-(2-aminoethoxy)phenyl]-3-phenylcyclopropa ne derivatives of the antiestrogen, Analog II, in which the basic side chains contain cyclic (piperidino and piperazino) and non-cyclic (dimethyl amino and diethyl amino) moieties, were synthesized. These compounds were prepared from an intermediate methanesulfonyloxyethoxy side chain ester of 1,1-dichloro-2,3-cis-diphenylcyclopropane using their respective side chain bases in triethylamine and acetonitrile. The gem-dichloro-cis-diarylcyclopropane derivatives were tested for their ability to inhibit the growth-stimulating effect of estradiol on immature mouse uteri and the growth of estrogen receptor (ER)-positive MCF-7E3, ER-negative MDA-MB-231 and the ER-positive MCF-7LY2 antiestrogen-resistant breast cancer cells in culture. The introduction of the various aminoethoxy side chains into Analog II did not improve its ER-binding affinity. Like Analog II, the derivatives did not exhibit any intrinsic estrogenicity, and compounds 9 and 10 antagonized estradiol action more completely than the parent compound. None of the compounds potentiated the uterine weight gain from the stimulating dose of estradiol (0.03 micrograms). Derivatives 9 (150 micrograms), 10 (150 micrograms) and 11 (150 micrograms) had uterine mean weights significantly below the estradiol-treated group, and were better antagonists than Analog II and MER25 at the same concentrations. All compounds exhibited a statistically significant (P < 0.01) reduction in control growth (antitumor activity) from 0.01 to 10 nM concentration in the MCF-7E3 cells. At 10 nM concentration, 8 (66%) and 9 (64%) had the greater antitumor activity over 10 (58%) and 11 (58%). No activity in this cell line was observed for Analog II, TAM and ICI 182,780. Antitumor action was also demonstrated in the MDA-MB-231 cells for all derivatives at 1.0 microM dose, with 9 having the greatest (27%) inhibition of control growth, followed by 8 (20%), 10 (18%) and 11 (12%). Analog II and ICI 182,780 had no antitumor activity in this cell line, while TAM exhibited only 8% inhibition. In the MCF-7E3 cell line at 1.0 microM, 9 exhibited 86% inhibition of the estradiol-stimulated growth (antiestrogenic activity), followed by 8 (64%), 10 (52%) and 11 (21%).(ABSTRACT TRUNCATED AT 400 WORDS)
为了制备有效的非甾体类抗雌激素药物，这类药物无内在雌激素活性且比三芳基乙烯类（他莫昔芬；TAM）具有更强的拮抗作用，合成了四种抗雌激素药物类似物II的N-取代（Z）-1,1-二氯-2-[4-(2-氨基乙氧基)phenyl]-3-苯基环丙烷衍生物，其中碱性侧链包含环状（哌啶基和哌嗪基）和非环状（二甲氨基和二乙氨基）部分。这些化合物由1,1-二氯-2,3-顺式-二苯基环丙烷的中间甲磺酰氧基乙氧基侧链酯，使用它们各自的侧链碱在三乙胺和乙腈中制备。对偕二氯-顺式-二芳基环丙烷衍生物进行了测试，考察其抑制雌二醇对未成熟小鼠子宫的生长刺激作用以及培养中的雌激素受体（ER）阳性MCF-7E3、ER阴性MDA-MB-231和ER阳性MCF-7LY2抗雌激素耐药乳腺癌细胞生长的能力。将各种氨基乙氧基侧链引入类似物II并未提高其与ER的结合亲和力。与类似物II一样，这些衍生物未表现出任何内在雌激素活性，化合物9和10比母体化合物更能完全拮抗雌二醇的作用。没有一种化合物能增强雌二醇刺激剂量（0.03微克）引起的子宫重量增加。衍生物9（150微克）、10（150微克）和11（150微克）的子宫平均重量显著低于雌二醇处理组，且在相同浓度下比类似物II和MER25是更好的拮抗剂。在MCF-7E3细胞中，所有化合物在0.01至10 nM浓度下对对照生长（抗肿瘤活性）均表现出统计学显著（P < 0.01）的降低。在10 nM浓度下，8（66%）和9（64%）比10（58%）和11（58%）具有更强的抗肿瘤活性。在该细胞系中未观察到类似物II、TAM和ICI 182,780有活性。在MDA-MB-231细胞中，所有衍生物在1.0 microM剂量下也表现出抗肿瘤作用，其中9对对照生长的抑制作用最大（27%），其次是8（20%）、10（18%）和11（12%）。类似物II和ICI 182,780在该细胞系中无抗肿瘤活性，而TAM仅表现出8%的抑制作用。在MCF-7E3细胞系中，在1.0 microM时，9对雌二醇刺激的生长表现出86%的抑制作用（抗雌激素活性），其次是8（64%）、10（52%）和11（21%）。（摘要截短于400字）
