Griffin M T, Magarian R A, Jain P, Pento J T, Mousissian G K, Graves D C
Medicinal Chemistry/Pharmacodynamics Section, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City 73190.
Anticancer Drug Des. 1992 Feb;7(1):49-66.
As part of our continuous effort to produce non-steroidal antiestrogens demonstrating less intrinsic estrogenicity and greater antagonism than those in use, a series of Analog II (1,1-dichloro-2,3-diphenylcyclopropanes) derivatives was synthesized. The compounds were tested for their ability to inhibit the growth-stimulating action of estradiol in the immature mouse uterus and estrogen receptor (ER) (+) MCF-7 human breast cancer cells in vitro. Like Analog II, the derivatives were found to have no intrinsic estrogenicity (except 30) and they antagonized estradiol action less completely than the lead compound. Polarity improved the ER binding affinity of Analog II, but was quite small for all compounds, except 30, for which it was comparable to tamoxifen. Six compounds (8, 10, 14, 23, 29 and 30) demonstrated antiproliferative activity toward MCF-7 cells, in vitro, and the mean inhibition period over 6 days ranged from 20 to 37%. Only compound 30 was reversed by estradiol.
作为我们持续努力的一部分，旨在生产出比现有非甾体抗雌激素具有更低内在雌激素活性和更强拮抗作用的药物，我们合成了一系列类似物II（1,1 - 二氯 - 2,3 - 二苯基环丙烷）衍生物。对这些化合物进行了测试，考察它们在体外抑制雌二醇对未成熟小鼠子宫的生长刺激作用以及雌激素受体（ER）（+）MCF - 7人乳腺癌细胞的能力。与类似物II一样，发现这些衍生物没有内在雌激素活性（除30号化合物外），并且它们对雌二醇作用的拮抗作用不如先导化合物完全。极性提高了类似物II与ER的结合亲和力，但对所有化合物（除30号化合物外）来说都非常小，30号化合物的该亲和力与他莫昔芬相当。六种化合物（8、10、14、23、29和30）在体外对MCF - 7细胞表现出抗增殖活性，6天内的平均抑制率范围为20%至37%。只有30号化合物的作用能被雌二醇逆转。
