Synthesis and evaluation of the antiproliferative activity of benzylidenes of 16-dehydroprogesterone series

Scherbakov, Alexander M.; Заварзин, И. В.; Vorontsova, S. K.; Hajra, Alakananda; Andreeva, Olga E.; Yadykov, Anton V.; Левина, И. С.; Volkova, Yu. A.; Ширинян, Валерий З.

doi:10.1016/j.steroids.2018.06.013

Cited by 20 publications

(15 citation statements)

References 45 publications

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“…To our delight, pentacyclic steroid 2g was obtained without a significant decrease in yield (total 3 steps yield is 52%), which clearly demonstrates the practical applicability of our proposed method. (Benzylidene 1g was obtained according to a previously developed method [53]).…”

Section: Gram-scale Synthesis Of Pentacyclic Steroid 2gmentioning

confidence: 99%

“…Silica column chromatography was performed using silica gel 60 (70−230 mesh); TLC analysis was conducted on silica gel 60 F254 plates. Benzylidines 1a-m were prepared according to the previously reported method [53].…”

Section: General Informationmentioning

confidence: 99%

“…In a continuation of our research on the synthesis of semi-synthetic steroid derivatives and evaluation of their antitumor activity [36,37,52,53], we focused on the development of a convenient method for the synthesis of D-annulated pentacyclic steroid of the progesterone series IV bearing the cyclopentanone moiety as an additional ring. The Nazarov cyclization reaction represents one of the most effective methods for the construction of five-membered carbocyclic rings, and it has been applied in the total synthesis of many useful natural products.…”

Section: Introductionmentioning

confidence: 99%

“…However, to the best of our knowledge, this reaction was not applied for the annulation of an additional cyclopentanone ring onto the steroid skeleton. Another important issue, which prompted us to perform this study, is that the starting benzylidenes 1 are readily available by the method proposed in our recent work [52,53]. Besides, the synthesized benzylidenes exhibited relatively high antiproliferative activity.…”

Section: Introductionmentioning

confidence: 99%

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Novel d-Annulated Pentacyclic Steroids: Regioselective Synthesis and Biological Evaluation in Breast Cancer Cells

Vorontsova

Yadykov

Scherbakov³

et al. 2020

Molecules

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The acid-catalyzed cyclization of benzylidenes based on 16-dehydropregnenolone acetate (16-DPA) was studied. It was found that these compounds readily undergo regioselective interrupted Nazarov cyclization with trapping chloride ion and an efficient method of the synthesis of d-annulated pentacyclic steroids based on this reaction was proposed. The structures of the synthesized pentacyclic steroids were determined by NMR and X-ray diffraction. It was found that the reaction affords a single diastereomer, but the latter can crystallize as two conformers depending on the structure. Antiproliferative activity of synthesized compounds was evaluated against two breast cancer cell lines: MCF-7 and MDA-MB-231. All tested compounds showed relatively high antiproliferative activity. The synthetic potential of the protocol developed was illustrated by the gram-scale experiment.

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Section: Gram-scale Synthesis Of Pentacyclic Steroid 2gmentioning

confidence: 99%

Section: General Informationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Novel d-Annulated Pentacyclic Steroids: Regioselective Synthesis and Biological Evaluation in Breast Cancer Cells

Vorontsova

Yadykov

Scherbakov³

et al. 2020

Molecules

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“…神经退行性疾病发病和治疗的复杂性使我们迫切需要设计多靶向配体来解决这些疾病所涉及的互补途径 [3] . 由于含查尔酮类结构(苯亚甲基、查尔酮、类黄酮、异黄酮等)的各种化合物易于合成且产率较高, 以及广泛的生物活性而备受关注, 尤其是抗菌、抗炎、抗癌、抗氧化、神经保护、良好的脑通透性以及 AchE 抑制剂 [4] . 例如, 含查尔酮结构的天然产物姜黄素可通过显著保护神经元免于受小胶质细胞介导的炎症反应引起的损伤而表现出良好的抗 AD 作用 [5] .…”

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Synthesis and Anti-inflammatory Activity Evaluation of 2-Dehydroepiandrosterone Benzene Methyl Derivatives

Zhu¹,

Yang²,

Gao³

et al. 2019

Chin. J. Org. Chem.

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Alzheimer's Disease (AD) is one of the major health crises in the 21st century, and due to the complexity of its pathogenesis, there has no good solution to cure this disease. In order to find more economical and effective drugs for the treatment of neurodegenerative diseases, a series of novel 2-dehydroepiandrosterone benzathine derivatives were synthesized and their activity on the NO release of microglia cell line BV-2 activated by lipopolysaccharide (LPS), as well as their effect on cell viability were studied. The structures of the synthesized compounds were confirmed by 1 H NMR, 13 C NMR and HRMS. The results showed that all compounds had inhibitory effects on the NO release of LPS-activated mouse microglial cell line BV2 after 24 h of treatment, and it was dose-dependent. In particular, the IC 50 values of 2-(3-chloro)benzylidene-15β,16βmethylene-androstane-4,6-diene-3,17-dione (5a) and 2-(3,4,5-trimethoxy)benzylidene-15β,16β-methylene-androstane-4,6-diene-3,17-dione (5j) were 2.69 and 3.28 μmol•L-1 , respectively, which were better than the positive control Minocycline. The results showed that these compounds may be effective in the development of neurodegenerative diseases involving activation of microglia, and the mechanism deserved further study.

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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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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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Synthesis and evaluation of the antiproliferative activity of benzylidenes of 16-dehydroprogesterone series

Cited by 20 publications

References 45 publications

Novel d-Annulated Pentacyclic Steroids: Regioselective Synthesis and Biological Evaluation in Breast Cancer Cells

Novel d-Annulated Pentacyclic Steroids: Regioselective Synthesis and Biological Evaluation in Breast Cancer Cells

Synthesis and Anti-inflammatory Activity Evaluation of 2-Dehydroepiandrosterone Benzene Methyl Derivatives

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

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