Cyrene™ as a tyrosinase inhibitor and anti-browning agent.

The tyrosinase pathway takes part in the enzymatic process of food browning and is primarily responsible for food spoilage - manifesting itself from a decrease in its nutritional value to a deterioration of taste, which consequently leads to a gradual loss of shelf life. Finding safe and bio-based tyrosinase inhibitors and anti-browning agents may be of great importance in agriculture and food industries. Herein, we showed that Cyrene™ exhibits tyrosinase inhibitory activity (IC50: 268.2 µM), the 1.44 times higher than ascorbic acid (IC50: 386.5 µM). Binding mode studies demonstrated that the carbonyl oxygen of Cyrene™ coordinates with both copper ions. Surprisingly, both hydroxyl groups of Cyrene gem-diol perform a monodentate binding mode with both copper ions, at similar distances. This fact suggests that both compounds could have a similar binding mode and, as consequence, similar biological activities in tyrosinase inhibition assays and anti-browning activities.

Effect of N-phenyl substituent on thermal, optical, electrochemical and luminescence properties of 3-aminophthalimide derivatives.

The seven N-phthalimide derivatives substituted with the amine group at the 3-C position in the phenylene ring were synthesized. The effect of N-substituent chemical structure was investigated. The thermal, electrochemical and optical studies were performed and supported by the density functional theory calculations (DFT). The electrochemical investigations of the synthesized low-molecular phthalimides revealed the one oxidation and reduction process with the HOMO energy level under - 5.81 eV and energy-band gap below 3 eV. The N-phthalimide derivatives were emitted light in a blue spectral region in solutions (in polar and non-polar) with the quantum yield between 2 and 68%, dependent on the substituent at the nitrogen atom, solvent and concentration. The N-phthalimide derivatives were emissive also in a solid state as a thin film and powder. They were tested as a component of the active layer with PVK:PBD matrix and as an independent active layer in the organic light-emitting diodes. The registered electroluminescence spectra exhibited the maximum emission band in the 469-505 nm range, confirming the possibility of using N-phthalimides with PVK:PBD matrix as the blue emitters.

Coumarin-Based Compounds as Inhibitors of Tyrosinase/Tyrosine Hydroxylase: Synthesis, Kinetic Studies, and In Silico Approaches.

Cancer represents the main cause of morbidity and mortality worldwide, constituting a serious health problem. In this context, melanoma represents the most aggressive and fatal type of skin cancer, with death rates increasing every year. Scientific efforts have been addressed to the development of inhibitors targeting the tyrosinase enzyme as potential anti-melanoma agents due to the importance of this enzyme in melanogenesis biosynthesis. Coumarin-based compounds have shown potential activity as anti-melanoma agents and tyrosinase inhibitors. In this study, coumarin-based derivatives were designed, synthesized, and experimentally evaluated upon tyrosinase. Compound FN-19, a coumarin-thiosemicarbazone analog, exhibited potent anti-tyrosinase activity, with an IC50 value of 42.16 ± 5.16 µM, being more active than ascorbic acid and kojic acid, both reference inhibitors. The kinetic study showed that FN-19 acts as a mixed inhibitor. Still, for this compound, molecular dynamics (MD) simulations were performed to determine the stability of the complex with tyrosinase, generating RMSD, RMSF, and interaction plots. Additionally, docking studies were performed to elucidate the binding pose at the tyrosinase, suggesting that the hydroxyl group of coumarin derivative performs coordinate bonds (bidentate) with the copper(II) ions at distances ranging from 2.09 to 2.61 Å. Then, MM/PBSA calculations revealed that van der Waals interactions are the most relevant intermolecular forces for complex stabilization. Furthermore, it was observed that FN-19 has a binding energy (ΔEMM) value similar to tropolone, a tyrosinase inhibitor. Therefore, the data obtained in this study will be useful for designing and developing novel coumarin-based analogs targeting the tyrosinase enzyme.

Effect of the Chloro-Substitution on Electrochemical and Optical Properties of New Carbazole Dyes.

