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.