Anti-tumor withanolides as signal transducers and activators of transcription 3 (STAT3)-inhibition from Withania obtusifolia

• Published in: Fitoterapia 2024-09, Vol.177, p.106124, Article 106124
• Main Authors: Zou, Qingya, Chunduru, Jayendra, LaRoe, Nicholas, Yang, Yijia, Mohamed, Tarik A., Hegazi, Nesrine M., Ibrahim, Mahmoud A.A., Hegazy, Mohamed-Elamir F., Pappas, Dimitri, Paré, Paul W.
• Format: Article
• Language: English
• Subjects: Anti-tumor; STAT3-inhibitor, molecular networking; Withania obtusifolia; Withanolides
• ISSN: 0367-326X
• DOI: 10.1016/j.fitote.2024.106124

The Solanaceae family and the Withania genus specifically are rich sources of medicinal plants. Liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS/MS) revealed a predominance of withanolides from an organic extract of Withania obtusifolia. A constructed molecular network uncovered the presence of potentially novel withanolides. A series of withanolides were then isolated and structurally characterized from the extract including two new withanolides (withafolia A and withafolia B) and seven previously reported metabolites. Of the isolated compounds, cytotoxicity of withanolide J, physaperuvin G, and a commercial STAT3 inhibitor (S3I-201) were assessed against a human leukemia HL-60 cell line resulting in IC50 values of 26, 29, and 120 μM, respectively. In silico molecular docking simulations indicate that withanolide J and physaperuvin G can bind as an inhibitor in the active site of STAT3 with docking scores comparable to the selective STAT3 inhibitor, S3I-201. [Display omitted] •Two previously unreported withanolides were isolated from the aerial parts of Withania obtusifolia.•Withanolide J and physaperuvin G showed moderate anti-tumor activity.•Anti-tumor withanolide J and physaperuvin G serve as STAT3 inhibitors.