Novel 10‐Alkoxy 1,4‐Dien‐3‐One Estranes as Multitarget Anticancer Agents Against Estrogen‐Positive Breast Cancer

Breast cancer remains the most prevalent cancer among women, driving the continuous search for novel anticancer agents. In this study, a series of 10‐alkoxy steroids containing a 1,4‐dien‐3‐one moiety was synthesized via a one‐step dearomatization of the A‐ring of estradiol and an estrane derivative with a D‐homo lactone moiety. All compounds exhibited favorable in silico ADMET properties, while five derivatives showed significant cytotoxic activity in vitro. The strongest effects against the estrogen‐positive breast cancer cell line MCF‐7 were observed for two 10β‐methoxy, one 10β‐butoxy, and two 10β‐propargyloxy derivatives. The activity of the 10β‐butoxy‐17β‐hydroxy and 10β‐propargyloxy‐17β‐hydroxy steroids correlates with strong binding affinity toward estrogen receptor α and inhibition of AKR1C3 and AKR1C4 enzymatic activity. Additionally, the propargyloxy derivative showed substrate‐like binding to human recombinant aromatase. Molecular docking results are in qualitative agreement with these findings, predicting binding modes similar to known ligands and possible hydrophobic interactions between the C‐10 alkoxy groups and the active sites of target proteins, particularly the heme group of aromatase. These results highlight novel estrane derivatives as promising candidates for estrogen‐positive breast cancer therapy through combined effects involving AKR1C3 inhibition and interaction with aromatase and estrogen receptor.