Estrogen receptor alpha (ER) is a key biomarker for breast cancer, and the presence or absence of ER in breast and other hormone-dependent cancers decides treatment regimens and patient prognosis. ER is activated after ligand binding - typically by steroid. 2682 steroid compounds were used in a molecular docking study to identify novel ligands for ER and to predict compounds that may show anticancer activity. The effect of the most promising compounds was determined by a novel luciferase reporter assay. Two compounds, 7 and 12, showing ER inhibitory activity comparable to clinical inhibitors such as tamoxifen or fulvestrant were selected. We propose that the inhibitory effect of compounds 7 and 12 on ER is related to the presence of a double bond in their D-ring, which may protect against ER activation by reducing the electron density of the keto group, or may undergo metabolism leading to an active compound. Western blotting revealed that compound 12 decreased the level of ER in the breast cancer cell line MCF7, which was associated with reduced expression of both isoforms of the progesterone receptor, a well-known downstream target of ER. However, compound 12 has a different mechanism of action from fulvestrant. Furthermore, we found that compound 12 interferes with mitochondrial functions, probably by disrupting the electron transport chain, leading to induction of the intrinsic apoptotic pathway even in ER-negative breast cancer cells. In conclusion, the combination of computational and experimental methods shown here represents a rapid approach to determine the activity of compounds towards ER. Our data will not only contribute to research focused on the regulation of ER activity but may also be useful for the further development of novel steroid receptor-targeted drugs applicable in clinical practice.
- MeSH
- Estrogen Receptor alpha genetics metabolism MeSH
- Estradiol pharmacology therapeutic use MeSH
- Estrone * pharmacology MeSH
- Fulvestrant pharmacology therapeutic use MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Breast Neoplasms * drug therapy metabolism MeSH
- Receptors, Estrogen metabolism MeSH
- Molecular Docking Simulation MeSH
- Tamoxifen pharmacology MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
A chemoselective procedure for MCPBA oxidation of 26-thiodiosgenin to corresponding sulfoxides and sulfone was elaborated. An unusual equilibration of sulfoxides in solution was observed. Moreover, α-alkylation of sulfoxide and sulfone was investigated. Finally, the biological activity of obtained compounds was examined.
- MeSH
- Diosgenin * MeSH
- Oxidation-Reduction MeSH
- Sulfur chemistry MeSH
- Sulfones MeSH
- Sulfoxides chemistry MeSH
- Publication type
- Journal Article MeSH
1,10-Phenanthroline was decorated with triterpenoid-based substituents bearing additional spermine units to form amphiphilic molecules. The synthetic procedure designed for the new phenanthroline-triterpenoid amphiphiles is described in detail. Besides 1,10-phenanthroline, all target structures bear 1,4-disubstituted 1,2,3-triazole rings. The target compounds self-assembled into either helical-like or sheet-like nanostructures, depending on the structure of the target molecule, either based on betulinic acid or oleanolic acid, and on the way of binding spermine subunits to the rest of the molecules. They also proved their ability to coordinate 64Cu(II) ions. Finally, the target compounds showed cytotoxicity that was partly dependent on the formation of nanostructures.
In search of new cytotoxic derivatives based on the lupane scaffold, methyl betulonate and methyl 20,29-dihydrobetulonate were conjugated with Reformatsky reagents to provide homolupanes extended at the C3-carbon atom. Further transformations of the functional groups afforded a series of derivatives with 2-hydroxyethyl and allyl alcohol moieties. Their varying antiproliferative activity in vitro was then investigated in four cancer cell lines and in normal human BJ fibroblasts. In cervical carcinoma HeLa cells, derivatives 5, 6 and 17 were the most promising with lower micromolar IC50s and no toxicity to fibroblasts, thus showing a high therapeutic index. In addition, induction of apoptosis was found in HeLa cells after 24 h treatment with compounds 5, 6, 13 and 29. This newly synthesized series is more interesting than the published lupane and homolupane triterpenes and saponins, due to their nontoxicity towards healthy human cells and stronger cytotoxicity to various cancer cell lines. This approach increases their potential as anticancer agents.
