N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp, 119991, Moscow, Russia.
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp, 119991, Moscow, Russia.
Eur J Med Chem. 2019 Oct 1;179:694-706. doi: 10.1016/j.ejmech.2019.06.048. Epub 2019 Jun 18.
Unique derivatives of androstene and estrane series containing N-sulfonylimidate pendants were prepared from 17α-ethynyl steroids via Cu-catalyzed azide-alkyne cycloaddition to tosyl azide in the presence of alcohols. The synthesized compounds were screened for cytotoxicity against human breast cancer cell lines and ERα agonist activity. The hit compound 3,17β-dimethoxy-17α-[iso-propyl-2'-N-tosylacetimidate]estra-1,3,5-triene (4n) had no ERα-mediated hormonal activity and was found to exhibit potent cytotoxic effect in an ERα-positive breast cancer cell line. N-Sulfonylimidate 4n displayed high antiproliferative potency against triple-negative MDA-MB-231 breast cancer cells, while it was non-toxic towards normal mammary epithelial cells. Compound 4n was found to alter activity of various signaling pathways (NF-κB, Slug, cyclin D1, ERK) supporting the growth and invasiveness of tumor cells.
从 17α-乙炔甾体通过 Cu 催化的叠氮-炔环加成反应，在醇的存在下与对甲苯磺酰叠氮反应，制备了含有 N-磺酰亚胺酯侧链的雄烯和雌烷系列的独特衍生物。对合成的化合物进行了人乳腺癌细胞系的细胞毒性筛选和 ERα 激动剂活性筛选。具有命中化合物 3,17β-二甲氧基-17α-[异丙基-2'-N-对甲苯磺酰乙酰胺基]雌甾-1,3,5-三烯（4n）的没有 ERα 介导的激素活性，并且在 ERα 阳性乳腺癌细胞系中表现出有效的细胞毒性作用。N-磺酰亚胺酯 4n 对三阴性 MDA-MB-231 乳腺癌细胞表现出高的抗增殖效力，而对正常乳腺上皮细胞则没有毒性。发现化合物 4n 改变了支持肿瘤细胞生长和侵袭的各种信号通路（NF-κB、Slug、细胞周期蛋白 D1、ERK）的活性。
