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•The study of the functions of mPRs requires the ligands that selectively interact only with mPRs.•For the first time, the available information on the structures of compounds ...interacting with mPRs was summarized and analyzed.•Main trends of steroid scaffold modification to develop new selective mPRs ligands are proposed.•Two new mPRs ligands with unique selectivity were found.
Progesterone modulates many processes in the body, acting through nuclear receptors (nPR) in various organs and tissues. However, a number of effects are mediated by membrane progesterone receptors (mPRs), which are members of the progestin and adipoQ (PAQR) receptor family. These receptors are found in most tissues and immune cells. They are expressed in various cancer cells and appear to play an important role in the development of tumors. The role of mPRs in the development of insulin resistance and metabolic syndrome has also attracted attention. Since progesterone efficiently binds to both nPRs and mPRs, investigation of the functions of the mPRs both at the level of the whole body and at the cell level requires ligands that selectively interact with mPRs, but not with nPRs, with an affinity comparable with that of the natural hormone. The development of such ligands faces difficulties primarily due to the lack of data on the three-dimensional structure of the ligand-binding site of mPR. This review is the first attempt to summarize available data on the structures of compounds interacting with mPRs and analyze them in terms of the differences in binding to membrane and nuclear receptors. Based on the identified main structural fragments of molecules, which affect the efficiency of binding to mPRs and are responsible for the selectivity of interactions, we propose directions of modification of the steroid scaffold to create new selective mPRs ligands.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Progesterone exerts multiple effects in different tissues through nuclear receptors (nPRs) and through membrane receptors (mPRs) of adiponectin and progestin receptor families. The effect of ...progesterone on the cells through different types of receptors can vary significantly. At the same time, it affects the processes of proliferation and apoptosis in normal and tumor tissues in a dual way, stimulating proliferation and carcinogenesis in some tissues, suppressing them and stimulating cell death in others. In this study, we have shown the presence of high level of mPRβ mRNA and protein in the HepG2 cells of human hepatocellular carcinoma. Expression of other membrane and classical nuclear receptors was not detected. It could imply that mPRβ has an important function in the HepG2 cells. The main goal of the work was to study functions of this protein and mechanisms of its action in human hepatocellular carcinoma cells. Previously, we have identified selective mPRs ligands, compounds LS-01 and LS-02, which do not interact with nuclear receptors. Their employment allows differentiating the effects of progestins mediated by different types of receptors. Effects of progesterone, LS-01, and LS-02 on proliferation and death of HepG2 cells were studied in this work, as well as activating phosphorylation of two kinases, p38 MAPK and JNK, under the action of three steroids. It was shown that all three progestins after 72 h of incubation with the cells suppressed their viability and stimulated appearance of phosphatidylserine on the outer surface of the membranes, which was detected by binding of annexin V, but they did not affect DNA fragmentation of the cell nuclei. Progesterone significantly reduced expression of the proliferation marker genes and stimulated expression of the p21 protein gene, but had a suppressive effect on the expression of some proapoptotic factor genes. All three steroids activated JNK in these cells, but had no effect on the p38 MAPK activity. The effects of progesterone and selective mPRs ligands in HepG2 cells were the same in terms of suppression of proliferation and stimulation of apoptotic changes in outer membranes, therefore, they were mediated through interaction with mPRβ. JNK is a member of the signaling cascade activated in these cells by the studied steroids.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Progesterone and its synthetic analogues act on cells through different types of receptors, affecting proliferation and apoptosis. These compounds exert their effect through the nuclear receptors and ...the insufficiently studied membrane progesterone receptors (mPRs) belonging to the progestin and adiponectin Q receptor (PAQR) family. We have identified two selective ligands of mPRs that activate only this type of progesterone receptors – 19-hydroxypregn-4-en-20-one (LS-01) and 19-hydroxy-5β-pregn-3-en-20-one (LS-02). The goal of this work is to study the effect of these compounds on proliferation and death of human pancreatic adenocarcinoma cells BxPC3 and involvement of the two kinases (p38 MAPK and JNK) in signaling pathways activated by progestins through mPRs. It was shown that progesterone and the compound LS-01 significantly (
