Synthesis, molecular modelling studies and biological evaluation of new oxoeicosanoid receptor 1 agonists

Stępniewski, Tomasz Maciej; Torrens‐Fontanals, Mariona; Rodríguez‐Espigares, Ismael; Giorgino, Toni; Primdahl, Karoline Gangestad; Vik, Anders; Stenstrøm, Yngve; Selent, Jana; Hansen, Trond Vidar

doi:10.1016/j.bmc.2018.05.036

Cited by 10 publications

(8 citation statements)

References 56 publications

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“…In particular, the natural substrate 5-oxo-ETE and T were docked in the receptor channel, finding that the two ligands occupy a similar position close to helices 3, 4, and 5 [ 21 ]. Stepniewski et al used molecular modelling simulations to explore the binding of 5-oxo-ETE and derivatives [ 22 ], based on the previous information that was provided by Blattermann et al [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Binding of Androgen- and Estrogen-Like Flavonoids to Their Cognate (Non)Nuclear Receptors: A Comparison by Computational Prediction

et al. 2021

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Flavonoids are plant bioactives that are recognized as hormone-like polyphenols because of their similarity to the endogenous sex steroids 17β-estradiol and testosterone, and to their estrogen- and androgen-like activity. Most efforts to verify flavonoid binding to nuclear receptors (NRs) and explain their action have been focused on ERα, while less attention has been paid to other nuclear and non-nuclear membrane androgen and estrogen receptors. Here, we investigate six flavonoids (apigenin, genistein, luteolin, naringenin, quercetin, and resveratrol) that are widely present in fruits and vegetables, and often used as replacement therapy in menopause. We performed comparative computational docking simulations to predict their capability of binding nuclear receptors ERα, ERβ, ERRβ, ERRγ, androgen receptor (AR), and its variant ART877A and membrane receptors for androgens, i.e., ZIP9, GPRC6A, OXER1, TRPM8, and estrogens, i.e., G Protein-Coupled Estrogen Receptor (GPER). In agreement with data reported in literature, our results suggest that these flavonoids show a relevant degree of complementarity with both estrogen and androgen NR binding sites, likely triggering genomic-mediated effects. It is noteworthy that reliable protein–ligand complexes and estimated interaction energies were also obtained for some suggested estrogen and androgen membrane receptors, indicating that flavonoids could also exert non-genomic actions. Further investigations are needed to clarify flavonoid multiple genomic and non-genomic effects. Caution in their administration could be necessary, until the safe assumption of these natural molecules that are largely present in food is assured.

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Section: Introductionmentioning

confidence: 99%

Binding of Androgen- and Estrogen-Like Flavonoids to Their Cognate (Non)Nuclear Receptors: A Comparison by Computational Prediction

et al. 2021

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“…Here we report that RACK1 is significantly downregulated by synthetic steroids that bind oxoeicosanoid receptor 1 (OXER1), a member of the G-protein-coupled receptors (GPCR) family involved in the biological action of the arachidonic acid metabolite 5-oxo-eicosatetraenoic acid (5-oxoETE) 30 . OXER1 is involved in both inflammation and oncogenesis, but its role and its significance in BC progression are just emerging 31 . Indeed, immunohistochemical analyses revealed that membrane staining for OXER1 is higher in tumor compared to non-cancerous tissues 32 .…”

Section: Introductionmentioning

confidence: 99%

OXER1 and RACK1-associated pathway: a promising drug target for breast cancer progression