- MeSH
- Antineoplastic Agents * pharmacology MeSH
- HeLa Cells MeSH
- Betulinic Acid MeSH
- Drug Screening Assays, Antitumor MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Triterpenes * pharmacology MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
(1) Background: To compare the effect of selected triterpenoids with their structurally resembling derivatives, designing of the molecular ribbons was targeted to develop compounds with selectivity in their pharmacological effects. (2) Methods: In the synthetic procedures, Huisgen 1,3-dipolar cycloaddition was applied as a key synthetic step for introducing a 1,2,3-triazole ring as a part of a junction unit in the molecular ribbons. (3) Results: The antimicrobial activity, antiviral activity, and cytotoxicity of the prepared compounds were studied. Most of the molecular ribbons showed antimicrobial activity, especially on Staphylococcus aureus, Pseudomonas aeruginosa, and Enterococcus faecalis, with a 50-90% inhibition effect (c = 25 µg·mL-1). No target compound was effective against HSV-1, but 8a displayed activity against HIV-1 (EC50 = 50.6 ± 7.8 µM). Cytotoxicity was tested on several cancer cell lines, and 6d showed cytotoxicity in the malignant melanoma cancer cell line (G-361; IC50 = 20.0 ± 0.6 µM). Physicochemical characteristics of the prepared compounds were investigated, namely a formation of supramolecular gels and a self-assembly potential in general, with positive results achieved with several target compounds. (4) Conclusions: Several compounds of a series of triterpenoid molecular ribbons showed better pharmacological profiles than the parent compounds and displayed certain selectivity in their effects.
- Publication type
- Journal Article MeSH
Brassinosteroids are a class of plant hormones that regulate a broad range of physiological processes such as plant growth, development and immunity, including the suppression of biotic and abiotic stresses. In this paper, we report the synthesis of new brassinosteroid analogues with a nitrogen-containing side chain and their biological activity on Arabidopis thaliana. Based on molecular docking experiments, two groups of brassinosteroid analogues were prepared with short and long side chains in order to study the impact of side chain length on plants. The derivatives with a short side chain were prepared with amide, amine and ammonium functional groups. The derivatives with a long side chain were synthesized using amide and ammonium functional groups. A total of 25 new brassinosteroid analogues were prepared. All 25 compounds were tested in an Arabidopsis root sensitivity bioassay and cytotoxicity screening. The synthesized substances showed no significant inhibitory activity compared to natural 24-epibrassinolide. In contrast, in low concentration, several compounds (8a, 8b, 8e, 16e, 22a and 22e) showed interesting growth-promoting activity. The cytotoxicity assay showed no toxicity of the prepared compounds on cancer and normal cell lines.
Six new (1, 2, 6, 8, 13, and 20) and twenty previously isolated (3-5, 7, 9-12, 14-19, and 21-26) steroids featuring thirteen different carbocycle motifs were isolated from the organic extract of the soft coral Sinularia polydactyla collected from the Hurghada reef in the Red Sea. The structures and the relative configurations of the isolated natural products have been determined based on extensive analysis of their NMR and MS data. The cytotoxic, anti-inflammatory, anti-angiogenic, and neuroprotective activity of compounds 3-7, 9-12, 14-20, and 22-26, as well as their effect on androgen receptor-regulated transcription was evaluated in vitro in human tumor and non-cancerous cells. Steroids 22 and 23 showed significant cytotoxicity in the low micromolar range against the HeLa and MCF7 cancer cell lines, while migration of endothelial cells was inhibited by compounds 11, 12, 22, and 23 at 20 µM. The results of the androgen receptor (AR) reporter assay showed that compound 11 exhibited the strongest inhibition of AR at 10 µM, while it is noteworthy that steroids 10, 16, and 20 displayed increased inhibition of AR with decreasing concentrations. Additionally, compounds 11 and 23 showed neuroprotective activity on neuron-like SH-SY5Y cells.
