2. Academic Validation
  3. Discovery of colchicine aryne cycloadduct as a potent molecule for the abrogation of epithelial to mesenchymal transition via modulating cell cycle regulatory CDK-2 and CDK-4 kinases in breast cancer cells

Discovery of colchicine aryne cycloadduct as a potent molecule for the abrogation of epithelial to mesenchymal transition via modulating cell cycle regulatory CDK-2 and CDK-4 kinases in breast cancer cells

  • Bioorg Chem. 2024 Sep:150:107581. doi: 10.1016/j.bioorg.2024.107581.
Waseem Iqbal Lone 1,  Jagdish Chand 2,  Puneet Kumar 1,  Yashi Garg 3,  Zabeer Ahmed 3,  Debaraj Mukherjee 4,  Anindya Goswami 5,  Jasha Momo H Anãl 6
Affiliations

Affiliations

  • 1 Natural Products and Medicinal Chemistry Division, CSIR- Indian Institute of Integrative Medicine, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
  • 2 Pharmacology Division, CSIR- Indian Institute of Integrative Medicine, Jammu 180001, India.
  • 3 Pharmacology Division, CSIR- Indian Institute of Integrative Medicine, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
  • 4 Department of Chemical Sciences, Bose Institute, EN-80, Sector V, Kolkata 700091, WB, India.
  • 5 Pharmacology Division, CSIR- Indian Institute of Integrative Medicine, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. Electronic address: agoswami@iiim.res.in.
  • 6 Natural Products and Medicinal Chemistry Division, CSIR- Indian Institute of Integrative Medicine, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. Electronic address: hmunshel.jasha@iiim.res.in.
PMID: 38908129 DOI: 10.1016/j.bioorg.2024.107581
Abstract

In this study, we synthesized a new-generation library of colchicine derivatives via cycloaddition of colchicine utilizing position C-8 and C-12 diene system regioselectivity with aryne precursor to generate a small, focused library of derivatives. We assessed their Anticancer activity against various Cancer cell lines like MCF-7, MDA-MB-231, MDA-MB-453, and PC-3. Normal human embryonic kidney cell line HEK-293 was used to determine the toxicity. Among these derivatives, silicon-tethered compound B-4a demonstrated the highest potency against breast Cancer cells. Subsequent mechanistic studies revealed that B-4a effectively modulates cell cycle regulatory kinases (CDK-2 and CDK-4) and their associated cyclins (cyclin-B1, cyclin-D1), inducing Apoptosis. Additionally, B-4a displayed a noteworthy impact on tubulin polymerization, compared to positive control flavopiridol hydrochloride in a dose-dependent manner, and significantly disrupted the vimentin Cytoskeleton, contributing to G1 arrest in breast Cancer cells. Moreover, B-4a exhibited substantial anti-metastatic properties by inhibiting breast Cancer cell migration and invasion. These effects are attributed to the down-regulation of major epithelial to mesenchymal transition (EMT) factors, including vimentin and Twist-1, and the upregulation of the epithelial marker E-cadherin in an apoptosis-dependent manner.

Keywords

Anticancer; Colchicine; Cytoskeletal protein; Less toxic; Tropolone alkaloid.

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