Synthesis of bicoumarin thiophosphate derivatives as steroid sulfatase inhibitors

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

doi:10.1016/j.ejmech.2015.06.051

Cited by 17 publications

(13 citation statements)

References 29 publications

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“…As shown in Figure , the phosphate groups were in close proximity to the proposed catalytic amino acid, FGly75 and were surrounded by a hydrophobic amino acid residues in the active site of STS. Encouraged by previous work [Demkowicz et al, ] we evaluated biflavone thiophosphate derivatives, which led to values within the lowest energy range (−6.2 to −7.0 kcal mol −1 ). In this particular case, one nonpolar part of the biflavone skeleton was oriented inside the STS active site and underwent nonpolar interactions with amino acid side chains of the hydrophobic pocket formed by Leu74, Arg98, Arg99, Val101, Leu103, Val177, Phe178, Thr180, Thr484, Val486, and Phe488.…”

Section: Resultsmentioning

confidence: 99%

Steroid Sulfatase Inhibitors Based on Phosphate and Thiophosphate Flavone Analogs

Kozak

Daśko

Masłyk

et al. 2015

Drug Development Research

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A series of phosphate and thiophosphate flavone derivatives were synthesized and biologically evaluated in vitro for inhibition of steroid sulfatase (STS) activity. The described synthesis includes the straightforward preparation of 7-hydroxy-2-phenyl-4H-chromen-4-one 3a, 2-(4-fluorophenyl)-7-hydroxy-4H-chromen-4-one 3b, 7-hydroxy-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one 3c, 7-hydroxy-2-(p-tolyl)-4H-chromen-4-one 3d modified with different phosphate or thiophosphate moieties. The inhibitory properties of the synthesized compounds were tested against human placenta STS. Some of the novel STS inhibitors had good activities against STS. In particular, the bis-(4-oxo-2-(p-tolyl)-4H-chromen-7-yl) hydrogenthiophosphate, 6i had the most potent inhibitory effect with an IC50 value of 3.25 µM as compared to an IC50 value of 8.50 µM for the 2-(4-trifluoromethylphenyl)-chromen-4-one-7-O-sulfamate used as a reference.

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Section: Resultsmentioning

confidence: 99%

Steroid Sulfatase Inhibitors Based on Phosphate and Thiophosphate Flavone Analogs

Kozak

Daśko

Masłyk

et al. 2015

Drug Development Research

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“…9). It is already proven that the identified hydrogen bond between the phosphate moieties and the Thr484 residue could favour the binding and may have a significant impact on the enzyme-ligand complex stability [7]. On the contrary, in the case of the compound l (Fig.…”

Section: Docking Results For Pm7 Optimized Geometriesmentioning

confidence: 93%

“…8). This could favour the binding and may have a significant impact on the enzyme-ligand complex stability [7]. Interestingly, the reference compound had shown similar orientation in the active site pocket like compounds j and l. On the contrary, in the case of compounds like k, m and s (Fig.…”

Section: Pathdock Outcomementioning

confidence: 94%

“…In order to verify the reproducibility and validation of the docking calculations, 667-COUMATE was submitted as reference molecule for one-ligand run calculation. The active pocket consisted of identical amino acid residues for 667-COUMATE from literature [7] suggesting that this method is valid enough to be used for docking studies of other test ligands. Docking of all ligands to protein was performed using AutoDock following the same protocol used for reference compound.…”

Section: Docking Studiesmentioning

confidence: 99%

“…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%

See 2 more Smart Citations

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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Design, synthesis and apoptosis inducing activity of nonsteroidal flavone-methanesulfonate derivatives on MCF-7 cell line as potential sulfatase inhibitor

et al. 2021

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In recent years, focusing on new potent anticancer agents with selective activity is one of the greatest challenges in cancer therapy. Breast cancer is the most common cancer and the main cause of cancer deaths in women. The sulfatase enzyme plays an important role in converting the sulfated steroids into non-sulfate steroid hormones, which increases the growth and development of many hormone-dependent cancers, such as breast cancer. In this regard, structure-based optimization was conducted to design novel avone-sulfonates pharmacophore as a new steroid sulfatase inhibitor. In the present work, the conventional methods for the synthesis of 4-oxo-2-phenyl-4H-chromen-7-yl methanesulfonate derivatives were reported. Their cytotoxicity was evaluated with MTT assay against a breast cancer cell line (MCF-7).The apoptosis inducing activity of the most cytotoxic compound 3c with an IC 50 value of 0.615 µM was evaluated in comparison to docetaxel in the presence of estradiol which is a crucial growth factor to survive the cancerous cells. The results of double staining Annexin V-FITC/PI analysis suggested that the cytotoxic activity of this compound 3c in MCF-7 cells occurs via apoptosis. Molecular docking studies were conducted to clarify the inhibition mode of the most promising compound (3c) over the sulfatase (1P49) binding site. The analysis revealed the role of hydrogen bond interaction with Gly181 and hydrophobic interactions through the 1P49 active site in the ligand-receptor complex as signi cant descriptors to rationalize the potential inhibition activity.

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Synthesis of bicoumarin thiophosphate derivatives as steroid sulfatase inhibitors

Cited by 17 publications

References 29 publications

Steroid Sulfatase Inhibitors Based on Phosphate and Thiophosphate Flavone Analogs

Steroid Sulfatase Inhibitors Based on Phosphate and Thiophosphate Flavone Analogs

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

Design, synthesis and apoptosis inducing activity of nonsteroidal flavone-methanesulfonate derivatives on MCF-7 cell line as potential sulfatase inhibitor

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