et al. 2020

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Recent data indicate that receptor for activated C kinase 1 (RACK1) is a putative prognostic marker and drug target in breast cancer (BC). High RACK1 expression is negatively associated with overall survival, as it seems to promote BC progression. In tumors, RACK1 expression is controlled by a complex balance between glucocorticoids and androgens. Given the fact that androgens and androgenic derivatives can inhibit BC cell proliferation and migration, the role of androgen signaling in regulating RACK1 transcription in mammary tumors is of pivotal interest. Here, we provide evidence that nandrolone (19-nortosterone) inhibits BC cell proliferation and migration by antagonizing the PI3K/Akt/NF-κB signaling pathway, which eventually results in RACK1 downregulation. We also show that nandrolone impairs the PI3K/Akt/NF-κB signaling pathway and decreases RACK1 expression via binding to the membrane-bound receptor, oxoeicosanoid receptor 1 (OXER1). High levels of OXER1 are observed in several BC cell lines and correlate with RACK1 expression and poor prognosis. Our data provide evidence on the role played by the OXER1-dependent intracellular pathway in BC progression and shed light on the mechanisms underlying membrane-dependent androgen effects on RACK1 regulation. Besides the mechanistic relevance, the results of the study are of interest from a translational prospective. In fact, they identify a new and actionable pathway to be used for the design of innovative and rational therapeutic strategies in the context of the personalized treatment of BC. In addition, they draw attention on nandrolone-based compounds that lack hormonal activity as potential anti-tumor agents.

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“…Starting from ketolactone 23 ( epi ‐5( R ) series), the initial modification of the C1–C5 segment started with a Zemplén‐type ring‐opening with Et 3 N in MeOH to give methyl ester 27 a (R=H) with 96 % yield [49a,b] . Immediate protection of the C5 OH group proved necessary to avoid any re‐lactonization, introduction of a TBS ether under standard conditions gave the disilylether 27 b (R=TBS) with 95 % yield [33c,49c] .…”

Section: Resultsmentioning

confidence: 99%

“…Obviously, the lactone moiety required a carefully chosen functional group variation prior to the ketone reductions. Zemplén reaction using Et 3 N/MeOH smoothly gave the corresponding hydroxyester 33 a (R=H) with 98 % yield [49a,b] . Intending suppression of any re‐lactonization, the C5 OH group immediately had been protected as an acetate ( 33 b , R=Ac) with 96 % yield [55] .…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Enantiopure 6,11‐Methylene Lipoxin B₄ Methyl Ester

Trippe

Nava²,

Frank

et al. 2021

Eur J Org Chem

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The synthesis of Lipoxin B4 analogs (LXB4) to gain access to stabilized inflammation resolving compounds is an actual field of research. Focusing on variation and stabilization of the conjugated E,Z,E,E C6–C13 tetraene moiety of natural LXB4, a methylene bridge introduced between C6 and C11 suppresses any Z/E isomerization of the C8–C9 olefin. Intending to enable prospective structure variations in connection with the C1–C5 and C14–C20 fragments, a convergent total synthesis has been developed. Optically active C1–C12 building blocks were build‐up from cycloheptatriene 1‐carbonester (C6–C11, C21) and glutaryl chloride (C1–C5) using Friedel‐Crafts‐type acylation and chiral HPLC. The C13–C20 segment had been generated via a five‐step sequence starting from heptanoyl chloride. Horner key olefination enabled the assembly of the carbon backbone. A final five‐step sequence including a chelate Cram reduction of the unsaturated ketone moiety afforded the target 6,11‐methylene LXB4 methyl ester.

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Synthesis, molecular modelling studies and biological evaluation of new oxoeicosanoid receptor 1 agonists

Cited by 10 publications

References 56 publications

Binding of Androgen- and Estrogen-Like Flavonoids to Their Cognate (Non)Nuclear Receptors: A Comparison by Computational Prediction

Binding of Androgen- and Estrogen-Like Flavonoids to Their Cognate (Non)Nuclear Receptors: A Comparison by Computational Prediction

OXER1 and RACK1-associated pathway: a promising drug target for breast cancer progression

Synthesis of Enantiopure 6,11‐Methylene Lipoxin B₄ Methyl Ester

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Synthesis, molecular modelling studies and biological evaluation of new oxoeicosanoid receptor 1 agonists

Cited by 10 publications

References 56 publications

Binding of Androgen- and Estrogen-Like Flavonoids to Their Cognate (Non)Nuclear Receptors: A Comparison by Computational Prediction

Binding of Androgen- and Estrogen-Like Flavonoids to Their Cognate (Non)Nuclear Receptors: A Comparison by Computational Prediction

OXER1 and RACK1-associated pathway: a promising drug target for breast cancer progression

Synthesis of Enantiopure 6,11‐Methylene Lipoxin B4 Methyl Ester

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Synthesis of Enantiopure 6,11‐Methylene Lipoxin B₄ Methyl Ester