A comprehensive study of novel pregnenolone-isoxazole hybrids as selective inducers of mitochondrial apoptosis in breast cancer cells

A comprehensive study of novel pregnenolone-isoxazole hybrids as selective inducers of mitochondrial apoptosis in breast cancer cells Научная публикация

Журнал

RSC Medicinal Chemistry
ISSN: 2632-8682

Вых. Данные

Год: 2026, Том: 17, Номер: 6, Страницы: 2963-2983 Страниц : 21 DOI: 10.1039/d6md00076b

Авторы

Malakhova Victoria ¹ , Scherbakov Alexander ^2,3 , Salnikova Diana ^2,3,1 , Khamidullina Alvina ^4,1,5 , Sorokin Danila ² , Vasilenko Dmitry ⁶ , Chernoburova Elena ¹ , Averina Elena ⁶ , Zavarzin Igor ¹ , Volkova Yulia ¹

Организации

1	N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prospect 47, Moscow 119991, Russia
2	Department of Experimental Tumor Biology, Institute of Experimental Oncology and Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, Kashirskoe shosse 24, Moscow 115522, Russia
3	Gause Institute of New Antibiotics, Bol'shaya Pirogovskaya ulitsa 11, Moscow 119021, Russia
4	Laboratory of Molecular Oncobiology, Institute of Gene Biology, Russian Academy of Sciences, ulitsa Vavilova 34/5, Moscow 119334, Russia
5	Ufa Institute of Chemistry, Ufa Federal Research Center of the RAS, prospect Octyabrya 71, Ufa 450054, Russia
6	Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1-3, Moscow, 119991 Russia

Heterocyclic derivatives of steroids have emerged as promising anticancer agents by concurrently targeting multiple pathways, including apoptosis induction, cell cycle arrest, and mitochondrial dysfunction. Here, we report novel pregnenolone-isoxazole hybrids as selective anticancer agents targeting mitochondrial apoptosis. Starting from 20-vinyl pregnenes, nitroisoxazole-substituted pregnenolone derivatives were synthesized and subjected to nucleophilic aromatic substitution, yielding a variety of pregnenolone-isoxazole hybrids bearing azido, phenylthio, and amino groups. In total, 33 new compounds were prepared and evaluated for their in vitro antiproliferative activity against breast cancer cells. The lead compound, 20-[3′-(5″-nitro)isoxazole]-pregna-5-ene-3β-ol-20-one, demonstrated IC50 values of 2.8 μM or lower against MCF7, MCF7/HT2, MDA-MB-231, and HCC1954 breast cancer cell lines under both normoxic and hypoxic conditions. This compound induced mitochondria-dependent apoptosis in MCF7 cells in a concentration-dependent manner. Modulation of key proliferation pathways, including the PI3K/Akt and ERK cascades, further supported the antiproliferative potential of these derivatives. Considering its high cytotoxicity and antiproliferative activity in breast cancer cells, the lead compound has been identified as a promising candidate for further development.

Malakhova V. , Scherbakov A. , Salnikova D. , Khamidullina A. , Sorokin D. , Vasilenko D. , Chernoburova E. , Averina E. , Zavarzin I. , Volkova Y.
A comprehensive study of novel pregnenolone-isoxazole hybrids as selective inducers of mitochondrial apoptosis in breast cancer cells
RSC Medicinal Chemistry. 2026. V.17. N6. P.2963-2983. DOI: 10.1039/d6md00076b WOS Scopus OpenAlex

Опубликована online:

8 апр. 2026 г.

≡ Web of science:	WOS:001761912800001
≡ Scopus:	2-s2.0-105038387837
≡ OpenAlex:	W7151805199