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  3. Design and synthesis of Entadamide A derivatives targeting breast cancer: Insights into In silico, In vitro and In vivo models

Design and synthesis of Entadamide A derivatives targeting breast cancer: Insights into In silico, In vitro and In vivo models

  • Eur J Med Chem. 2026 Jan 15;302(Pt 1):118308. doi: 10.1016/j.ejmech.2025.118308.
Sathi Bhulakshmi 1,  Nidhi Sharma 2,  Nikhila Yaladanda 2,  V Lakshma Nayak 3,  Raju Adepu 4,  Srinivasa Rao Mutheneni 2,  Sai Balaji Andugulapati 5,  Katragadda Suresh Babu 6
Affiliations

Affiliations

  • 1 Division of Natural Products and Medicinal Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.
  • 2 Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India; Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.
  • 3 Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.
  • 4 Division of Natural Products and Medicinal Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
  • 5 Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India; Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India. Electronic address: balaji@iict.res.in.
  • 6 Division of Natural Products and Medicinal Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India. Electronic address: suresh@iict.res.in.
PMID: 41172646 DOI: 10.1016/j.ejmech.2025.118308
Abstract

In this study, a series of Entadamide A (methylthio acrylamide) derivatives (3a-3x) have been designed and synthesized via Steglich esterification reaction with various cinnamic acids, long chain fatty acids, and benzoic acids. All these derivatives were systematically characterized (using NMR and Mass spectroscopy) and evaluated for their Anticancer properties against various Cancer cells. Among the compounds synthesized, long chain fatty acid derivatives (especially compounds 3u and 3x) manifested excellent Anticancer properties against the breast Cancer cell lines (MCF-7) with IC50 values of 2.82 μM and 2.18 μM. Further mechanistic investigations demonstrated that compounds 3u and 3x significantly induced Apoptosis while downregulating anti-apoptotic gene expression and also markedly reduced the expression of epithelial-to-mesenchymal transition (EMT) markers and stemness-associated genes. Functional assays confirmed that treatment with compounds 3u and 3x inhibited cell migration and sphere-forming capability in a dose-dependent manner. In 4T1-induced orthotopic mouse models, both compounds, 3u and 3x significantly suppressed tumor growth kinetics and reduced tumour volume compared to controls. The molecular docking study was performed to analyse the probable binding affinities of compounds with ABCB1, ABCG2 and BMI1/Ring1B-UbcH5c ubiquitin Ligase complex proteins. Collectively, these findings indicate that the Entadamide A derivatives 3u and 3x exert potent anti-tumour activity in breast Cancer models and provide a strong foundation for further translational development.

Keywords

Breast cancer; Entada phaseoloides; Entadamide A; Steglich esterification; Sulfur containing amides.

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