期刊
BIOORGANIC CHEMISTRY
卷 137, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2023.106573
关键词
Apoptosis; Atropisomerism; Docetaxel resistance; Isoquinolines; STAT3; Triple-negative breast cancer
In this study, atropisomeric 8-aryltetrahydroisoquinolines were synthesized and evaluated for their biological activities. A highly bioactive racemic compound was produced, showing high antiproliferative activities against various cancer cell lines, including docetaxel-resistant breast cancer cell lines. Each enantiomer could be selectively synthesized using chiral phosphoric acid-catalyzed atroposelective Pictet-Spengler cyclization. The (R)-enantiomer exhibited higher biological activity compared to the (S)-enantiomer and overcame docetaxel resistance in triple-negative breast cancer cell lines via downregulation of STAT3 activation, inducing cellular apoptosis.
Herein, atropisomeric 8-aryltetrahydroisoquinolines have been synthesized and biologically evaluated. Based on our structure-activity relationship study, a highly bioactive racemic compound has been produced, and it exhibited high antiproliferative activities against various cancer cell lines, including docetaxel-resistant breast cancer cell lines. Each enantiomer can be synthesized in an enantioselective manner by employing the chiral phosphoric acid-catalyzed atroposelective Pictet-Spengler cyclization. An axially (R)-configured enantiomer showed a higher biological activity compared with the axially (S)-configured enantiomer. Further biological studies suggested that the (R)-enantiomer overcomes docetaxel resistance via the downregulation of signal transducer and activator of transcription 3 activation and consequently induces cellular apoptosis in docetaxel-resistant triple-negative breast cancer cell lines.
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