Coumarins from Citrus aurantiifolia (Christm.) Swingle Peel with Potential Cytotoxic Activity Against MCF-7 Breast Cancer Cell Line: In Vitro and In Silico Studies.

Aim: Breast cancer remains a prevalent and challenging health issue for women globally. In the pursuit of more effective and less harmful therapies, researchers have focused on natural compounds, especially phenolic compounds found in various plants and fruits.

Purpose: This study aims to explore the potency of coumarin compounds from Citrus aurantiifolia (Christm.) Swingle peel as alternative treatment for breast cancer through in vitro and in silico studies.

Methods: Three coumarins were isolated from C. aurantiifolia peel through multiple steps of column chromatograph. Their cytotoxic activities against the MCF-7 breast cancer cell line were evaluated using the MTT assay. Additionally, in silico studies, including molecular docking and molecular dynamics simulations, were conducted to evaluate the interactions of the most potent compound with estrogen receptor alpha (ERα).

Results: Chemical investigation of C. aurantiifolia peel led to the isolation of three compounds: 5-geranyloxy-7-methoxycoumarin (1), 5-geranyloxypsoralen (2), and 8-geranyloxypsoralen (3). Cytotoxic assays revealed that compound 2 exhibited the highest cytotoxic potency against MCF-7 breast cancer cell line with an IC₅₀ of 138.51 ± 14.44 µg/mL, followed by compounds 1 and 3 with IC₅₀ values of 204.69 ± 22.91 and 478.15 ± 34.85 µg/mL, respectively. Molecular docking studies against estrogen receptor alpha (ERα) showed that 5-geranyloxypsoralen (2) had a lower docking score (-10.63 kcal/mol) compared to estradiol (-9.99 kcal/mol). Molecular dynamics simulation revealed the binding stability ERα-Compound 2 complex as evidence from the root mean square deviation (RMSD) of 2.964 ± 0.460 Å. Furthermore, pharmacokinetic predictions suggested that 5-geranyloxypsoralen may possess favourable pharmacokinetic properties, highlighting its potential as a therapeutic agent.

Conclusion: The study highlights the potential of coumarin compounds from C. aurantiifolia peel as an alternative treatment for breast cancer, particularly 5-geranyloxypsoralen could be a promising therapeutic agent in breast cancer treatment, warranting further investigation.