Exploration and biological evaluation of 20‐vinyl pregnenes: A step forward toward selective modulators of the estrogen receptor α signaling for breast cancer treatment

Exploration and biological evaluation of 20‐vinyl pregnenes: A step forward toward selective modulators of the estrogen receptor α signaling for breast cancer treatment Научная публикация

Журнал

Archiv der Pharmazie
ISSN: 0365-6233 , E-ISSN: 1521-4184

Вых. Данные

Год: 2024, Том: 357, Номер: 7, Номер статьи : 2300651, Страниц : DOI: 10.1002/ardp.202300651

Авторы

Malakhova Victoria ¹ , Scherbakov Alexander ^2,3 , Sorokin Danila ³ , Leanavets Hanna ⁴ , Dzichenka Yaraslau ⁴ , Zavarzin Igor ¹ , Volkova Yulia ¹

Организации

1	N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia
2	Gause Institute of New Antibiotics, Moscow, Russia
3	N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
4	Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus

A series of D-ring modified steroids bearing a vinyl ketone pendant were synthesized and evaluated for antiproliferative activity against breast cancer cell line and cytochromes P450. The lead compound, 21-vinyl 20-keto-pregnene (2f) (IC50 = 2.4 µM), was shown to be a promising candidate for future anticancer drug design, particularly against estrogen receptor α (ERα)-positive breast cancer. The lead compound was found to have a significant effect on the signaling pathways in parental and 4-hydroxytamoxifen-resistant cells. Compound 2f modulated the ERK, cyclin D1, and CDK4 pathways and blocked the expression of ERα, the main driver of breast cancer growth. Compound 2f significantly reduced 17β-estradiol-induced progesterone receptor expression. Accumulation of cleaved poly(ADP-ribose) polymerase in cells treated with compound 2f indicated induction of apoptosis. The selectivity analysis showed that lead compound 2f produces no significant effects on cytochromes P450, CYP19A1, CYP21A2, and CYP7B1.

Malakhova V. , Scherbakov A. , Sorokin D. , Leanavets H. , Dzichenka Y. , Zavarzin I. , Volkova Y.
Exploration and biological evaluation of 20‐vinyl pregnenes: A step forward toward selective modulators of the estrogen receptor α signaling for breast cancer treatment
Archiv der Pharmazie. 2024. V.357. N7. 2300651 . DOI: 10.1002/ardp.202300651 WOS Scopus OpenAlex

≡ Web of science:	WOS:001196249100001
≡ Scopus:	2-s2.0-85189976110
≡ OpenAlex:	W4393946295