Maciej Masłyk

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

In the present work, we report convenient methods for the synthesis and biological evaluation of phosphate tricyclic coumarin derivatives as potential steroid sulfatase inhibitors. The described synthesis includes the straightforward preparation of 7-hydroxy-2,3-dihydro-1H-cyclopenta[c]chromen-4-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 various phosphate moieties. The inhibitory effects of the synthesized compounds were tested on STS isolated from human placenta as well as the MCF-7, MDA-MB-231 and MDA-MB-435S cancer cell lines. Most of the new STS inhibitors possessed IC50 values between 21 to 159 μM. In the course of our investigation, the largest inhibitory effects in the STS enzyme assays were observed for the three compounds 9p, 9r and 9s, with IC50 values of 36.4, 37.8 and 21.5 μM, respectively (IC50 value of 1.0 μM for the 665-COUMATE used as a reference). The compound 9r, exhibited the highest potency against MCF-7, an estrogen receptor positive (ER+) cell line, with a GI50 value of 24.7 μM. The structure-activity relationships of the synthesized coumarin derivatives with the STS enzyme are discussed.

Synthesis, Biological Activity and Structural Study of New Benzotriazole-Based Protein Kinase CK2 Inhibitors

A new series of 4,5,6,7-tetrabromobenzotriazole (TBB) derivatives was synthesized and characterized as CK2 inhibitors. They were readily synthesized using a click chemistry approach based on a Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC). Some of the synthesized compounds present interesting inhibitory activities using an in vitro assay, with Ki values in the low micro molar range and a high degree of selectivity against a panel of 24 kinases. Selected compounds were tested for their antiproliferative effect on several cancer cell lines, and for their proapoptotic activity towards human Jurkat T-leukemia and MCF-7 breast adenocarcinoma cells, showing that they can be proposed as promising anticancer agents. Docking studies as well as crystallographic analysis allowed us to identify ligand–CK2 interactions that account for the molecular recognition process, and can help to further optimize this family of compounds as CK2 inhibitors.

Multisite-directed inhibitors of protein kinase CK2: new challenges

New 4,5,6,7-tetrabromo benzotriazole derivatives have been synthesized, and their activities against CK2 have been tested. A click chemistry approach based on the copper-catalyzed azide–alkyne cycloaddition has been utilized to connect benzotriazoles, which efficiently interact with the ATP-binding site, to other subunits designed to simultaneously bind to the active and the substrate-binding sites of the enzyme. Docking studies allowed us to identify key interactions between CK2 and the designed ligands, which will be useful to optimize this series of multisite-directed inhibitors.

Towards β-selectivity in functional estrogen receptor antagonists

Based on the benzo[b]naphtho[1,2-d]furan and benzo[b]naphtho[1,2-d]thiophene frameworks, a series of ligands with different basic side chains (BSCs) has been synthesized and pharmacologically evaluated. Also, their binding modes have been modelled using docking techniques. It was found that the introduction of a BSC in these systems brings about a decrease of affinity for both estrogen receptors α and β in an in vitro competitive binding assay. However, two full antagonists of the estrogen receptor β (9c and 9f) have been discovered, with potency in the low micromolar concentration in a cell-based luciferase reporter assay, and completely devoid of activity against the α receptor at the same concentration range. Differences in the ERα/ERβ binding modes have also been rationalized with the help of molecular modelling techniques. This interesting functional profile could be used to elucidate the physiological role of each ER subtype.

Synthesis and Antimicrobial Activity of 4-Substituted 1,2,3-Triazole-Coumarin Derivatives

A new series of coumarin-1,2,3-triazole conjugates with varied alkyl, phenyl and heterocycle moieties at C-4 of the triazole nucleus were synthesized using a copper(I)-catalysed Huisgen 1,3-dipolar cycloaddition reaction of corresponding O-propargylated coumarin (3) or N-propargylated coumarin (6) with alkyl or aryl azides. Based on their minimal inhibitory concentrations (MICs) against selected microorganisms, six out of twenty-six compounds showed significant antibacterial activity towards Enterococcus faecalis (MIC = 12.5–50 µg/mL). Moreover, the synthesized triazoles show relatively low toxicity against human erythrocytes.

Synthesis and steroid sulfatase inhibitory activities of N-alkanoyl tyramine phosphates and thiophosphates†

A series of phosphate and thiophosphate analogs based on the frameworks of N-alkanoyl tyramines have been synthesized and biologically evaluated. Their binding modes have been modeled using docking techniques. The inhibitory effects of the synthesized compounds were tested on STS isolated from the human placenta as well as the MCF-7, MDA-MB-231 and SkBr3 cancer cell lines. Most of the new STS inhibitors possessed potent activity against STS. In the course of our investigation, 4-(2-dodecanoylamino-ethyl)-phenyl dimethyl phosphate 4a demonstrated the greatest inhibitory effect, with IC50 values of 0.39 μM (IC50 value of 15.44 μM for the 4-(2-dodecanoylamino-ethyl)-phenyl sulfamate used as a reference). The compound 4a exhibited the highest potency against the MCF-7, MDA-MB-231 and SkBr3 cancer cell lines, with a GI50 values of 8.80, 6.48 and 5.76 μM, respectively. The structure–activity relationships of the synthesized phosphate- and thiophosphate-based tyramine derivatives with the STS enzyme are discussed.

Phosphate and thiophosphate biphenyl analogs as steroid sulfatase inhibitors.

Preclinical Research

Emodin, a natural inhibitor of protein kinase CK2, suppresses growth, hyphal development, and biofilm formation of Candida albicans

Emodin (1,3,8‐trihydroxy‐6‐methyl‐anthraquinone) is a natural secondary plant product, originally isolated from the rhizomes of Rheum palmatum. Many reports show its diuretic, vasorelaxant, antibacterial, antiviral, anti‐ulcerogenic, immunosuppressive, hepatoprotective, anti‐inflammatory and anticancer potential. Emodin is a pleiotropic molecule capable of interacting with several major molecular targets, e.g. NF‐κB, AKT/mTOR and STAT3. The compound can also act as an inhibitor of some protein kinases, with special affinity to protein kinase CK2. The aim of the presented report was to evaluate antifungal properties of emodin and its activity towards CK2 isolated from Candida cells. Our studies revealed that the compound suppressed growth of the cells of reference strains as well as clinical Candida strains, with minimal inhibitory concentration and minimal fungicidal concentration values between 12.5 and 200 μg/mL. Moreover, at a low concentration, the compound was able to effectively stop hyphal formation, thus showing a distinct antivirulent potential. Interestingly, we showed that emodin added to Candida culture inhibited the phosphorylation of many cellular proteins, presumably owing to the inhibition of protein kinase CK2. Notably, the enzyme isolated from the Candida cells was susceptible to emodin with IC50 of 2.8 μg/mL. Indeed, our computational modelling revealed that emodin was able to occupy the ATP‐binding pocket of CK2. Copyright

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

In the present work, we report the initial results of our study on a series of 3‐phenylcoumarin sulfamate‐based compounds containing C‐F bonds as novel inhibitors of steroid sulfatase. The new compounds are potent steroid sulfatase inhibitors, possessing more than 10 times higher inhibitory potency than coumarin‐7‐O‐sulfamate. In the course of our investigation, compounds 2b and 2c demonstrated the highest inhibitory effect on the enzymatic steroid sulfatase assay; both had IC50 values of 0.27 μm (the IC50 value of coumarin‐7‐O‐sulfamate is 3.5 μm, used as a reference).

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

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.