Carbazole derivatives are the structural key of many biologically active substances, including naturally occurring and synthetic ones. Three novel (E)-2-(2-(4-9H-carbazol-9-yl)benzylidene)hydrazinyl)triazole dyes were synthesized with different numbers of chlorine substituents attached at different locations. The presented research has shown the influence of the number and position of attachment of chlorine substituents on electrochemical, optical, nonlinear, and biological properties. The study also included the analysis of the use of the presented derivatives as potential fluorescent probes for in vivo and in vitro tests. Quantum-chemical calculations complement the conducted experiments.

Tropinone-Derived Alkaloids as Potent Anticancer Agents: Synthesis, Tyrosinase Inhibition, Mechanism of Action, DFT Calculation, and Molecular Docking Studies.

A new series of hybrid compounds with tropinone and thiazole rings in the structure was designed and synthesized as potential anticancer agents. They were tested against human multiple myeloma (RPMI 8226), lung carcinoma (A549), breast adenocarcinoma (MDA-MB-231), and mouse skin melanoma (B16-F10) cell lines. Toxicity was tested on human normal skin fibroblasts (HSF) and normal colon fibroblasts (CCD-18Co). The growth inhibition mechanism of the most active derivative was analyzed through investigation of its effect on the distribution of cell cycle phases and ability to induce apoptosis and necrosis in RPMI 8226 and A549 cancer cells. The tyrosinase inhibitory potential was assessed, followed by molecular docking studies. Compounds 3a-3h show high anticancer activity against MDA-MB-231 and B16-F10 cell lines with IC50 values of 1.51-3.03 µM. Moreover, the cytotoxic activity of the investigated compounds against HSF and CCD-18Co cells was 8-70 times lower than against the cancer cells or no toxicity was shown in our tests, with derivative 3a being particularly successful. The mechanism of action of compound 3a in RPMI 8226 cell was shown to be through induction of cell death through apoptosis. The derivatives show ability to inhibit the tyrosinase activity with a mixed mechanism of inhibition. The final molecular docking results showed for IC50 distinct correlation with experiment.

Benzo[b]thiophene-thiazoles as potent anti-Toxoplasma gondii agents: Design, synthesis, tyrosinase/tyrosine hydroxylase inhibitors, molecular docking study, and antioxidant activity.

Synthesis and investigation of anti-Toxoplasma gondii activity of novel thiazoles containing benzo [b]thiophene moiety are presented. Among the derivatives, compound 3k with adamantyl group shows exceptionally high potency against Me49 strain with IC50 (8.74 µM) value which is significantly lower than the activity of trimethoprim (IC50 39.23 µM). In addition, compounds 3a, 3b and 3k showed significant activity against RH strain (IC50 51.88-83.49 µM). The results of the cytotoxicity evaluation showed that Toxoplasma gondii growth was inhibited at non-cytotoxic concentrations for the mammalian L929 fibroblast (CC30 ∼ 880 µM). The most active compound 3k showed tyrosinase inhibition effect, with IC50 value of 328.5 µM. The binding energies calculated for compounds 3a-3e, 3k are strongly correlated with the experimentally determined values of tyrosinase inhibition activity. Moreover, the binding energies corresponding to the same ligands and calculated for both tyrosinase and tyrosine hydroxylase are also correlated with each other, suggesting that tyrosinase inhibitors may also have an inhibitory effect on tyrosine hydroxylase. Compounds 3j and 3k have also very strong antioxidant activity (IC50 15.9 and 15.5 µM), respectively, which is ten times higher than well-known antioxidant BHT.

Discovery of tropinone-thiazole derivatives as potent caspase 3/7 activators, and noncompetitive tyrosinase inhibitors with high antiproliferative activity: Rational design, one-pot tricomponent synthesis, and lipophilicity determination.

We have designed novel tropinone-thiazole derivatives that showed high antiproliferative activity against a variety of cancer cell lines via caspase 3/7 activation mechanism. Among the derivatives, compounds 3b-3h were found to exhibit high activity against human leukemia (MV4-11), human lung carcinoma (A549), human breast carcinoma (MCF-7), and skin melanoma (B16-F10) cancer cell lines, with IC50 values of 5.43-11.06 µM. The lead compound 3g increases caspase 3/7 activity in A549 cells 25 times more than the control, and 2 times more than reference drug camptothecin. We have also found that tropinone-thiazole derivatives exhibit high tyrosinase inhibitory activity. The lead compounds 3g and 3h showed tyrosinase inhibition effect, with IC50 values 3.22 and 3.51 µM, respectively. These inhibitory activities are 22 times higher than the activity of kojic acid (IC50 72.27 µM) and 120 times higher than activity of ascorbic acid (IC50 386.5 µM). For compounds 3g and 3h, the experimentally determined lipophilicity correlates very well with their enzymatic activities. These data suggest that presented compounds could constitute lead anticancer drug candidates.

