Carborane-modified paclitaxel analogues: Position-dependent modulation of mitotic catastrophe and lysosomal function.

Paclitaxel remains a cornerstone of anticancer therapy; however, its clinical application is limited by resistance and toxicity. Herein, we report the design and synthesis of novel carborane-modified paclitaxel analogues to investigate the impact of boron cluster incorporation on taxane activity. A series of derivatives bearing ortho-, meta-, and para-carborane moieties at the 3'-N (compounds 12-14) or 2'-O (compounds 18-20) positions were obtained via click chemistry and selective acylation. Biological evaluation in MCF-7 breast cancer cells revealed position-dependent modulation of cellular responses: 3'-N-substituted analogues preferentially induced mitotic catastrophe, with compound 13 exhibiting the most pronounced effects, while 2'-O-modified derivatives predominantly affected lysosomal function. These effects were accompanied by alterations in cell cycle progression, cytoskeletal organization, and mitochondrial activity. Importantly, the compounds exhibited selective activity against cancer cells over non-cancerous MRC-5 cells. The structure-based molecular docking study predicted the possibility of additional hydrogen bonding with a carborane-containing derivative within the binding site of β-tubulin. The results demonstrate that incorporation of carborane clusters enables tunable modulation of taxane-induced cell death pathways, providing new insights into structure-activity relationships in paclitaxel analogues and highlighting the potential of boron-based modifications in anticancer drug design.