A letrozole-based dual aromatase–sulphatase inhibitor with in vivo activity

Wood, Paul M.; Woo, L. W. Lawrence; Humphreys, Anna; Chander, Surinder K.; Purohit, Atul; Reed, Michael J.; Potter, Barry V. L.

doi:10.1016/j.jsbmb.2004.12.028

Cited by 41 publications

(72 citation statements)

References 18 publications

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“…The IC 50 value of letrozole was 30 nmol/L, in accordance with the literature data (0.67 nmol/L) [46] , indicating that this aromatase assay was comparable with the conventional human placen- [35] . Five hits were chosen based on their inhibition rate in the primary screening, and 4 lead compounds were confirmed in the secondary screening.…”

Section: Discussionsupporting

confidence: 90%

“…The IC 50 value of letrozole was 30 nmol/L, in accordance with the literature data (0.67 nmol/L) [46] , indicating that this aromatase assay was comparable with the conventional human placen- npg tal microsome methods. Subsequently, the high-throughput aromatase assay was utilized to screen a compound library of 7 000 samples for identifying aromatase inhibitors.…”

Section: Discussionsupporting

confidence: 90%

“…Letrozole was dissolved in DMSO to make a stock solution of 10 mmol/L, and the solution was serially diluted using assay buffer. A representative concentration-response curve of letrozole was plotted using PRISM version 5.0 software (GraphPad Software Inc, CA, USA) ( Figure 3A), and IC 50 value was 26.0±6.6 nmol/L, which coincides with previously reported data [36][37][38] . Our results indicate that the aromatase HTRF assay is a potentially robust assay that can be used to determine the potency of aromatase inhibitors.…”

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confidence: 86%

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Discovery of novel aromatase inhibitors using a homogeneous time-resolved fluorescence assay

Lao

et al. 2014

Acta Pharmacol Sin

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Aim: aromatase is an important target for drugs to treat hormone-dependent diseases, including breast cancer. The aim of this study was to develop a homogeneous time-resolved fluorescence (HTRF) aromatase assay suitable for high-throughput screening (HTS). Methods: A 384-well aromatase HTRF assay was established, and used to screen about 7000 compounds from a compound library. Anti-proliferation activity of the hit was evaluated using alamarBlue(R) assay in a hormone-dependent breast cancer cell line T47D. Molecular docking was conducted to elucidate the binding mode of the hit using the Discovery Studio program. Results: The Z′ value and signal to background (S/B) ratio were 0.74 and 5.4, respectively. Among the 7000 compounds, 4 hits (XHN22, XHN26, XHN27 and triptoquinone A) were found to inhibit aromatase with IC 50 values of 1.60±0.07, 2.76±0.24, 0.81±0.08 and 45.8±11.3 μmol /L, respectively. The hits XHN22, XHN26 and XHN27 shared the same chemical scaffold of 4-imidazolyl quinoline. Moreover, the most potent hit XHN27 at 10 and 50 μmol/L inhibited the proliferation of T47D cells by 45.3% and 35.2%, respectively. The docking study revealed that XHN27 docked within the active site of aromatase and might form a hydrogen bond and had a π-cation interaction with amino acid residues of the protein.Conclusion: XHN27, an imidazolyl quinoline derivative of flavonoid, is a potent aromatase inhibitor with anti-proliferation activity against breast cancer in vitro. The established assay can be used in HTS for discovering novel aromatase inhibitor.Keywords: aromatase; breast cancer; imidazolyl quinoline; triptoquinone A; homogeneous time-resolved fluorescence assay; highthroughput screening; molecular docking; drug discovery Acta Pharmacologica Sinica (2014Sinica ( ) 35: 1082Sinica ( -1092 doi: 10.1038/aps.2014 [12,13] . Previous studies have demonstrated that AIs provide an increased survival benefit compared with other therapies and have acceptable toxicity profiles with decreased virginal bleeding and thromboembolism and increased rash, diarrhea and vomiting [14,15] . As AIs sometimes have more severe bone, brain and heart side effects, research for alternative compounds is necessary [15][16][17] .Natural products, extracted from traditional medicines and foods, may be helpful for discovering novel AIs that may selectively target aromatase in the breast and reduce systemic toxicity [18] . Among these compounds, flavonoids [19] are the most commonly investigated agents due to their prominent aromatase inhibitory activity and high breast selectivity [18] . Moreover, flavonoids may modulate the multi-step process of carcinogenesis through cellular and molecular mechanisms [19] . Biochanin A (BCA), isolated from red clover (Trifolium pretense), is a common isoflavone product that can inhibit aromatase activity and cell growth in MCF-7 cells [20] . Furthermore, cyp19a1 mRNA abundance was significantly reduced by BCA through promoter regulation in SK-BR-3 cells [20] .The classical tritiated water release assay [21,22] is ...

