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

• Published in: Bioorganic chemistry Vol. 150; p. 107581
• Main Authors: Iqbal Lone, Waseem, Chand, Jagdish, Kumar, Puneet, Garg, Yashi, Ahmed, Zabeer, Mukherjee, Debaraj, Goswami, Anindya, Momo H. Anãl, Jasha
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2024
• Subjects: Anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Colchicine; Colchicine - chemistry; Colchicine - pharmacology; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; Cyclin-Dependent Kinase 2 - metabolism; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - metabolism; Cycloaddition Reaction; Cytoskeletal protein; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Epithelial-Mesenchymal Transition - drug effects; Female; Humans; Less toxic; Molecular Structure; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Structure-Activity Relationship; Tropolone alkaloid; Cytoskeletal protein; Less toxic; Colchicine; Anticancer; Tropolone alkaloid
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107581

[Display omitted] •Regioselective cycloaddition on colchicine with arynes leads to synthesizing various colchicine derivatives.•Endo-facial cycloaddition occurs preferentially on the tropolone moiety of colchicine.•Silicon-tethered derivative of colchicine B-4a was found to be most potent against breast cancer and abrogated cell cycle regulatory kinases (CDK-2 and CDK-4) activity. 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.