2. Academic Validation
  3. 7S,15R-Stereoisomer of phenylethylamino derivative of colchicine exhibits potent in-vitro and in-vivo anti-cancer activity against prostate Cancer: Assessing the impact of stereochemistry on biological activity

7S,15R-Stereoisomer of phenylethylamino derivative of colchicine exhibits potent in-vitro and in-vivo anti-cancer activity against prostate Cancer: Assessing the impact of stereochemistry on biological activity

  • Bioorg Chem. 2025 Apr:157:108262. doi: 10.1016/j.bioorg.2025.108262.
Chilakala Nagarjuna Reddy 1,  Abhisheik Chowdary Eedara 2,  Sumera Malik 3,  Dilip M Mondhe 3,  Sandip B Bharate 4,  Sai Balaji Andugulapati 5
Affiliations

Affiliations

  • 1 Natural Products & Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001 India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002 India.
  • 2 Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002 India; Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007 India.
  • 3 Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002 India; Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001 India.
  • 4 Natural Products & Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001 India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002 India; Department of Natural Products & Medicinal Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007 India. Electronic address: sbharate@iict.res.in.
  • 5 Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002 India; Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007 India. Electronic address: balaji@iict.res.in.
PMID: 39946986 DOI: 10.1016/j.bioorg.2025.108262
Abstract

The non-selective toxicity of colchicine remains a major barrier to its development as an Anticancer agent. Here, we report a colchicine derivative, 8l, which exhibits potent and selective antiproliferative activity in prostate Cancer cells. The present study investigates the impact of stereochemistry at the C10-substituted chiral amine fragment on the biological activity. Our findings reveal that the stereochemical configuration of 8l (7S,15R diastereomer) is critical for its efficacy, showing 12.5-fold greater antiproliferative activity than its counterpart, the 7S,15S diastereomer 8z. Additionally, 8l demonstrates superior α-tubulin polymerization inhibition compared to 8z, that were further corroborated by docking and simulation studies. Mechanistic insights indicate that 8l increases Reactive Oxygen Species levels by modulating the NRF-2/KEAP-1 axis. In vivo, administration of 8l at doses of 0.3 and 0.6 mg/kg significantly suppresses tumor growth in a PC-3 xenograft mouse model. Collectively, this study highlights the therapeutic potential of 8l as a colchicine-based Anticancer agent, effectively attenuating tumor progression through modulation of the NRF-2/KEAP-1 axis.

Keywords

Colchicine; PC-3 cells; Prostate cancer; Reactive oxygen species; Stereochemistry.

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