- MeSH
- Anti-Inflammatory Agents isolation & purification pharmacology MeSH
- Antineoplastic Agents isolation & purification pharmacology MeSH
- Human Umbilical Vein Endothelial Cells drug effects metabolism MeSH
- Neovascularization, Physiologic drug effects MeSH
- HeLa Cells MeSH
- Angiogenesis Inhibitors isolation & purification pharmacology MeSH
- Anthozoa chemistry MeSH
- Humans MeSH
- MCF-7 Cells MeSH
- Molecular Structure MeSH
- Neoplasms drug therapy metabolism pathology MeSH
- Neurons drug effects metabolism pathology MeSH
- Neuroprotective Agents isolation & purification pharmacology MeSH
- Steroids isolation & purification pharmacology MeSH
- Cell Survival drug effects MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Comparative Study MeSH
- Geographicals
- Indian Ocean MeSH
- Publication type
- Meeting Abstract MeSH
Seven previously undescribed sesquiterpene lactones, three known sesquiterpene lactones (ixerin D, 15-p-hydroxyphenylacetyllactucin, and 15-p-hydroxyphenylacetyllactucin-8-sulfate), and two known quinic acid derivatives (3-O-feruloylquinic acid and 3,5-di-O-caffeoylquinic acid) were isolated from Sonchus palustris L. roots. Four formerly undescribed compounds were elucidated to be 3β,14-dihydroxycostunolide-3-O-β-D-glucopyranosyl-(2-O-p-hydroxyphenylacetyl)-14-O-p-hydroxyphenylacetate, 15-p-methoxyphenylacetyllactucin, 15-p-methoxyphenylacetyllactucin-8-sulfate, and 8-p-hydroxyphenylacetyllactucin-15-sulfate. Additionally, three undescribed conjugates of lactucin and a eudesmanolide type sesquiterpenic acid, sonchpalustrin, 4″-O-methylsonchpalustrin, and isosonchpalustrin, were characterized. The structures of the newly discovered natural products were elucidated using 1D and 2D NMR spectroscopy and UHPLC-HRMS. 15-p-Hydroxyphenylacetyllactucin and 15-p-methoxyphenylacetyllactucin showed significant in vitro cytotoxicity against CEM and BJ cells with IC50 values ranging from 3.9 to 9.8 μM. Compounds 3 and 4 showed also strong anti-inflammatory activity in vitro.
- MeSH
- Antineoplastic Agents, Phytogenic chemistry isolation & purification pharmacology MeSH
- Asteraceae chemistry MeSH
- Phytochemicals chemistry isolation & purification pharmacology MeSH
- Cells, Cultured MeSH
- Lactones chemistry isolation & purification pharmacology MeSH
- Drug Screening Assays, Antitumor MeSH
- Humans MeSH
- Cell Proliferation drug effects MeSH
- Sesquiterpenes chemistry isolation & purification pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
The target diosgenin-betulinic acid conjugates are reported to investigate their ability to enhance and modify the pharmacological effects of their components. The detailed synthetic procedure that includes copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (click reaction), and palladium-catalyzed debenzylation by hydrogenolysis is described together with the results of cytotoxicity screening tests. Palladium-catalyzed debenzylation reaction of benzyl ester intermediates was the key step in this synthetic procedure due to the simultaneous presence of a 1,4-disubstituted 1,2,3-triazole ring in the molecule that was a competing coordination site for the palladium catalyst. High pressure (130 kPa) palladium-catalyzed procedure represented a successful synthetic step yielding the required products. The conjugate 7 showed selective cytotoxicity in human T-lymphoblastic leukemia (CEM) cancer cells (IC50 = 6.5 ± 1.1 µM), in contrast to the conjugate 8 showing no cytotoxicity, and diosgenin (1), an adaptogen, for which a potential to be active on central nervous system was calculated in silico. In addition, 5 showed medium multifarious cytotoxicity in human T-lymphoblastic leukemia (CEM), human cervical cancer (HeLa), and human colon cancer (HCT 116). Betulinic acid (2) and the intermediates 3 and 4 showed no cytotoxicity in the tested cancer cell lines. The experimental data obtained are supplemented by and compared with the in silico calculated physico-chemical and absorption, distribution, metabolism, and excretion (ADME) parameters of these compounds.
- MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Cycloaddition Reaction MeSH
- Diosgenin chemistry MeSH
- Hydrogenation MeSH
- Catalysis MeSH
- Drug Screening Assays, Antitumor MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Palladium chemistry MeSH
- Pentacyclic Triterpenes chemistry MeSH
- Pressure MeSH
- Cell Survival drug effects MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
