Secosteroid–2-Pyrazoline Hybrids: Design, Synthesis, Biological Evaluation and Development of Therapeutic Combinations Against ERα-Positive Breast Cancer Cells

Secosteroid–2-Pyrazoline Hybrids: Design, Synthesis, Biological Evaluation and Development of Therapeutic Combinations Against ERα-Positive Breast Cancer Cells Full article

Journal

Biomedicines
ISSN: 2227-9059

Output data

Year: 2025, Volume: 13, Number: 12, Article number : 3057, Pages count : DOI: 10.3390/biomedicines13123057

Authors

Ilovaisky Alexey I. ¹ , Scherbakov Alexander M. ^2,3 , Bogdanov Fedor B. ² , Miciurov Dumitru ¹ , Chernoburova Elena I. ¹ , Merkulova Valentina M. ¹ , Bozhenko Eugene I. ¹ , Dmitrenok Andrey S. ¹ , Salnikova Diana I. ^1,2 , Sorokin Danila V. ² , Khamidullina Alvina I. ^1,4 , Krasil’nikov Mikhail A. ² , Zavarzin Igor V. ¹ , Terent’ev Alexander O. ¹

Affiliations

1	N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospekt 47, 119991 Moscow, Russia
2	N.N. Blokhin National Medical Research Center of Oncology, Kashirskoye Shosse 24, 115522 Moscow, Russia
3	Gause Institute of New Antibiotics, Bol’shaya Pirogovskaya Ulitsa 11, 119021 Moscow, Russia
4	Institute of Gene Biology, Russian Academy of Sciences, Ulitsa Vavilova 34/5, 119334 Moscow, Russia

Background/Objectives: Breast cancer remains one of the most prevalent and life-threatening malignancies worldwide. This study describes the design and biological evaluation of a series of secosteroid–2-pyrazoline hybrids as novel antitumor agents against ERα-positive breast cancer cell lines MCF-7 and T47D. Methods: A simple and efficient method for synthesizing secosteroid–2-pyrazoline hybrids was developed starting from 13α-hydroxy-3-methoxy-13,17-secoestra-1,3,5(10)-triene-17-oic acid hydrazide and 1,3-diketones. The resulting secosteroid derivatives were evaluated against hormone-dependent MCF-7 and T47D breast cancer cells. Furthermore, the selectivity and effects of three lead compounds on signaling pathways in MCF-7 cells were examined. Flow cytometry was used to assess the cell-cycle distribution of MCF-7 cells treated with the lead compound. Results: Among the synthesized hybrids, compounds 3f, 3j, and 3k exhibited potent antiproliferative activity with IC50 values of 0.2–0.5 μM against breast cancer cells, while demonstrating very low cytotoxicity towards normal cells (IC50 > 25 μM), indicating a favorable safety profile. The antitumor activity of lead compound 3j was additionally investigated in combination with standard chemotherapeutics, docetaxel and doxorubicin, yielding synergistic effects. The lead compounds showed a dual mechanism of action by inhibiting S6 kinase and promoting Bcl-2 phosphorylation at 0.9 μM, without significantly affecting hormonal breast cancer targets such as ERα, GREB1, and AR. Compound 3j induced apoptosis accompanied by a reduction of the G1/G0 phase in MCF-7 cells. Conclusions: These findings highlight secosteroid–2-pyrazoline hybrids as promising candidates for the development of next-generation breast cancer therapeutics targeting apoptosis and S6K signaling pathways.

Ilovaisky A.I. , Scherbakov A.M. , Bogdanov F.B. , Miciurov D. , Chernoburova E.I. , Merkulova V.M. , Bozhenko E.I. , Dmitrenok A.S. , Salnikova D.I. , Sorokin D.V. , Khamidullina A.I. , Krasil’nikov M.A. , Zavarzin I.V. , Terent’ev A.O.
Secosteroid–2-Pyrazoline Hybrids: Design, Synthesis, Biological Evaluation and Development of Therapeutic Combinations Against ERα-Positive Breast Cancer Cells
Biomedicines. 2025. V.13. N12. 3057 . DOI: 10.3390/biomedicines13123057 OpenAlex

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