Biological evaluation of signal transducer and activator of transcription 3 (STAT3) targeting by phaeosphaeride A and its analogs

  • Bioorg Med Chem Lett. 2024 Dec 1:114:130004. doi: 10.1016/j.bmcl.2024.130004.
Yuichiro Hirayama  1 ,  Masahiro Matsunaga  2 ,  Ayaka Fukao  2 ,  Kenichi Kobayashi  3
Affiliations
  • 1. School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, 061-0293, Japan. Electronic address: [email protected].
  • 2. School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, 061-0293, Japan.
  • 3. School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, 061-0293, Japan. Electronic address: [email protected].
PMID: 39426431 DOI: 10.1016/j.bmcl.2024.130004
Abstract

The inhibitory activities of phaeosphaeride A (PPA), phaeosphaeride B, and four synthetic derivatives against phosphorylation of signal transducer and activator of transcription 3 (STAT3) and cell proliferation in cervical (HeLa) and breast (MDA-MB-231) Cancer cells were evaluated. PPA inhibited IL-6-induced STAT3 phosphorylation and cell proliferation at similar concentrations. The structure-activity relationship studies revealed that the enantiomer of PPA was the most potent of the evaluated phaeosphaerides in both inhibiting STAT3 phosphorylation and cell growth. PPA clearly inhibited the IL-6-activated STAT3 signaling pathway. However, the presence or absence of activation of the STAT3 signaling pathway in cells showed no relationship to the antiproliferative activity. Notably, the possible covalent bond-forming ability of PPA was critical for its biological activities.

Keywords
Natural product; Phaeosphaeride A; Signal transducer and activator of transcription 3; Structure–activity relationship.
Products