Design, synthesis, antiproliferative activity, estrogen receptors binding affinity of C-3 pregnenolone-dihydropyrimidine derivatives for the treatment of breast cancer

[Display omitted] •Synthesized C-3 modified dihydropyrimidine-pregnenolone analogs.•Excellent antiproliferative activity against MCF-7 breast cancer cells.•Safe against non-malignant HEK-293.•Competitive binding assay was performed on estrogen receptors ERα and ERβ.•Docking studies and in-silico pharmacokinetic prediction. Breast cancer (BCa) is very common malignancy and globally, has become the second leading cause of cancer death among women. For the treatment of BCa, estrogen receptors-alpha (ERα) has proven to be a therapeutic target. In continuation of our previous reported dihydropyrimidine-based pregnenolone derivatives, we modified at C-3 hydroxyl group. Structural architecture of estrogen receptors (ER) with excellent ER binding affinity was used for modification. MTT assay was used to evaluate the synthesized steroidal analogs for their antiproliferative activities against ER-positive MCF-7, ER-negative MDA-MB-231 (ER-) breast cancer cells and non-cancerous HEK-293 cells. Structure activity relationship (SAR) studies revealed that diethanolamine containing pregnenolone derivatives showed significant cytotoxicity against ER + MCF-7 and also showed good binding affinity with ERα and are relatively safe against HEK-293 cell model. Docking studies demonstrated that high binding affinity of diethanolamine analogs is due to their binding interaction with key amino acid residues present in the binding site of Erα.