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

• Published in: Bioorganic & medicinal chemistry letters 2024-12, Vol.114, p.130004, Article 130004
• Main Authors: Hirayama, Yuichiro, Matsunaga, Masahiro, Fukao, Ayaka, Kobayashi, Kenichi
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - metabolism; Molecular Structure; Natural product; Phaeosphaeride A; Phosphorylation - drug effects; Signal transducer and activator of transcription 3; Signal Transduction - drug effects; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - metabolism; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2024.130004

[Display omitted] •Phaeosphaeride A (PPA) inhibits IL-6-induced STAT3 phosphorylation in cancer cells.•The enantiomer of PPA shows the most potent inhibition of STAT3 phosphorylation and cell growth.•The presence or absence of STAT3 signaling pathway activation in cells did not affect the intensity of cytotoxicity.•The possible covalent bond-forming ability of PPA is critical for its biological activities. 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.