Novel pentacyclic derivatives and benzylidenes of the progesterone series cause anti-estrogenic and antiproliferative effects and induce apoptosis in breast cancer cells.

Autor: Scherbakov AM; Department of Experimental Tumor Biology, Blokhin N.N. National Medical Research Center of Oncology, Kashirskoye shosse 24, 115522, Moscow, Russia. a.sherbakov@ronc.ru., Vorontsova SK; N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prospect 47, 119991, Moscow, Russia., Khamidullina AI; Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Vavilov Street 34/5, 119334, Moscow, Russian Federation., Mrdjanovic J; Oncology Institute of Vojvodina, Faculty of Medicine, University of Novi Sad, Put Dr Goldmana 4, 21204, Sremska Kamenica, Serbia., Andreeva OE; Department of Experimental Tumor Biology, Blokhin N.N. National Medical Research Center of Oncology, Kashirskoye shosse 24, 115522, Moscow, Russia., Bogdanov FB; Department of Experimental Tumor Biology, Blokhin N.N. National Medical Research Center of Oncology, Kashirskoye shosse 24, 115522, Moscow, Russia.; Faculty of Medicine, Moscow State University, Lomonosovsky prospect 27 bldg. 1, 119991, Moscow, Russia., Salnikova DI; Department of Experimental Tumor Biology, Blokhin N.N. National Medical Research Center of Oncology, Kashirskoye shosse 24, 115522, Moscow, Russia., Jurisic V; Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000, Kragujevac, Serbia., Zavarzin IV; N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prospect 47, 119991, Moscow, Russia., Shirinian VZ; N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prospect 47, 119991, Moscow, Russia.
Jazyk: angličtina
Zdroj: Investigational new drugs [Invest New Drugs] 2023 Feb; Vol. 41 (1), pp. 142-152. Date of Electronic Publication: 2023 Jan 25.
DOI: 10.1007/s10637-023-01332-z
Abstrakt: The promising antitumor effects of progesterone derivatives have been identified in many studies. However, the specific mechanism of action of this class of compounds has not been fully described. Therefore, in this study, we investigated the antiproliferative and (anti)estrogenic activities of novel pentacyclic derivatives and benzylidenes of the progesterone series. The antiproliferative effects of the compounds were evaluated on hormone-dependent MCF7 breast cancer cells using the MTT test. Estrogen receptor α (ERα) activity was assessed by a luciferase-based reporter assay. Immunoblotting was used to evaluate the expression of signaling proteins. All benzylidenes demonstrated inhibitory effects with IC 50 values below 10 µM, whereas pentacyclic derivatives were less active. These patterns may be associated with the lability of the geometry of benzylidene molecules, which contributes to an increase in the affinity of interaction with the receptor. The selected compounds showed significant anti-estrogenic potency. Benzylidene 1d ((8 S,9 S,10R,13 S,14 S,17 S)-17-[(2E)-3-(4-fluorophenyl)prop-2-enoyl]-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15-decahydrocyclopenta[a]phenanthren-3-one) was the most active in antiproliferative and anti-estrogenic assays. Apoptosis induced by compound 1d was accompanied by decreases in CDK4, ERα, and Cyclin D1 expression. Compounds 1d and 3d were characterized by high inhibitory potency against resistant breast cancer cells. Apoptosis induced by the leader compounds was confirmed by PARP cleavage and flow cytometry analysis. Compound 3d caused cell arrest in the G2/M phase. Further analysis of novel derivatives of the progesterone series is of great importance for medicinal chemistry, drug design, and oncology.
(© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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