Synthesis and Discovery of Estra-1,3,5(10),6,8-pentaene-2,16α-diol

A metallacycle-centered
approach to the assembly of partially aromatic
synthetic steroids was investigated as a means to prepare a boutique
collection of unique steroidal agents. The synthesis and discovery
of estra-1,3,5(10),6,8-pentaene-2,16α-diol (VII) is described, along with structure–activity relationships
related to its cytotoxic properties. Overall, VII was
found to have a GI50 = 0.2 μg/mL (∼800 nM)
in MDA-MB-231 human breast cancer cells, be an efficacious estrogen
receptor agonist with potency for ERβ > ERα (ERβ
EC50 = 21 nM), possess selective affinity to the cdc-2-like
kinase CLK4 (Kd = 350 nM), and be phenotypically related
to paclitaxel by an unbiased panel assessment.

本研究以金属环（metallacycle）为核心策略，对部分芳香族合成类固醇的组装方法展开探究，以期制备一组独特甾体类化合物的专属小型集合。本文报道了雌烷-1,3,5(10),6,8-五烯-2,16α-二醇（VII）的合成与发现，以及与其细胞毒活性相关的构效关系。整体实验结果显示，在MDA-MB-231人乳腺癌细胞中，VII的半数生长抑制浓度（GI50）为0.2 μg/mL（约800 nM）；其作为高效雌激素受体激动剂，对雌激素受体β（ERβ）的活性优于雌激素受体α（ERα），ERβ的半数有效浓度（EC50）为21 nM；VII对cdc2样激酶CLK4具有选择性亲和力，解离常数（Kd）为350 nM；经无偏筛选组评估，其表型与紫杉醇（paclitaxel）具有相关性。