# Estrone‐α‐2‐Deoxy‐Glucoside as a Targeted Therapy for Triple‐Negative Breast Cancer: Aromatase Inhibition and Cytotoxicity

## TL;DR

A new compound called Estrone-α-2DG was developed to inhibit aromatase and kill triple-negative breast cancer cells, offering a dual-action treatment.

## Contribution

The study introduces Estrone-α-2DG as a novel steroidal glycoside with dual aromatase inhibition and cytotoxic effects on triple-negative breast cancer.

## Key findings

- E1-α-2DG and E2-α-2DG showed potent aromatase inhibition with IC50 values of 0.101 μM and 0.159 μM, respectively.
- E1-α-2DG selectively inhibited MDA-MB-231 breast cancer cells with an IC50 of 20.46 μM without harming non-cancerous cells.
- Molecular docking showed that E1-α-2DG forms hydrogen bonds with key residues in CYP19A1.

## Abstract

Aromatase inhibitors (AIs) are vital in the treatment of estrogen‐dependent breast cancer, especially in postmenopausal women. In this study, a series of steroidal glycosides (SGs) derived from trans‐androsterone (tAND), estrone (E1), and estradiol (E2) were synthesized using a one‐pot multi‐enzyme glycosylation approach and structurally characterized via HPLC, MS, and NMR. Among the synthesized compounds, E1‐α‐2DG (2b) and E2‐α‐2DG (3b) demonstrated the most potent aromatase inhibition, with IC50 values of 0.101 ± 0.001 μM and 0.159 ± 0.009 μM, respectively. Molecular docking revealed that these glycosides form key hydrogen bonds with catalytic residues and the heme group of CYP19A1. In vitro cytotoxicity showed that E1‐α‐2DG selectively inhibited the growth of MCF‐7 and MDA‐MB‐231 breast cancer cells in a dose‐dependent manner, with the highest potency observed against triple‐negative MDA‐MB‐231 cells (IC50 = 20.46 ± 2.92 μM), while exhibiting no toxicity toward non‐cancerous HEK293 cells. These findings suggest that glycosylation enhances the pharmacological potential of steroidal scaffolds and highlights E1‐α‐2DG as a promising lead compound for the development of safer, dual‐function breast cancer therapies.

Estrone‐α‐2DG, synthesized via a one‐pot multi‐enzyme system, selectively inhibits aromatase (IC50 = 0.101μM) and triple negative breast cancer cells (IC50 = 20.46 μM), offering a dual function therapeutic scaffold.