期刊
CHEMMEDCHEM
卷 16, 期 1, 页码 259-291出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202000762
关键词
breast cancer; dehydrogenases; hydroxysteroids; inhibition; structure-activity relationships; tetrahydroisoquinoline
资金
- Slovenian Research Agency [J3-8212]
The type 1 enzyme 17 beta-Hydroxysteroid dehydrogenases, expressed in malignant cells, has therapeutic potential in estrogen-dependent diseases. Synthetic decoration of the nonsteroidal N-phenyl-1,2,3,4-tetrahydroisoquinoline (THIQ) template explored its viability as a steroid mimic. One compound showed high activity, demonstrating the potential of this novel approach.
17 beta-Hydroxysteroid dehydrogenases catalyse interconversion at the C17 position between oxidized and reduced forms of steroidal nuclear receptor ligands. The type 1 enzyme, expressed in malignant cells, catalyses reduction of the less-active estrone to estradiol, and inhibitors have therapeutic potential in estrogen-dependent diseases such as breast and ovarian cancers and in endometriosis. Synthetic decoration of the nonsteroidal N-phenyl-1,2,3,4-tetrahydroisoquinoline (THIQ) template was pursued by using Pomeranz-Fritsch-Bobbitt, Pictet-Spengler and Bischler-Napieralski approaches to explore the viability of this scaffold as a steroid mimic. Derivatives were evaluated biologically in vitro as type 1 enzyme inhibitors in a bacterial cell homogenate as source of recombinant protein. Structure-activity relationships are discussed. THIQs possessing a 6-hydroxy group, lipophilic substitutions at the 1- or 4-positions in combination with N-4 '-chlorophenyl substitution were most favourable for activity. Of these, one compound had an IC50 of ca. 350 nM as a racemate, testifying to the applicability of this novel approach.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据