Triazene salts: Design, synthesis, ctDNA interaction, lipophilicity determination, DFT calculation, and antiproliferative activity against human cancer cell lines.

Synthesis, characterization and investigation of antiproliferative activity of nine triazene salts against human cancer cells lines (MV-4-11, MCF-7, JURKAT, HT-29, Hep-G2, HeLa, Du-145 and DAUDI), and normal human mammary epithelial cell line (MCF7-10A) is presented. The structures of novel compounds were determined using 1H and 13C NMR, and GC-APCI-MS analyses. Among the derivatives, compound 2c, 2d, 2e and 2f has very strong activity against biphenotypic B myelomonocytic leukemia MV4-11, with IC50 values from 5.42 to 7.69 µg/ml. The cytotoxic activity of compounds 2c-2f against normal human mammary gland epithelial cells MCF-10A is 6-11 times lower than against cancer cell lines. Our results also show that compounds 2c and 2f have very strong activity against DAUDI and HT-29 with IC50 4.91 µg/ml and 5.59 µg/ml, respectively. Their lipophilicity was determined using reversed-phase ultra-performance liquid chromatography and correlated with antiproliferative activity. Our UV-Vis spectroscopic results indicate also that triazene salts tends to interact with negatively charged DNA phosphate chain. To support the experiment, theoretical calculations of the 1H NMR shifts were carried out within the Density Functional Theory.

Synthesis, molecular docking, ctDNA interaction, DFT calculation and evaluation of antiproliferative and anti-Toxoplasma gondii activities of 2,4-diaminotriazine-thiazole derivatives.

Synthesis, characterization, and investigation of antiproliferative activities against human cancer cell lines (MV4-11, MCF-7, and A549) and Toxoplasma gondii parasite of twelve novel 2,4-diaminotriazine-thiazoles are presented. The toxicity of the compounds was studied at three different cell types, normal mouse fibroblast (Balb/3T3), mouse fibroblast (L929), and human VERO cells. The structures of novel compounds were determined using 1H and 13C NMR, FAB(+)-MS, and elemental analyses. Among the derivatives, 4a-k showed very high activity against MV4-11 cell line with IC50 values between 1.13 and 3.21 µg/ml. Additionally, the cytotoxic activity of compounds 4a-k against normal mouse fibroblast Balb/3T3 cells is about 20-100 times lower than against cancer cell lines. According to our results, compounds 4a, 4b, 4d, and 4i have very strong activity against human breast carcinoma MCF-7, with IC50 values from 3.18 to 4.28 µg/ml. Moreover, diaminotriazines 4a-l showed significant anti-Toxoplasma gondii activity, with IC50 values 9-68 times lower than those observed for sulfadiazine. Molecular docking studies indicated DNA-binding site of hTopoI and hTopoII as possible anticancer targets and purine nucleoside phosphorylase as possible anti-toxoplasmosis target. Our UV-Vis spectroscopic results indicate also that diaminotriazine-thiazoles tends to interact with DNA by intercalation. Additionally, the structure and the interaction and binding energies of a model complex formed by compound 4a and two thymine molecules are investigated using quantum mechanical methods.

Acyloxymethyl esters of isophosphoramide mustard as new anticancer prodrugs.

A series of new prodrugs: [bis(2-chloroethylamino)phosphoryloxy]methyl acetate, [bis(2-chloroethylamino)phosphoryloxy]methyl pivalate and [bis(2-chloroethylamino)phosphoryloxy]methyl benzoate, was obtained in the reaction of isophosphoramide mustard (iPAM) with the corresponding acyloxymethyl halides. The cytotoxic activity of these new compounds is also shown. All compounds were highly active in the inhibition of cancer cell proliferation against the human lung (A594), prostate (PC-3) and breast (MCF-7) cancer cell lines.