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Section: Discussionsupporting

confidence: 90%

“…The IC 50 value of letrozole was 30 nmol/L, in accordance with the literature data (0.67 nmol/L) [46] , indicating that this aromatase assay was comparable with the conventional human placen- npg tal microsome methods. Subsequently, the high-throughput aromatase assay was utilized to screen a compound library of 7 000 samples for identifying aromatase inhibitors.…”

Section: Discussionsupporting

confidence: 90%

supporting

confidence: 86%

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Discovery of novel aromatase inhibitors using a homogeneous time-resolved fluorescence assay

Lao

et al. 2014

Acta Pharmacol Sin

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“…This phenomenon of an apparently weak inhibitor in vitro showing strong STS inhibition in vivo is not unprecedented, as similar observations were made with some examples of anastrozole-, letrozole-, and YM511-based DASIs. [24,[26][27][28] Because STS inhibition is a time-and concentration-dependent inactivation, it seems likely that even DASIs with micromolar IC 50 values against STS could be effective optimised agents. It may be unnecessary to optimise the STS IC 50 values to the low-nanomolar range, as might be instinctively expected.…”

Section: Inhibition Of Aromatase and Sulfatase In Vivomentioning

confidence: 99%

“…[24,25] We reported and validated such a DASI concept in several recent publications. [24,[26][27][28] The initial strategy for designing DASIs led to the incorporation of a phenol sulfamate moiety, the pharmacophore required for irreversible STS inhibition, into the scaffold of YM511 (4, Figure 1), which is a potent and selective nonsteroidal investigative AI. [29] Several examples of YM511-based DASIs (6 a-d, Figure 1) were prepared and some of them exhibit desirable dual inhibition in vitro, displaying potent STS inhibition whilst preserving the high level of aromatase inhibition observed with 4.…”

mentioning

confidence: 99%

Synthesis of Aromatase Inhibitors and Dual Aromatase Steroid Sulfatase Inhibitors by Linking an Arylsulfamate Motif to 4‐(4H‐1,2,4‐triazol‐4‐ylamino)benzonitrile: SAR, Crystal Structures, in vitro and in vivo Activities

et al. 2008

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4-(((4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)phenyl sulfamate (6 a) was the first dual aromatase-sulfatase inhibitor (DASI) reported. Several series of its derivatives with various linker systems between the steroid sulfatase (STS) and the aromatase inhibitory pharmacophores were synthesised and evaluated in JEG-3 cells. The X-ray crystal structures of the aromatase inhibitors, DASI precursors 42 d and 60, and DASI 43 h were determined. Nearly all derivatives show improved in vitro aromatase inhibition over 6 a but decreased STS inhibition. The best aromatase inhibitor is 42 e (IC(50)=0.26 nM) and the best DASI is 43 e (IC(50 aromatase)=0.45 nM, IC(50 STS)=1200 nM). SAR for aromatase inhibition shows that compounds containing an alkylene- and thioether-based linker system are more potent than those that are ether-, sulfone-, or sulfonamide-based, and that the length of the linker has a limited effect on aromatase inhibition beyond two methylene units. Compounds 43 d-f were studied in vivo (10 mg kg(-1), single, p.o.). The most potent DASI is 43 e, which inhibited PMSG-induced plasma estradiol levels by 92 % and liver STS activity by 98 % 3 h after dosing. These results further strengthen the concept of designing and developing DASIs for potential treatment of hormone-related cancers.

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Benzyl Triazole‐Based Aromatase Inhibitors for the Treatment of Breast Cancer

George¹,

Epps²

2012

Bioactive Heterocyclic Compound Classes

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A letrozole-based dual aromatase–sulphatase inhibitor with in vivo activity

Cited by 41 publications

References 18 publications

Discovery of novel aromatase inhibitors using a homogeneous time-resolved fluorescence assay

Discovery of novel aromatase inhibitors using a homogeneous time-resolved fluorescence assay

Synthesis of Aromatase Inhibitors and Dual Aromatase Steroid Sulfatase Inhibitors by Linking an Arylsulfamate Motif to 4‐(4H‐1,2,4‐triazol‐4‐ylamino)benzonitrile: SAR, Crystal Structures, in vitro and in vivo Activities

Benzyl Triazole‐Based Aromatase Inhibitors for the Treatment of Breast Cancer

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