Despite extensive investigation into the anti-cancer activity of the natural polyphenol curcumin, its therapeutic application is restricted by its inherent physicochemical properties. Synthetic curcumin analogues, however, offer a promising strategy to improve the drug-like potential of curcumin. In this study, we evaluated three curcumin-based benzothiazepane analogues for their ability to selectively target colon cancer cells. Their cytotoxicity was assessed on intestinal cancerous HCT-116 and non-cancerous IPEC-J2 cells using cell viability assays and microscopic imaging. Two analogues, AT007 and AT096, demonstrated enhanced anti-cancer selectivity compared to curcumin. Interestingly, this effect correlated with the aggregation of these compounds in cell medium, which was influenced by compound concentration and medium composition (particularly the presence of albumin). Confocal microscopy confirmed the presence of particles up to 12 µm inside both cell lines, yet downstream metabolic and transcriptomic responses revealed distinct coping mechanisms that may underlie the higher survival of IPEC-J2 cells. Rather than direct molecular interactions typical of soluble compounds, the observed selectivity appears to result from indirect, particle-driven physical effects, potentially involving (intracellular) membrane disruption. Our findings suggest that aggregation behaviour can be a key determinant in improving the potency and selectivity of bioactive compounds, opening new opportunities for the design and screening of more selective anti-cancer therapeutics.