Synthesis, functionalization and biological activity of arylated derivatives of (+)-estrone

Ivanov, A. P.; Ejaz, Syeda Abida; Shah, Syed Jawad Ali; Ehlers, Peter; Villinger, Alexander; Frank, Éva; Schneider, Gyula; Wölfling, János; Rahman, Qamar; Iqbal, Jamshed; Langer, Peter

doi:10.1016/j.bmc.2016.12.009

Cited by 11 publications

(6 citation statements)

References 31 publications

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“…In this context, it should be noted that Ivanov et al worked on the optimization of the Suzuki−Miyaura reaction conditions for the synthesis of 2-aryl-E1 and 2,4-diaryl-E1 by using different ligands, and notably sterically encumbered biaryl ligands. 34 We were able to obtain E1 derivatives with a pyridinyl at C2 in good yields (approximately 70−80%) under conventional Suzuki coupling reaction conditions through the introduction of the MOM group at C3.…”

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confidence: 96%

Structure-Based Design and Synthesis of New Estrane–Pyridine Derivatives as Cytochrome P450 (CYP) 1B1 Inhibitors

Dutour

Cortés‐Benítez

Roy³

et al. 2017

ACS Med. Chem. Lett.

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Inhibition of cytochrome P450 (CYP) 1B1 is a promising therapeutic strategy, as such an inhibitor could modulate the bioactivation of procarcinogens while reducing drug resistance. Based on docking studies, the synthesis of 12 estra-1,3,5(10)-triene derivatives containing a pyridin-3-/4-yl moiety at position C2, C3, or C4 was performed, and we measured their inhibitory activity on CYP1B1 using the ethoxyresorufin--deethylase (EROD) assay. The position of the nitrogen atom in the aromatic ring has little influence on their inhibition potency, but compounds with a pyridinyl at C2 of the steroid nucleus are more potent CYP1B1 inhibitors than those with a pyridinyl at C3 or C4. Estradiol derivatives (OH at C17β) are also 10-fold more potent inhibitors than estrone derivatives (carbonyl at C17). Thus, 2-(pyridin-3-yl)-estradiol () is the best CYP1B1 inhibitor (IC = 0.011 μM) from this series of compounds, and the best steroid inhibitor reported until now. It is also 7.5-fold more potent than the well-known nonsteroidal CYP1B1 inhibitor α-naphthoflavone (IC = 0.083 μM).

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confidence: 96%

Structure-Based Design and Synthesis of New Estrane–Pyridine Derivatives as Cytochrome P450 (CYP) 1B1 Inhibitors

Dutour

Cortés‐Benítez

Roy³

et al. 2017

ACS Med. Chem. Lett.

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“…The preference of Bi(V) for arylation of estrone at the 4-position is apparently unique in the literature, and provides a direct complement to metal-catalyzed directed C-H arylations which favor functionalization of the 2-position. 17,71,72,73,74 Both 2-and 4-arylated estrones exhibit biological activity, 75 so the ability to access both regioisomers in a single operation is of potential utility in discovery projects.…”

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confidence: 99%

Modular bismacycles for the selective C–H arylation of phenols and naphthols

et al. 2020

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Given the important role played by 2-hydroxybiaryls in organic, medicinal and materials chemistry, concise methods for the synthesis of this common motif are extremely valuable. In seeking to extend the synthetic chemists' lexicon in this regard, we have developed an expedient and general strategy for the ortho-arylation of phenols and naphthols using readily-available boronic acids. Our methodology relies on in situ generation of a uniquely reactive Bi(V) arylating agent from a benchstable Bi(III) precursor via telescoped B-to-Bi transmetallation and oxidation. By exploiting reactivity

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“…Phenylations of natural or 13a-oestrone derivatives at C-2 were earlier carried out via Pd-catalysed cross-coupling reactions of steroidal aryl halides with boronic acid reagents 17,34,35 . However, this strategy requires multiple steps and prefunctionalisation of the reagents.…”

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confidence: 99%

Transition metal-catalysed A-ring C–H activations and C(sp²)–C(sp²) couplings in the 13α-oestrone series and in vitro evaluation of antiproliferative properties

Traj

Abdolkhaliq

Németh

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Facile syntheses of 3-O-carbamoyl, -sulfamoyl, or -pivaloyl derivatives of 13a-oestrone and its 17-deoxy counterpart have been carried out. Microwave-induced, Ni-catalysed Suzuki-Miyaura couplings of the newly synthesised phenol esters with phenylboronic acid afforded 3-deoxy-3-phenyl-13a-oestrone derivatives. The carbamate and pivalate esters proved to be suitable for regioselective arylations. 2-(4-Substituted) phenyl derivatives were synthesised via Pd-catalysed, microwave-assisted C-H activation reactions. An efficient, one-pot, tandem methodology was elaborated for the introduction of the carbamoyl or pivaloyl group followed by regioselective C-2-arylation and subsequent removal of the directing group. The antiproliferative properties of the novel 13a-oestrone derivatives were evaluated in vitro on five human adherent cancer cell lines of gynaecological origin. 3-Sulfamate derivatives displayed substantial cell growth inhibitory potential against certain cell lines. The newly identified antiproliferative compounds having hormonally inactive core might be promising candidates for the design of more active anticancer agents.

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Synthesis, functionalization and biological activity of arylated derivatives of (+)-estrone

Cited by 11 publications

References 31 publications

Structure-Based Design and Synthesis of New Estrane–Pyridine Derivatives as Cytochrome P450 (CYP) 1B1 Inhibitors

Structure-Based Design and Synthesis of New Estrane–Pyridine Derivatives as Cytochrome P450 (CYP) 1B1 Inhibitors

Modular bismacycles for the selective C–H arylation of phenols and naphthols

Transition metal-catalysed A-ring C–H activations and C(sp²)–C(sp²) couplings in the 13α-oestrone series and in vitro evaluation of antiproliferative properties

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Synthesis, functionalization and biological activity of arylated derivatives of (+)-estrone

Cited by 11 publications

References 31 publications

Structure-Based Design and Synthesis of New Estrane–Pyridine Derivatives as Cytochrome P450 (CYP) 1B1 Inhibitors

Structure-Based Design and Synthesis of New Estrane–Pyridine Derivatives as Cytochrome P450 (CYP) 1B1 Inhibitors

Modular bismacycles for the selective C–H arylation of phenols and naphthols

Transition metal-catalysed A-ring C–H activations and C(sp2)–C(sp2) couplings in the 13α-oestrone series and in vitro evaluation of antiproliferative properties

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Transition metal-catalysed A-ring C–H activations and C(sp²)–C(sp²) couplings in the 13α-oestrone series and in vitro evaluation of antiproliferative properties