Synthesis and Biological Evaluation of Fluorinated 3‐Phenylcoumarin‐7‐<i>O</i>‐Sulfamate Derivatives as Steroid Sulfatase Inhibitors

Demkowicz, Sebastian; Daśko, Mateusz; Kozak, Witold; Krawczyk, K; Witt, Dariusz; Masłyk, Maciej; Kubiński, Konrad; Rachoń, Janusz

doi:10.1111/cbdd.12652

Cited by 20 publications

(15 citation statements)

References 15 publications

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“…[5] Various approaches have been used in the design of effective STS inhibitors. [11] In most cases, compounds containing C-F bonds showed slightly higher STS inhibitory activity than the corresponding analogs without the fluorine atom. [6] One of the most promising compounds was steroidal EMATE (Figure 1), which exhibited a very high activity in MCF-7 cells, with an IC 50 value of 65 pm.…”

Section: Introductionmentioning

confidence: 97%

Synthesis and biological evaluation of N‐acylated tyramine sulfamates containing C–F bonds as steroid sulfatase inhibitors

et al. 2017

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Steroid sulfatase (STS) is responsible for the hydrolysis of biologically inactive sulfated steroids into their active un-sulfated forms and promotes the growth of various hormone-dependent cancers (e.g., breast cancer). Therefore, the STS enzyme is a promising therapeutic target for the treatment of steroid-sensitive cancers. Herein, we report the synthesis and biological evaluation of sulfamate analogs as potential STS inhibitors based on N-acylated tyramines that contain C-F bonds. The inhibitory effects of the analogs were tested using STS isolated from human placenta. Of the analogs tested, 4-(2-perfluoroundecanoylaminoethyl)-phenyl sulfamate, 5r, demonstrated the greatest inhibitory effect, with an IC value of 2.18 μm (IC value of 2.13 μm for coumarin-7-O-sulfamate was used as a reference). These findings were supported by the results our computational analyses performed using molecular docking techniques.

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Section: Introductionmentioning

confidence: 97%

Synthesis and biological evaluation of N‐acylated tyramine sulfamates containing C–F bonds as steroid sulfatase inhibitors

et al. 2017

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“…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%

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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“… 16 , 17 Further development of this series of nonsteroidal inhibitors led to the discovery of the tricyclic coumarin sulfamate ( 2 ) (Irosustat, STX64, 667COUMATE, BN83495, Figure 1 ) which has proven to be the most successful STS inhibitor to date. 12 , 16 Recently, other examples of both mono- 20 , 21 and two-ring sulfamate-based STS inhibitors 22 have been published, but these compounds are generally still of relatively modest inhibitory activity. Irosustat was the first STS inhibitor to enter clinical trials for postmenopausal patients with advanced HDBC and has shown encouraging results.…”

Section: Introductionmentioning

confidence: 99%

C-3- and C-4-Substituted Bicyclic Coumarin Sulfamates as Potent Steroid Sulfatase Inhibitors

et al. 2018

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Synthetic routes to potent bicyclic nonsteroidal sulfamate-based active-site-directed inhibitors of the enzyme steroid sulfatase (STS), an emerging target in the treatment of postmenopausal hormone-dependent diseases, including breast cancer, are described. Sulfamate analogs 9–27 and 28–46 of the core in vivo active two-ring coumarin template, modified at the 4- and 3-positions, respectively, were synthesized to expand structure–activity relationships. α-Alkylacetoacetates were used to synthesize coumarin sulfamate derivatives with 3-position modifications, and the bicyclic ring of other parent coumarins was primarily constructed via the Pechmann synthesis of hydroxyl coumarins. Compounds were examined for STS inhibition in intact MCF-7 breast cancer cells and in placental microsomes. Low nanomolar potency STS inhibitors were achieved, and some were found to inhibit the enzyme in MCF-7 cells ca. 100–500 more potently than the parent 4-methylcoumarin-7-O-sulfamate 3, with the best compounds close in potency to the tricyclic clinical drug Irosustat. 3-Hexyl-4-methylcoumarin-7-O-sulfamate 29 and 3-benzyl-4-methylcoumarin-7-O-sulfamate 41 were particularly effective inhibitors with IC50 values of 0.68 and 1 nM in intact MCF-7 cells and 8 and 32 nM for placental microsomal STS, respectively. They were docked into the STS active site for comparison with estrone 3-O-sulfamate and Irosustat, showing their sulfamate group close to the catalytic hydrated formylglycine residue and their pendant group lying between the hydrophobic sidechains of L103, F178, and F488. Such highly potent STS inhibitors expand the structure–activity relationship for these coumarin sulfamate-based agents that possess therapeutic potential and may be worthy of further development.

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Synthesis and Biological Evaluation of Fluorinated 3‐Phenylcoumarin‐7‐O‐Sulfamate Derivatives as Steroid Sulfatase Inhibitors

Cited by 20 publications

References 15 publications

Synthesis and biological evaluation of N‐acylated tyramine sulfamates containing C–F bonds as steroid sulfatase inhibitors

Synthesis and biological evaluation of N‐acylated tyramine sulfamates containing C–F bonds as steroid sulfatase inhibitors

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

C-3- and C-4-Substituted Bicyclic Coumarin Sulfamates as Potent Steroid Sulfatase Inhibitors

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