Synthesis and biological evaluation of fluorinated N -benzoyl and N -phenylacetoyl derivatives of 3-(4-aminophenyl)-coumarin-7- O -sulfamate as steroid sulfatase inhibitors

Daśko, Mateusz; Przybyłowska, Maja; Rachoń, Janusz; Masłyk, Maciej; Kubiński, Konrad; Misiak, Majus; Składanowski, Andrzej; Demkowicz, Sebastian

doi:10.1016/j.ejmech.2017.01.028

Cited by 23 publications

(13 citation statements)

References 26 publications

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“…In the course of our research, we synthesized all of the newly designed STS inhibitors, which are N ‐thiophosphorylated derivatives of 3‐(4‐aminophenyl)‐coumarin‐7‐ O ‐sulfamate ( 9a‐g ), using the pathway shown in Scheme . In the first step, we synthesized 7‐hydroxy‐3‐(4‐aminophenyl)‐coumarin 7 according the procedure that we previously described (Daśko et al, ). Next, coumarin derivative 7 was N ‐thiophosphorylated with the corresponding chlorothiophosphate in anhydrous pyridine.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, extensive research on the preparation of many coumarin derivatives as STS inhibitors has been carried out. Inhibitory activity against STS was determined in the case of phosphate and thiophosphate derivatives of tricyclic coumarin (Kozak et al, ; Kozak et al, ), fluorinated derivatives of 3‐phenylcoumarin‐7‐ O ‐sulfamate (Demkowicz et al, ) and fluorinated N ‐benzoyl and N ‐phenylacetoyl derivatives of 3‐(4‐aminophenyl)‐coumarin‐7‐ O ‐sulfamate (Daśko et al, ). For example, compounds 4 and 5 demonstrated inhibitory activity with an IC 50 value of 180 nM (for both compounds) in an assay with isolated STS.…”

Section: Introductionmentioning

confidence: 99%

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Novel steroid sulfatase inhibitors based on N‐thiophosphorylated 3‐(4‐aminophenyl)‐coumarin‐7‐O‐sulfamates

Daśko

Demkowicz

Biernacki

et al. 2019

Drug Development Research

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In the present work, we described convenient methods for the synthesis of N‐thiophosphorylated 3‐(4‐aminophenyl)‐coumarin‐7‐O‐sulfamates as steroid sulfatase (STS) inhibitors. To design the structures of the potential STS inhibitors, molecular modeling techniques were used. A computational docking method was used to determine the binding modes of the synthesized inhibitors as well as to identify potential interactions between specified functional groups on the inhibitors and the amino acid residues present in the active site of the enzyme. The inhibitory activities of the synthesized compounds were tested in an enzymatic assay with STS isolated from a human placenta. Within the set of newly synthesized compounds, 9e demonstrated the highest inhibitory activity in the enzymatic assay with an IC50 value of 0.201 μM (the IC50 value of 667‐COUMATE in the same test was 0.062 μM). Furthermore, we tried to verify if the obtained STS inhibitors are able to pass through the cellular membrane effectively in cell line experiments. In the course of our study, we determined the STS activity in the MCF‐7 cell line after incubation in the presence of the inhibitors (at 100 nM concentration). For this evaluation, we included newly synthesized compounds 9a‐g and their N‐phosphorylated analogs 6a‐h, whose synthesis has been previously described. We found that the lowest STS activities were measured in the presence of N‐phosphorylated derivatives 6e (0.1% of STS activity) and 6f (0.2% of STS activity). The measured STS activity in the presence of 667‐COUMATE (used as a reference) was 0.1%. Moreover, at concentrations up to 1 μM, the most active compounds (6e, 6f, 9b, and 9e) did not exert any toxic effects on zebrafish embryos.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel steroid sulfatase inhibitors based on N‐thiophosphorylated 3‐(4‐aminophenyl)‐coumarin‐7‐O‐sulfamates

Daśko

Demkowicz

Biernacki

et al. 2019

Drug Development Research

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“…Docking calculations may be used as a hit-identification tool, when the structure of a molecular target (or its active/binding site alone) is known as well as during the computational optimisation of the chemical structure of lead compounds before the synthesis of their derivatives 69 . In case of STS inhibitors based on fluorinated 3-phenylcoumarin sulphamates, molecular docking techniques allowed the determination of binding modes of synthesised compounds to the STS structure and the identification of potential interactions between inhibitors and amino acid residues located in the STS active site 61,62 . For example, the fluorine atoms from some docked derivatives are within short distances to the Arg98 or Thr484 residues, suggesting the presence of additional stabilising interactions that may influence the binding of a potential drug molecule to the enzyme's active site.…”

Section: Nonsteroidal Sts Inhibitors Containing a Sulphamate Moietymentioning

confidence: 99%

“…, demonstrated the highest activity in an STS enzyme assay with IC 50 values of 270 nM in both cases. Further investigation on this type of STS inhibitors, involving the synthesis of analogues with an additional aromatic ring attached via the amide moiety, led to the development of their more potent N-benzoyl and N-phenylacetoyl derivatives62 . The most active compounds, 22 and 23(Table 2), inhibited a purified STS enzyme with IC 50 values of 180 nM in both cases.…”

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confidence: 99%

Recent progress in the development of steroid sulphatase inhibitors – examples of the novel and most promising compounds from the last decade

Daśko

Demkowicz

Biernacki

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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The purpose of this review article is to provide an overview of recent achievements in the synthesis of novel steroid sulphatase (STS) inhibitors. STS is a crucial enzyme in the biosynthesis of active hormones (including oestrogens and androgens) and, therefore, represents an extremely attractive molecular target for the development of hormone-dependent cancer therapies. The inhibition of STS may effectively reduce the availability of active hormones for cancer cells, causing a positive therapeutic effect. Herein, we report examples of novel STS inhibitors based on steroidal and nonsteroidal cores that contain various functional groups (e.g. sulphamate and phosphorus moieties) and halogen atoms, which may potentially be used in therapies for hormone-dependent cancers. The presented work also includes examples of multitargeting agents with STS inhibitory activities. Furthermore, the fundamental discoveries in the development of the most promising drug candidates exhibiting STS inhibitory activities are highlighted.

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“…7). 170 Novel small molecules targeting Mps1 were designed by computer assisted docking analyses and synthesized. The lead compounds have strong anti-proliferative potential through Mps1/TTK inhibition in both basal and luminal BC cell lines, exhibiting IC 50 values ranging from 0.05 to 1.0 mM.…”

Section: Computer-aided Synthesis Of Compoundsmentioning

confidence: 99%

Current research on anti-breast cancer synthetic compounds

et al. 2018

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Synthesis and biological evaluation of fluorinated N -benzoyl and N -phenylacetoyl derivatives of 3-(4-aminophenyl)-coumarin-7- O -sulfamate as steroid sulfatase inhibitors

Cited by 23 publications

References 26 publications

Novel steroid sulfatase inhibitors based on N‐thiophosphorylated 3‐(4‐aminophenyl)‐coumarin‐7‐O‐sulfamates

Novel steroid sulfatase inhibitors based on N‐thiophosphorylated 3‐(4‐aminophenyl)‐coumarin‐7‐O‐sulfamates

Recent progress in the development of steroid sulphatase inhibitors – examples of the novel and most promising compounds from the last decade

Current research on anti-breast cancer synthetic compounds

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