The antiproliferative and pro-apoptotic effects of 3-deoxy-3α-fluoro-chenodeoxycholic acid and 12β-methyl-3,7-dioxo-17-epi-25-homo-18-nor-5β-cholan-25-oic acid on human breast cancer cell lines.
Ravishankar Divyashree, Watts Joseph M, Luxenburger Andreas, Harris Lawrence D, Jiao Wanting, Dispa Thibaut, Weymouth-Wilson Alex, Furneaux Richard H, Linclau Bruno, Greco Francesca, Osborn Helen M I
Abstract
Bile acid derivatives have emerged as promising candidates in cancer therapeutics due to their ability to modulate key cellular signalling pathways, including those involved in apoptosis, cell cycle regulation, and inflammation. Structural modifications of natural bile acids have been shown to enhance their cytotoxicity against a variety of cancer cell types, including breast cancer. In this study we designed and synthesised a focused library of bile acid derivatives both via modification of the tetracyclic ring system to incorporate fluorine, and by structurally altering the bile acid nucleus. The anti-proliferative activities of nine synthesised derivatives, as well as bardoxolone methyl (CDDO-Me) which is a well-characterised IκB kinase (IKK) and NF-κB inhibitor and Nrf2 activator, were assessed in vitro against two clinically relevant breast cancer cell lines: MCF-7 (estrogen receptor-positive) and MDA-MB-231 (triple negative). Hence we report herein that two of the synthetic derivatives, specifically 3-deoxy-3α-fluoro-chenodeoxycholic acid (8, NZP208) and 12β-methyl-3,7-dioxo-17-epi-25-homo-18-nor-bile acid (9, NZP302) have low micromolar IC50 values against the selected cell lines, with IC50 values for 8 being 6.44 ± 0.37 μM for MCF-7 and 7.16 ± 0.03 μM for MDA-MB-231, and for 9 being 5.53 ± 0.05 μM for MCF-7 and 7.24 ± 0.06 μM for MDA-MB-231. We further discuss structure-activity relationships for these compounds and show that they cause cell death in both cell lines via a statistically significant induction of apoptosis. In addition, in silico assessment predicted appropriate ADMET properties and compliance with Lipinski's rule of five.
Key Findings
- Two synthetic bile acid derivatives, 3-deoxy-3α-fluoro-chenodeoxycholic acid (NZP208) and 12β-methyl-3,7-dioxo-17-epi-25-homo-18-nor-bile acid (NZP302), showed low micromolar IC50 values against MCF-7 and MDA-MB-231 breast cancer cell lines.
- Both compounds induced statistically significant apoptosis in the tested breast cancer cell lines.
- In silico assessments predicted favorable ADMET properties and compliance with Lipinski's rule of five for these derivatives.
Clinical Significance
These findings suggest that the novel bile acid derivatives NZP208 and NZP302 have potential as effective therapeutic agents against breast cancer, warranting further development and evaluation for clinical use.
Citation
Ravishankar Divyashree, Watts Joseph M, Luxenburger Andreaset al.. The antiproliferative and pro-apoptotic effects of 3-deoxy-3α-fluoro-chenodeoxycholic acid and 12β-methyl-3,7-dioxo-17-epi-25-homo-18-nor-5β-cholan-25-oic acid on human breast cancer cell lines. Bioorganic & medicinal chemistry letters. 2026-Sep-19.