1. Exploration and biological evaluation of 20-vinyl pregnenes: A step forward toward selective modulators of the estrogen receptor α signaling for breast cancer treatment.
- Author
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Malakhova V, Scherbakov A, Sorokin D, Leanavets H, Dzichenka Y, Zavarzin I, and Volkova Y
- Subjects
- Humans, Female, Structure-Activity Relationship, Pregnenes pharmacology, Pregnenes chemical synthesis, Pregnenes chemistry, Cell Line, Tumor, Apoptosis drug effects, Molecular Structure, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Drug Resistance, Neoplasm drug effects, Vinyl Compounds pharmacology, Vinyl Compounds chemical synthesis, Vinyl Compounds chemistry, Estrogen Receptor alpha metabolism, Estrogen Receptor alpha antagonists & inhibitors, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Signal Transduction drug effects, Antineoplastic Agents pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects
- Abstract
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) (IC
50 = 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., (© 2024 Deutsche Pharmazeutische Gesellschaft.)- Published
- 2024
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