p
< 0.05) inhibited the BxPC3 cell viability, with JNK serving as a mediator. The identified targets of these two steroids are the genes of the proteins Ki67, cyclin D1, PCNA, and p21. Progesterone and the compound LS-01 significantly (
p
< 0.05) stimulate DNA fragmentation, enhancing the cell death. The p38 mitogen-activated protein kinase (MAPK) is a key mediator of this process. The BCL2A1 protein gene was identified as a target of both steroids. The compound LS-02 significantly (
p
< 0.05) alters membrane permeability and changes the exposure of phosphatidylserine on the outer membrane leaflet, also enhancing the cell death. This compound acts on these processes by activating both kinases, JNK and p38 MAPK. The compound LS-02 targets the genes encoding the proteins HRK, caspase 9, and DAPK.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•Synthesis benzylidenes of the 16-dehydroprogesterone.•Evaluation of antitumor activity against two breast cancer cell lines.•Compounds 3e,m,n regulate ERα signaling and reveal p53-independent ...mechanism of pro-apoptotic action in MCF-7 cells.
Novel benzylidenes (chalcones) of the 16-dehydroprogesterone series have been characterized and their antitumor activity against two breast cancer cell lines was evaluated. Benzylidenes exhibit significant antiproliferative effect on cells and inhibit cell growth in hormone-dependent MCF-7 and hormone-independent MDA-MB-231 breast cancer cell lines. Compound 3d exhibits the highest activity against two breast cancer cell lines, with the IC50 value of about 2 µM. Compounds 3e,m,n display considerable selectivity for hormone-dependent breast cancer cells, with the IC50 value lower than 6 µM. Moreover, these steroidal benzylidenes regulate ERα signaling and reveal p53-independent mechanism of pro-apoptotic action in MCF-7 cells. The new class of antitumor compounds holds promise as the basis for the design of agents for cancer therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK, ZRSKP
New estrogen receptor α (ERα) antagonists – 3,20-dihydroxy-19-norpregna-1,3,5(10)-trienes containing an additional carbocyclic ring D′ at the 16α,17α positions – were synthesized. The effects of the ...new compounds on the MCF-7 breast cancer cells and ERα activation were investigated. All the steroids studied were synthesized starting from estrone methyl ether. The scaffold of compounds containing the six-membered ring D′ was constructed via the Diels–Alder reaction of butadiene with 3-methoxy-19-norpregna-1,3,5(10),16-tetraen-20-one 5. The hydrogenation of primary 16α,17α-cyclohexeno-adduct 7 followed by 3-demethylation (by HBr–AcOH) and reduction of 20-oxo group (by LiAlH4) or in one step by DIBAH gave target mono- and dihydroxy steroids 9–11. The Corey–Chaykovsky reaction of the same 3-methoxy-19-norpregna-1,3,5(10),16-tetraen-20-one 5 gave 16α,17α-methylene-substituted compound. The reaction of the latter with DIBAH immediately yielded 3,20-dihydroxy-16α,17α-methyleno-19-norpregna-1,3,5(10)-triene 13. The same procedures using 3-methoxy-19-norpregna-1,3,5(10),16-tetraen-20-one 5 produced corresponding 3,20-dihydroxy-16,17-19-norpregna-1,3,5(10)-triene 16 and 3,20-dihydroxy-19-norpregna-1,3,5(10),16-tetraene 17. All compounds were fully characterized by 1D and 2D NMR, HRMS, and X-ray diffraction. The molecular docking showed that the target compounds can bind to ER, their binding mode being similar to that of natural estradiol. 16α,17α-Methylene- or unsubstituted compounds exhibit the highest cytotoxicity against MCF-7 cells, being simultaneously relatively weak ERα inhibitors. 3,20-Dihydroxy steroids containing the six-membered ring D′ proved to be the most effective ERα inhibitors. These compounds displayed moderate cytotoxicity comparable of that of tamoxifen and showed no toxic effect on MCF-10A normal, nontumorigenic epithelial cells. The new ER antagonists were found to be good candidates for further testing as agents for the treatment and prevention of ERα-positive breast cancers.
