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

被引：5
|
作者：
Wai, HtooTint [1 ]
Du, Kang [1 ]
Anesini, Jason [1 ]
Kim, Wan Shin [1 ]
Eastman, Alan [2 ]
Micalizio, Glenn C. [1 ]
机构：
[1] Dartmouth Coll, Burke Lab, Dept Chem, Hanover, NH 03756 USA
[2] Dartmouth Coll, Geisel Sch Med, Lebanon, NH 03755 USA
来源：
ORGANIC LETTERS | 2018年 / 20卷 / 19期
基金：
美国国家卫生研究院;
关键词：
ESTROGEN-RECEPTOR-BETA; COLCHICINE BINDING-SITE; ALPHA ER-ALPHA; ANTIMITOTIC ACTIVITY; SELECTIVE AGONISTS; 2-METHOXYESTRADIOL; CHEMISTRY; CANCER; PAIN; CYCLOPROPYLCARBINYL;
D O I：
10.1021/acs.orglett.8b02689
中图分类号：
O62 [有机化学];
学科分类号：
070303 ; 081704 ;
摘要：
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-2,16 alpha-diol (VII) is described, along with structure activity relationships related to its cytotoxic properties. Overall, VII was found to have a GI(50) = 0.2 mu g/mL (similar to 800 nM) in MDA-MB-231 human breast cancer cells, be an efficacious estrogen receptor agonist with potency for ER beta > ER alpha (ER beta EC50 = 21 nM), possess selective affinity to the cdc-2-like kinase CLK4 (K-d = 350 nM), and be phenotypically related to paclitaxel by an unbiased panel assessment.
引用
收藏
页码：6220 / 6224
页数：5
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