Synthesis and evaluation of 4-triazolylflavans as new aromatase inhibitors

Yahiaoui, Samir; Pouget, Christelle; Fagnere, Catherine; Champavier, Yves; Habrioux, G; Chulia, Albert J.

doi:10.1016/j.bmcl.2004.07.090

Cited by 20 publications

(7 citation statements)

References 16 publications

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“…These structures were designed based on many backbones of flavonoid (flavones, isoflavones, and flavnans) containing imidazole or triazole ring( 12 ) and the structure of compounds was initially synthesized by S. Castellano, et al( 17 ). Here, important pharmacophore parts of these compounds were incorporated together and new structures were designed.…”

Section: Methodsmentioning

confidence: 99%

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Binding mode of triazole derivatives as aromatase inhibitors based on docking, protein ligand interaction fingerprinting, and molecular dynamics simulation studies

et al. 2017

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Aromatase inhibitors (AIs) as effective candidates have been used in the treatment of hormone-dependent breast cancer. In this study, we have proposed 300 structures as potential AIs and filtered them by Lipinski's rule of five using DrugLito software. Subsequently, they were subjected to docking simulation studies to select the top 20 compounds based on their Gibbs free energy changes and also to perform more studies on the protein-ligand interaction fingerprint by AuposSOM software. In this stage, anastrozole and letrozole were used as positive control to compare their interaction fingerprint patterns with our proposed structures. Finally, based on the binding energy values, one active structure (ligand 15) was selected for molecular dynamic simulation in order to get information for the binding mode of these ligands within the enzyme cavity. The triazole of ligand 15 pointed to HEM group in aromatase active site and coordinated to Fe of HEM through its N4 atom. In addition, two π-cation interactions was also observed, one interaction between triazole and porphyrin of HEM group, and the other was 4-chloro phenyl moiety of this ligand with Arg115 residue.

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Section: Methodsmentioning

confidence: 99%

“…The most important parts of flavones and isoflavones based on the previous studies, were also utilized in molecular library design( 12 ).…”

Section: Introductionmentioning

confidence: 99%

Binding mode of triazole derivatives as aromatase inhibitors based on docking, protein ligand interaction fingerprinting, and molecular dynamics simulation studies

et al. 2017

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“…Flavanoid derivatives with an imidazole group at C4 were found to be potent inhibitors of aromatase, with IC 50 s of 41 and 91 nM ( 104 and 105 ) . Interestingly, the imidazole derivatives were one order of magnitude more potent than the corresponding 1 H ‐triazole derivatives ( 106 and 107 ), and two orders of magnitude more potent than the 4 H ‐triazole derivatives ( 108 ) . As well, it was found that a free hydroxy at C7 was more active than a methoxy at the same position.…”

Section: Flavonoids As Aismentioning

confidence: 99%

Polyphenolic natural products and natural product–inspired steroidal mimics as aromatase inhibitors

Nielsen

McNulty

2018

Medicinal Research Reviews

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The discovery of biologically active polyphenolic natural products, including chalcones, stilbenes, flavanones, and isoflavones as steroidal mimics has proven to be a subject of considerable importance in medicine. Some of these natural compounds have been shown to modulate key human metabolic processes via steroidal hormone receptors, or to inhibit crucial enzymes involved in the biosynthesis of steroidal hormones themselves. Isoflavone polyphenolics such as genistein are well known for this "phytoestrogenic" biological activity. This review focuses on the ability of select polyphenolics and their synthetic derivatives to function as steroidal mimics in the inhibition of the enzyme aromatase, thereby lowering production of endogenous estrogen growth hormones. The discovery of potent, natural product-based aromatase inhibitors (AIs) as hit compounds has led to the introduction of steroidal-based irreversible inhibitors, such as exemestane and reversible AIs such as anastrozole and letrozole, now standard therapy in the treatment of estrogen receptor-positive breast cancer and other hormone related indications. Pursuit of this strategy over the last few decades has been largely successful although complications and challenges remain. This review highlights the aromatase activity of natural stilbenes, chalcones, and flavanones and synthetically inspired versions thereof and draws attention to new and under-investigated areas within each class worthy of pursuit.

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“…27 Third, the Fe 2+ in the heme group of aromatase is capable of chelating to hetero atoms in inhibitors, especially N atoms. Many recent studies on aromatase inhibitors utilized pyridine, 24,28 triazole 29 or imidazole 29,30 N-heterocyclic groups to enhance the coordination between the heme iron atom of the enzyme and the heterocyclic nitrogen lone pair. Based on these structural features, the design of isoflavanone aromatase inhibitors was centered on enhancement of hydrophobic interactions, hydrogen bonding and heme iron coordination (Scheme 1).…”

Section: Resultsmentioning

confidence: 99%

Development of a new class of aromatase inhibitors: Design, synthesis and inhibitory activity of 3-phenylchroman-4-one (isoflavanone) derivatives

Bonfield

Amato

Bankemper

et al. 2012

Bioorganic & Medicinal Chemistry

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Aromatase (CYP19) catalyzes the aromatization reaction of androgen substrates to estrogens, the last and rate-limiting step in estrogen biosynthesis. Inhibition of aromatase is a new and promising approach to treat hormone-dependent breast cancer. We present here the design and development of isoflavanone derivatives as potential aromatase inhibitors. Structural modifications were performed on the A and B rings of isoflavanones via microwave-assisted, gold-catalyzed annulation reactions of hydroxyaldehydes and alkynes. The in vitro aromatase inhibition of these compounds was determined by fluorescence-based assays utilizing recombinant human aromatase (baculovirus/insect cell-expressed). The compounds 3-(4-phenoxyphenyl)chroman-4-one (1h), 6-methoxy-3-phenylchroman-4-one (2a) and 3-(pyridin-3-yl)chroman-4-one (3b) exhibited potent inhibitory effects against aromatase with IC50 values of 2.4 μM, 0.26 μM and 5.8 μM, respectively. Docking simulations were employed to investigate crucial enzyme/inhibitor interactions such as hydrophobic interactions, hydrogen bonding and heme iron coordination. This report provides useful information on aromatase inhibition and serves as a starting point for the development of new flavonoid aromatase inhibitors.

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Synthesis and evaluation of 4-triazolylflavans as new aromatase inhibitors

Cited by 20 publications

References 16 publications

Binding mode of triazole derivatives as aromatase inhibitors based on docking, protein ligand interaction fingerprinting, and molecular dynamics simulation studies

Binding mode of triazole derivatives as aromatase inhibitors based on docking, protein ligand interaction fingerprinting, and molecular dynamics simulation studies

Polyphenolic natural products and natural product–inspired steroidal mimics as aromatase inhibitors

Development of a new class of aromatase inhibitors: Design, synthesis and inhibitory activity of 3-phenylchroman-4-one (isoflavanone) derivatives

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