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•Series of 3,20-dihydroxy-19-norpregna-1,3,5(10)-trienes were synthesized.•Studied compounds can bind to ERα and their binding mode is similar to that of estradiol.•Synthesized 3,20-dihydroxy-19-norpregna-1,3,5(10)-trienes were cytotoxic against MCF-7.•Additional ring D′ is responsible for ERα antagonist activity of the compounds synthesized.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK, ZRSKP
6.
A new approach to the synthesis of 17-pyrazolylandrostane Komkov, Alexander V.; Menchikov, Leonid G.; Dmitrenok, Andrey S. ...
Chemistry of heterocyclic compounds (New York, N.Y. 1965),
08/2023, Volume:
59, Issue:
8
Journal Article
Peer reviewed
We propose a new approach to the synthesis of 17-pyrazolylandrostanes on the basis of 17β-3-(dimethylamino)acryloyl-16α,17α-epoxy-3β-hydroxyandrost-5-ene. This epoxyandrostene was shown to react with ...hydrazine hydrate, producing 17α-hydrazinyl-3β,16α-dihydroxy-17β-(1
H
-pyrazolyl-3-yl)androst-5-ene that was used in reactions with aromatic aldehydes, leading to 17-hydrazones. The treatment of 17β-3-(dimethylamino)acryloyl-16α,17α-epoxy-3β-hydroxyandrost-5-ene with phenylhydrazine led to the formation of 3β,16α-dihydroxy-17-(1-phenyl-1
H
-pyrazol-5-yl)androst-5-ene. At the same time, the reactions of epoxyandrostene with methylhydrazine or benzylamine proceeded with conservation of the epoxide ring and led to the formation of 16α,17-epoxyandrostanes containing a 1-methyl-1
H
-pyrazol-5-yl or 3-(benzylamino)acryloyl substituent at position 17, respectively. The obtained hydrazones exhibited a moderate antiproliferative activity against the MCF-7 breast cancer cell line. The strongest antiproliferative potential was identified in the case of 17α-(4-bromobenzylidene)hydrazinyl-3β,16α-dihydroxy-17β-(1
H
-pyrazol-3-yl)androst-5-ene with an IC
50
value around 16 μM.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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•Biotransformation of 6α-methyl-16α,17α-cyclohexanoprogesterone (mecigestone) and its 6-demethylated analog in rats was studied.•These 16α,17α-cyclohexane derivatives of progesterone ...(pregna-D'-pentaranes) metabolize like the natural hormone.•5β-, 5α-, 3β-Hydroxy-5α-, 20-hydroxy-5α-, 3,20-dihydroxy-5α-metabolites in urine samples were identified by HPLC-MS method.•11 Metabolite standards were synthesized.
Progesterone derivatives containing the D' additional cyclohexane ring in the 16α,17α-positions of steroid core (pregna-D′-pentaranes) exhibited high in vitro and in vivo selective progestogenic activity. The assessment of their biotransformation in the body, and the identification of possible metabolites are integral parts of a potential drug studies. Here we describe the results of in vivo metabolic transformation of 6α-methyl-16α,17α-cyclohexanopregn-4-ene-3,20-dione 1 and its 6-demethylated analog 2 and identification of their metabolites in rat urine. We synthesized and fully characterized (1D and 2D NMR, HRMS) 11 possible metabolites as the standards. Then we developed the LC–MS/MS assay including sample preparation and chromatography conditions for identification of the detected metabolites of 1 and 2.
