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

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

Журнал

Investigational New Drugs
ISSN: 0167-6997 , E-ISSN: 1573-0646

Вых. Данные

Год: 2023, Том: 41, Номер: 1, Страницы: 142-152 Страниц : 11 DOI: 10.1007/s10637-023-01332-z

Авторы

Scherbakov Alexander M. ¹ , Vorontsova Svetlana K. ² , Khamidullina Alvina I ³ , Mrdjanovic Jasminka ⁴ , Andreeva Olga E. ⁵ , Bogdanov Fedor B. ⁶ , Salnikova Diana I. ⁵ , Jurisic Vladimir ⁷ , Zavarzin Igor V. ² , Shirinian Valerii Z. ²

Организации

1	Blokhin N.N. National Medical Research Center of Oncology
2	N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia
3	Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russian Federation
4	Oncology Institute of Vojvodina, Faculty of Medicine, University of Novi Sad, Sremska Kamenica, Serbia
5	Department of Experimental Tumor Biology, Blokhin N.N. National Medical Research Center of Oncology, Moscow, Russia
6	Department of Experimental Tumor Biology, Blokhin N.N. National Medical Research Center of Oncology, Kashirskoye shosse 24, 115522, Moscow, Russia
7	Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia

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 IC50 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.

Scherbakov A.M. , Vorontsova S.K. , Khamidullina A.I. , Mrdjanovic J. , Andreeva O.E. , Bogdanov F.B. , Salnikova D.I. , Jurisic V. , Zavarzin I.V. , Shirinian V.Z.
Novel pentacyclic derivatives and benzylidenes of the progesterone series cause anti-estrogenic and antiproliferative effects and induce apoptosis in breast cancer cells
Investigational New Drugs. 2023. V.41. N1. P.142-152. DOI: 10.1007/s10637-023-01332-z WOS Scopus OpenAlex

Web of science:	WOS:000917801700001
Scopus:	2-s2.0-85146837786
OpenAlex:	W4317936710

БД	Цитирований
OpenAlex	28
Scopus	26
Web of science	26