Secosteroid–Isatin Hybrids as Novel Estrogen Receptor α Modulators with Selective Activity Against Hormone-Dependent Breast Cancer

Secosteroid–Isatin Hybrids as Novel Estrogen Receptor α Modulators with Selective Activity Against Hormone-Dependent Breast Cancer Full article

Journal

Molecules
ISSN: 1420-3049

Output data

Year: 2026, Volume: 31, Number: 22, Article number : 4071, Pages count : 1 DOI: 10.3390/molecules31224071

Authors

Ilovaisky Alexey I. ¹ , Scherbakov Alexander M. ^2,3 , Bogdanov Fedor B. ² , Merkulova Valentina M. ¹ , Chernoburova Elena I. ¹ , Dmitrenok Andrey S. ¹ , Salnikova Diana I. ^1,2,3 , Andreeva Olga E. ² , Sorokin Danila V. ² , Shchekotikhin Andrey E. ³ , Bozhenko Eugene I. ¹ , Minyaev Mikhail E. ¹ , Pham Quoc Long ^4,5,6 , Nghi Do Huu ^6,7 , Quynh Dang Thu ⁶ , Yaremenko Ivan A. ¹ , Zavarzin Igor V. ¹ , Terent’ev Alexander O. ¹

Affiliations

1	N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow 119991, Russia
2	N.N. Blokhin National Medical Research Center of Oncology, Kashirskoye Shosse 24, Moscow 115522, Russia
3	Gause Institute of New Antibiotics, Bol’shaya Pirogovskaya Ulitsa 11, Moscow 119021, Russia
4	Laboratory of Biophysics, Institute for Advanced Study in Technology, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam
5	Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam
6	Institute of Chemistry (ICH), Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet Street, Cau Giay, Hanoi 100000, Vietnam
7	Faculty of Engineering and Technology, Nam Can Tho University, 168 Nguyen Van Cu Street, Can Tho City 900000, Vietnam

Estrogen receptor α (ERα) remains the principal molecular driver of hormone-dependent breast cancer. In this study, we designed, synthesized, and biologically evaluated a new series of secosteroid–isatin hybrids as potential ERα-targeting anticancer agents. The lead compounds, (Z)-3a and (Z)-3b, inhibited MCF-7 cell growth with IC50 values of 6.8 and 6.0 μM, respectively, comparable to cisplatin; they were approximately threefold less potent against epithelial cells than against the target cell model of ERα-positive breast cancer. Mechanistic studies demonstrated that both compounds induced a concentration-dependent depletion of ERα protein, accompanied by downregulation of the ERα-dependent proliferative mediator cyclin D1 and the anti-apoptotic protein Mcl-1, together with accumulation of cleaved PARP, indicating activation of apoptotic cell death. Importantly, an estrogen response element (ERE)-driven luciferase reporter assay demonstrated potent concentration-dependent suppression of 17β-estradiol-induced ERα transcriptional activity, with nearly complete inhibition achieved at higher concentrations, confirming that these compounds function as effective antagonists of ERα-dependent gene transcription. Furthermore, both lead compounds exhibited predominantly synergistic interactions with doxorubicin and heliomycin, suggesting their potential utility in combination therapy. Collectively, these findings identify secosteroid–isatin hybrids as a previously unexplored class of ERα modulators with efficient suppression of estrogen receptor α signaling and induction of apoptosis, which highlights this scaffold as a promising platform for the development of next-generation therapeutics for hormone-dependent breast cancer.

Ilovaisky A.I. , Scherbakov A.M. , Bogdanov F.B. , Merkulova V.M. , Chernoburova E.I. , Dmitrenok A.S. , Salnikova D.I. , Andreeva O.E. , Sorokin D.V. , Shchekotikhin A.E. , Bozhenko E.I. , Minyaev M.E. , Pham Q.L. , Nghi D.H. , Quynh D.T. , Yaremenko I.A. , Zavarzin I.V. , Terent’ev A.O.
Secosteroid–Isatin Hybrids as Novel Estrogen Receptor α Modulators with Selective Activity Against Hormone-Dependent Breast Cancer
Molecules. 2026. V.31. N22. 4071 :1-1. DOI: 10.3390/molecules31224071

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