Synthesis and crystal structures of <i>D</i>-annulated pentacyclic steroids: looking within and beyond AR signalling in prostate cancer

Vorontsova, S. K.; Заварзин, И. В.; Ширинян, Валерий З.; Bozhenko, Eugene I.; Andreeva, Olga E.; Sorokin, Danila V.; Scherbakov, Alexander M.; Minyaev, Mikhail E.

doi:10.1039/d1ce01417j

Cited by 2 publications

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“…We studied the anticancer activities of three classes of steroids derived based on 16-dehydropregnenolone (Table 1 ). The desired compounds (benzylidenes 1a–h [ 37 ] and D-annulated pentacyclic steroids 2a–h [ 38 ] and 3b, с, e , and f [ 39 ]) were synthesized by previously described methods. General information on these compounds is provided in Sect.…”

Section: Methodsmentioning

confidence: 99%

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

Scherbakov¹,

Vorontsova

Khamidullina

et al. 2023

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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. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s10637-023-01332-z.

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Section: Methodsmentioning

confidence: 99%

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

Scherbakov¹,

Vorontsova

Khamidullina

et al. 2023

Invest New Drugs

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Difluoroboron Complexes as Versatile Precursors for Steroid Modification. Lumiestrone‐Based Steroid Derivatives: Synthesis and Structural Studies

Sukhanova,

Prezent,

Minyaev

et al. 2024

Chemistry An Asian Journal

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A preparation method for steroid‐based difluoroboron complexes has been developed using lumiestrone as a steroid example. Previously inaccessible lumiestrone‐based difluoroboron complexes annulated at positions 16 and 17 of the D ring have been prepared. Such difluoroboron complexes may have large synthetic potential for heterofunctionalization of steroids at the D ring. An application of a borylation mixture Ac2O‐BF3⋅OEt2 significantly simplify the preparation of steroid “dimers” bearing two estrone moieties connected at positions 2 and 2′ via a linker. Crystal structures of key representatives have been determined by X‐ray diffraction.

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Synthesis and crystal structures of D-annulated pentacyclic steroids: looking within and beyond AR signalling in prostate cancer

Abstract: Carbocyclic steroids D-annulated at 16α and 17α positions with a 5-membered ring E are easily accessible via the interrupted Nazarov cyclization. Three steroid series have been structurally studied: chlorine-containing D-annulated...

Cited by 2 publications

References 76 publications

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

Difluoroboron Complexes as Versatile Precursors for Steroid Modification. Lumiestrone‐Based Steroid Derivatives: Synthesis and Structural Studies

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