Synthesis and biological evaluation of atropisomeric tetrahydroisoquinolines overcoming docetaxel resistance in triple-negative human breast cancer cells

Abstract

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. © 2023 Elsevier Inc.