SAT-307 Drug-like ADME Profiles and Antimetastatic Properties of Monocarbonyl Curcumin Analogs C66 and B2BrBC with Improved Stability

Abstract Disclosure: R. Stojchevski: None. E. Sutanto: None. K. Dragarska: None. I. Todorovska: None. S. Velichkovikj: None. N. Hadzi-Petrushev: None. J. Bogdanov: None. M. Mladenov: None. L. Poretsky: None. D.B. Avtanski: None. Monocarbonyl analogs of curcumin (MACs) in recent years have emerged as promising candidates in breast cancer therapy, representing a strategic approach to improve curcumin's poor stability and pharmacological profile, thus paving the way for novel anticancer treatments. This study aimed to evaluate the stability of two MACs, C66 and B2BrBC, relative to curcumin and predict their absorption, distribution, metabolism, and excretion (ADME) properties, pharmacokinetic features, and estimated drug-likeness using SwissADME computational analysis. Additionally, the proapoptotic and antimetastatic potential of the analogs was investigated in two breast cancer cell lines, MCF-7 and BT-474. Our previous findings highlighted the potential therapeutic application of C66 and B2BrBC in mitigating breast cancer progression by modulating key markers for epithelial-to-mesenchymal transition. The results of the stability assay conducted under physiological conditions demonstrated that C66 and B2BrBC were significantly more stable than curcumin, which degraded by approximately 17% after 25 minutes, whereas the MACs showed only approximately 3% reduction. Moreover, the SwissADME analysis predicted favorable physicochemical properties for both compounds consistent with drug-likeness criteria and supported their potential as orally bioavailable drug candidates. Fluorescent microscopy using a caspase-3 dye confirmed the proapoptotic effects of C66 and B2BrBC, with B2BrBC inducing higher apoptotic activity in MCF-7 cells and C66 exhibiting higher caspase-3 activation in BT-474 cells. The MILLIPLEX assay conducted to measure the expression levels of various cancer metastasis biomarkers in cell culture media showed that both analogs significantly modulated key biomarkers associated with apoptotic pathways and bone metastasis, such as GDF-15, DKK-1, and OPG, underscoring their potential role in suppressing cancer progression. These findings highlight C66 and B2BrBC as stable, effective, and promising therapeutic agents against breast cancer, with notable effects on apoptosis and metastasis. Future studies should aim to further explore their clinical relevance and therapeutic applications. Presentation: Saturday, July 12, 2025