The 5α- and 5β-3,20-diketo-, 3β-hydroxy-20-keto-5α-, 3-keto-20(S)-hydroxy-5α-, 3β,20(S)-dihydroxy-5α-metabolites of compounds 1 and 2 were found in rat urine samples. The starting steroids 1 and 2, as well as both 3β,20(R)-dihydroxy metabolites were not detected in the examined biological urine samples. Thus, we demonstrate for the first time that exogenous progestines - pregna-D′-pentaranes - and endogenous progesterone follow similar metabolic pathways. Therefore, despite the presence of an additional ring D′ and the methyl group in position 6, the main enzymatic transformations are similar to those of the natural hormone.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
This study aimed to investigate the activities of novel 20(R)-3,20-dihydroxy-19-norpregn-1,3,5(10)-trienes (kuz7 and kuz8b) of natural 13β- and epimeric 13α-series against triple-negative MDA-MB-231 ...breast cancer cells. High antiproliferative activity of synthesized compounds kuz8b and kuz7 against MDA-MB-231 triple-negative cancer cells was revealed. The steroid kuz7 of natural 13β-configuration was more active against MDA-MB-231 cells than the 13α-steroid kuz8b. Cell cycle analysis revealed common patterns for the action of both tested compounds. The number of cells in the subG1 phase increased in a dose-dependent manner, indicating induction of apoptosis, which was also verified by PARP cleavage. In contrast, the number of cells in the G0/G1 phase decreases with increasing compound concentration. Steroid kuz7 at micromolar concentrations reduced the expression of GLUT1, a glucose transporter. High efficacy of the combination of kuz7 with biguanide metformin was shown, and synergistic effects on MDA-MB-231 cell growth and expression of the anti-apoptotic protein Bcl-2 were revealed. According to the obtained results, including the high activity of kuz7 against triple-negative cancer cells, the detected induction of apoptosis, and the decrease in GLUT1 expression, 13β-steroid kuz7 is of interest for further preclinical studies both alone and in combination with the metabolic drug metformin.
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•Series of 3,20-dihydroxy-13α-19-norpregna-1,3,5(10)-trienes were synthesized, their structures were characterized.•Target compounds are cytotoxic against MCF-7 and ...NCI/ADR-RES.•Target compounds exert dissimilar effects on ERα transcriptional activity.•Docking studies showed that compounds can bind to ERα but their binding modes are different.
New 3,20-dihydroxy-13α-19-norpregna-1,3,5(10)-trienes were synthesized. The effects of these compounds on breast cancer cells and ERα activation were investigated. The scaffold of compounds containing the six-membered ring D′ annulated at 16α,17α-positions was constructed via the Lewis acid catalyzed Diels-Alder reaction of butadiene with 3-methoxy-13α-19-norpregna-1,3,5(10),16-tetraen-20-one 5 under a pressure of 600 MPa. The hydrogenation of primary cyclohexene adduct 6 followed by the one-pot reduction–demethylation (DIBAH) gave target epimeric 3,20-dihydroxy steroids 8a and 8b. The Corey-Chaykovsky reaction of the same conjugated ketone 5 gave a 16α,17α-methylene-substituted compound. The reaction of the latter with DIBAH yielded 3,20(R,S)-dihydroxy-16α,17α-methyleno-13α-19-norpregna-1,3,5(10)-triene 10. The hydrogenation of the 16,17-double bond of compound 5 produced a mixture of 17α- and 17β-epimeric ketones, reduction–demethylation of which gave 3,20(S)-dihydroxy-13α,17α-19-norpregna-1,3,5(10)-triene 12a and 3,20(R)-dihydroxy-13α,17β-19-norpregna-1,3,5(10)-triene 12b. All compounds were fully characterized by 1D and 2D NMR, HRMS, and X-ray diffraction. All target compounds showed pronounced cytotoxic effect against MCF-7 breast cancer cells and NCI/ADR-RES doxorubicin-resistant cells at micromolar concentrations. The ERα-mediated luciferase reporter gene assay demonstrated that all compounds, except for compound 10, are ERα inhibitors, while cyclopropane compound 10 proved to be an ERα activator. Docking experiments showed that all compounds are well accommodated to LBD ERα but have some differences in the binding mode.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK, ZRSKP
