Benzothiazepane-Based Curcumin Analogs Show Selective Effects on Respiration, Permeability, and Growth of Gut-Liver (Co-Culture) Cell Models.

Curcumin, a natural polyphenol with anti-cancer potential, faces limitations due to metabolic instability, and non-specific toxicity. This study focused on four curcumin analogs (FM038, FM044, FM045, FM050) featuring oxobutenylidene-substituted benzothiazepane cores bearing pyridinyl or furan substituents. We systematically evaluated their selective toxic effect on human colon (Caco-2) and liver (HepG2) cells. This study reveals that structural modifications critically govern the selective cytotoxicity of curcumin analogs towards proliferating Caco-2 and HepG2 cells. Treatment with analogs featuring pyridin-2-yl substituents (FM045/FM050) resulted in a slightly reduced potency towards Caco-2 cells compared to curcumin, whereas FM044 (furan-2-yl) was non-toxic and FM038 (pyridin-3-yl, methylated core) maintained similar activity. In contrast, direct exposure to proliferating HepG2 cells resulted in less cytotoxicity compared to the Caco-2 cell line, which points to a cell-specific mode-of-action in growing cells. When combined in a co-culture, metabolites generated and/or transported by differentiated Caco-2 cells significantly decreased HepG2 viability at an apical concentration of 15 μM. Efflux analysis of respiration and acidification showed that FM050 induced the strongest mitochondrial dysfunction in Caco-2 cells, directly driving cytotoxicity, whereas HepG2 toxicity correlated with intrinsic detoxification capacity rather than mitochondrial disruption. A metabolic shift towards glycolysis was observed in both cell lines, indicating energy pathway modulation to a more dysfunctional phenotype. These findings highlight the dual role of structural optimization (e.g., methylation, heterocyclic substituents) for (cancer) cell-specific bioactivity and colonic metabolism and may guide future development of curcumin-based chemopreventive agents after in vivo validation and metabolite characterization.