Structure-based design and profiling of novel 17β-HSD14 inhibitors

Braun, Florian; Bertoletti, Nicole; Möller, Gabriele; Adamski, Jerzy; Frotscher, Martin; Guragossian, Nathalie; Gírio, Patrícia Alexandra Madeira; Borgne, Marc Le; Ettouati, Laurent; Falson, Pierre; Müller, Sebastian; Vollmer, Günther; Heine, A.; Klebe, G.; Marchais‐Oberwinkler, Sandrine

doi:10.1016/j.ejmech.2018.05.029

Cited by 9 publications

(7 citation statements)

References 37 publications

(84 reference statements)

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“…Very recently, 17β-HSD14 inhibitors containing a quinoline moiety have been published (Braun et al 2018). Compound 97 (figure 24) is the most interesting inhibitor in this series, showing high affinity to the target protein combined with a good selectivity profile toward the 17β-HSD types 1, 2 and 10 as well as ERα.…”

Section: Inhibitors Of 17β-hsd14mentioning

confidence: 99%

Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

Salah

Abdelsamie²,

Frotscher

2019

Molecular and Cellular Endocrinology

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During the past 25 years, the modulation of estrogen action by inhibition of 17β-hydroxysteroid dehydrogenase types 1 and 2 (17β-HSD1 and 17β-HSD2), respectively, has been pursued intensively. In the search for novel treatment options for estrogen-dependent diseases (EDD) and in order to explore estrogenic signaling pathways, a large number of steroidal and nonsteroidal inhibitors of these enzymes has been described in the literature. The present review gives a survey on the development of inhibitor classes as well as the structural formulas and properties of their most interesting representatives. In addition, rationally designed dual inhibitors of both 17β-HSD1 and steroid sulfatase (STS) as well as the first inhibitors of 17β-HSD14 are covered.

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Section: Inhibitors Of 17β-hsd14mentioning

confidence: 99%

Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

Salah

Abdelsamie²,

Frotscher

2019

Molecular and Cellular Endocrinology

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“…Five nonsymmetric novel C^N*N'^C' proligands, 2-aryl 1 -6-(aryl 2 (6-phenylpyridin-2-yl)amino)nicotinates, where aryl 1 = 4-FC 6 H 4 , aryl 2 = 4-BrC 6 H 4 (L1), aryl 1 = aryl 2 = thiophen-2-yl (L2), aryl 1 = aryl 2 = benzo[b]thiophen-2-yl (L3), aryl 1 = thiophen-2-yl, aryl 2 = 4-MeOC 6 H 4 (L4), aryl 1 = benzo[b]thiophen-2-yl, aryl 2 = 4-MeOC 6 H 4 (L5), were synthesized by using successive Suzuki [35] and Buchwald-Hartwig [33,34,36] coupling reactions (Scheme 1). Their synthesis and characterization are described in Part 1 of the Supporting Information.…”

Section: Resultsmentioning

confidence: 99%

“…General procedure for Suzuki coupling: N,6-Diarylpyridin-2-amines L' was synthesized according published procedure. [35] Arylboronic acid (commercially available; 1.2 mmol, 1.2 equiv.) and, after 5 min, Cs 2 CO 3 (4 mmol, 4 equiv.)…”

Section: Synthesis Of the Ligandsmentioning

confidence: 99%

Nonsymmetric [Pt(C^N*N′^C′)] Complexes: Aggregation‐Induced Emission in the Solid State and in Nanoparticles Tuned by Ligand Structure

Solomatina

Галенко

Kozina

et al. 2022

Chemistry A European J

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Five square-planar [Pt(C^N*N'^C')] complexes (Pt1-Pt5) with novel nonsymmetric tetradentate ligands (L1-L5) were synthesized and characterized. Varying the structure of the metalating aromatic systems result in substantial changes in photophysical properties and intermolecular interaction mode of the complexes in solution and in solid state. The complexes are strongly emissive in tetrahydrofuran solution, with the band maxima ranging from 560 to 690 nm. Three of these complexes (Pt1, Pt2, Pt4) afford nanospecies upon injection of their solution into water, which show aggrega-tion-induced emission (AIE) with a strong red shift of emission bands. In the solid state, crystalline samples of these complexes demonstrate mechanochromism upon grinding with a bathochromic shift of the emission. DFT and TD-DFT computational analysis of monomeric Pt1-Pt5 in solution and model dimeric emitters formed through intermolecular interaction of Pt1, Pt2, Pt4 molecules allowed assignment of observed AIE to the 3 MMLCT excited states of Pt-Pt bonded aggregates of these complexes.

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“…For enzymatic assays and inhibitor testing, all enzymes were cloned into bacterial or mammalian expression vectors. AKR1C3 and the human hydroxysteroid dehydrogenases HSD17B1, HSD17B2, HSD17B4 (SDR domain), HSD17B7, and HSD17B10 were cloned into a pGEX vector as described in [71,72]. The coding sequences for AKR1C1, AKR1C2, and AKR1C4 were cloned by Gateway technology into the pcDNA3-N-MycDest vector according to the manufacturer's instructions (Life Technologies, Carlsbad, CA, USA).…”

Section: Enzymesmentioning

confidence: 99%

“…For assays with HSD17B3, HEK293 cells stably expressing HSD17B3 were used [71]. Enzymes were expressed in E. coli BL21 DE3 or E. coli BL21 DE3 Codon Plus RP (Stratagene, San Diego, CA, USA) or in HEK293 cells as described in [71][72][73]. Bacterial and cell pellets were stored at −20 • C and −80 • C, respectively, until use.…”

Section: Enzymesmentioning

confidence: 99%

Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3

et al. 2022

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Naturally occurring substances are valuable resources for drug development. In this respect, chalcones are known to be antiproliferative agents against prostate cancer cell lines through various mechanisms or targets. Based on the literature and preliminary results, we aimed to study and optimise the efficiency of a series of chalcones to inhibit androgen-converting AKR1C3, known to promote prostate cancer. A total of 12 chalcones with different substitution patterns were synthesised. Structure–activity relationships associated with these modifications on AKR1C3 inhibition were analysed by performing enzymatic assays and docking simulations. In addition, the selectivity and cytotoxicity of the compounds were assessed. In enzymatic assays, C-6′ hydroxylated derivatives were more active than C-6′ methoxylated derivatives. In contrast, C-4 methylation increased activity over C-4 hydroxylation. Docking results supported these findings with the most active compounds fitting nicely in the binding site and exhibiting strong interactions with key amino acid residues. The most effective inhibitors were not cytotoxic for HEK293T cells and selective for 17β-hydroxysteroid dehydrogenases not primarily involved in steroid hormone metabolism. Nevertheless, they inhibited several enzymes of the steroid metabolism pathways. Favourable substitutions that enhanced AKR1C3 inhibition of chalcones were identified. This study paves the way to further develop compounds from this series or related flavonoids with improved inhibitory activity against AKR1C3.

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Structure-based design and profiling of novel 17β-HSD14 inhibitors

Cited by 9 publications

References 37 publications

Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

Nonsymmetric [Pt(C^N*N′^C′)] Complexes: Aggregation‐Induced Emission in the Solid State and in Nanoparticles Tuned by Ligand Structure

Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3

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