Phosphate tricyclic coumarin analogs as steroid sulfatase inhibitors: synthesis and biological activity

Kozak, Witold; Daśko, Mateusz; Masłyk, Maciej; Pieczykolan, Jerzy; Gielniewski, Bartłomiej; Rachoń, Janusz; Demkowicz, Sebastian

doi:10.1039/c4ra07135b

Cited by 20 publications

(17 citation statements)

References 24 publications

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“…Encouraged by our previous research on the synthesis and biological evaluation of tricyclic coumarin phosphate derivatives [18], we decided to synthesize 7-hydroxy-2,3-dihydro-1H-cyclopenta[c] chromen-2-one, 3-hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one and 3-hydroxy-8,9,10,11-tetrahydro-7H-cyclohepta[c]chromen-6-one modified with different thiophosphate groups (see Scheme 1). First, we prepared the above-mentioned coumarin scaffolds 1a-c using previously described procedures [18].…”

Section: Chemistrymentioning

confidence: 99%

“…The effects of the ring size within the coumarin scaffolds and the presence of different types of thiophosphate groups were compared with the tricyclic coumarin phosphate derivatives previously described [18]. The affinity of all synthesized compounds for STS was determined using an in vitro STS assay, following reported methods [19,20].…”

Section: Sts Enzyme Assaysmentioning

confidence: 99%

“…First, we prepared the above-mentioned coumarin scaffolds 1a-c using previously described procedures [18].…”

Section: Chemistrymentioning

confidence: 99%

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Synthesis and biological evaluation of thiophosphate tricyclic coumarin derivatives as steroid sulfatase inhibitors

Kozak

Daśko

Masłyk

et al. 2015

Journal of Asian Natural Products Research

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Steroid sulfatase (STS) enzyme inhibition is an important approach to the management of hormone-dependent breast cancer. In this paper, we report convenient methods for the synthesis and biological evaluation of thiophosphate tricyclic coumarin analogs exhibiting STS activity. The described methods are based on the straightforward preparation of 7-hydroxy-2,3-dihydro-1H-cyclopenta[c]chromen-2-one, 3-hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one, and 3-hydroxy-8,9,10,11-tetrahydro-7H-cyclohepta[c]chromen-6-one and their further modification by the introduction of various thiophosphate moieties. The inhibition properties of the synthesized compounds were tested toward STS isolated from human placenta. Most of the new STS inhibitors possessed good to moderate activity toward STS. During the course of our investigation, the largest inhibitory effects in the STS enzyme assays were observed for the two compounds 3f and 4r, with IC50 values of 13.3 and 30.3 μM, respectively (the IC50 value of 1 μM for the 665-COUMATE was used as a reference). The structure-activity relationships of the synthesized coumarin derivatives toward STS enzymes are discussed.

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Section: Chemistrymentioning

confidence: 99%

Section: Sts Enzyme Assaysmentioning

confidence: 99%

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Synthesis and biological evaluation of thiophosphate tricyclic coumarin derivatives as steroid sulfatase inhibitors

Kozak

Daśko

Masłyk

et al. 2015

Journal of Asian Natural Products Research

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“…The synthesis of tricyclic coumarin scaffolds has been performed via the Pechmann condensation from corresponding b-ketoesters and resorcin in the presence of concentrated H 2 SO 4 as an acidic catalyst [27]. The Pechmann condensation is one of the most common procedures for the preparation of coumarin and its derivatives.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis of bicoumarin thiophosphate derivatives as steroid sulfatase inhibitors

Demkowicz

Kozak

Daśko

et al. 2015

European Journal of Medicinal Chemistry

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“…One of the strategies employed for generating a lead STS inhibitor involved replacement of the sulphate group of the natural enzyme substrate with surrogates or mimics other than sulfamate moiety, such as phosphates or thiophosphates [6]. Recently, Demkowicz et al synthesized new phosphate and thiophosphate esters of tricyclic coumarin derivatives as potent STS inhibitors [7][8][9]. The most active compound, bis-(6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-3-yl) hydrogenthiophosphate (3) (Fig.…”

Section: Introductionmentioning

confidence: 99%

Geometry optimization of steroid sulfatase inhibitors - the influence on the free binding energy with STS

et al. 2017

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In the paper we review the application of two techniques (molecular mechanics and quantum mechanics) to study the influence of geometry optimization of the steroid sulfatase inhibitors on the values of descriptors coded their chemical structure and their free binding energy with the STS protein. We selected 22 STS-inhibitors and compared their structures optimized with MM+, PM7 and DFT B3LYP/6-31++G* approaches considering separately the bond lengths, angles, dihedral angles and total energies. We proved that different minimum energy conformers could be generated depending on the choice of the optimization method. However, the results indicated that selection of the geometry optimization method did not affect the optimal STS inhibitor coordinates, and hence the values of molecular descriptors which describe the 3D structure of the molecule. To study the interaction pattern of the STS inhibitors (optimized using different methods) with the target receptor we applied two strategies: AutoDock and PathDock. The docking studies point out that selection of software to docking simulation is one of the crucial factors determining the binding mode of STS inhibitors with their molecular target. Other factor is related to the ligand orientation in the binding pocket. Finally, obtained results indicate that MM+ and PM7 methods (faster and less expensive) could be successfully employed to geometry optimization of the STS inhibitors before their docking procedure as well as for molecular descriptors calculations.

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Phosphate tricyclic coumarin analogs as steroid sulfatase inhibitors: synthesis and biological activity

Abstract: In the present work, we report convenient methods for the synthesis and biological evaluation of phosphate tricyclic coumarin derivatives as potential steroid sulfatase inhibitors.

Cited by 20 publications

References 24 publications

Synthesis and biological evaluation of thiophosphate tricyclic coumarin derivatives as steroid sulfatase inhibitors

Synthesis and biological evaluation of thiophosphate tricyclic coumarin derivatives as steroid sulfatase inhibitors

Synthesis of bicoumarin thiophosphate derivatives as steroid sulfatase inhibitors

Geometry optimization of steroid sulfatase inhibitors - the influence on the free binding energy with STS

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