Among the human copper-containing monooxygenases, Tyrosinase (Ty) is an important enzyme involved in the determinant step of the biosynthetic pathway of melanin pigment. In this pathway, Ty catalyzes ...the tyrosine monooxygenation into L-DOPA-quinone, which is the precursor of the skin pigment melanin. Ty inhibitors/activators are a well-established approach for controlling in vivo melanin production, so their development has a huge economical and industrial impact. Moreover, recent publications highlight that targeting tyrosinase with inhibitors/activators to treat melanogenesis disorders is one of many possible approaches, due to the complex biochemical reaction involved in the melanin synthesis.
We report on the preparation and characterization of two new air‐stable mononuclear molybdenum(VI) complexes, termed MoVIO2(OPNO)2 (1) and MoVIO2(SPNO)2 (2). The potential of these complexes to act ...as functional mimics of molybdoenzymes from the DMSO reductase family was investigated. Initial catalytic studies suggest that 2 (but not 1) catalyzes the reduction of a sulfoxide into the thioether derivative. Studying the catalytic intermediates by UV/Vis spectroscopy, NMR spectroscopy, and DFT indicates that the active species (SPNO)2OMoV–O–MoVO(SPNO)2 (4), a dinuclear molybdenum(V) dimer with one µ‐oxo bridge, is formed upon successive reduction of the (SPNO)– ligands and the molybdenum(VI) ion.
Two new complexes of bis‐oxo‐molybdenum have been prepared and investigated in oxygen transfer reactions. Mo(OPNO)2O2 is inactive in this reaction under our conditions. In contrast, Mo(SPNO)2O2 can act as a (pre)catalyst in this reaction. On the basis of the combined theoretical and spectroscopic results, a mechanism is proposed involving a µ‐oxo MoV dimer.
We describe the synthesis and characterization of a new mononuclear palladium complex (PdL) based on a thiosemicarbazone ligand. X‐ray diffraction data collected on single crystals reveal that the ...complex is a neutral mononuclear entity with symmetric square‐planar geometry around the metal center. The complex exhibits an electrocatalytic behavior for proton reduction in DMF solvent using trifluoroacetic acid (TFA) as a proton source. Gas analysis under controlled electrocatalytic conditions during 4 h at a pool mercury working electrode showed a moderate production of dihydrogen. By combining experimental techniques to theoretical calculations, the results are analyzed and compared to those obtained for the previously reported NiL complex in an effort to rationalize the influence of the metal center on the catalytic performance of PdL to mediate hydrogen evolution.
How does the metal center influence the reaction mechanism and the catalytic properties for hydrogen production of thiosemicarbazone‐based complexes?
Tyrosinase (Ty) is a copper-containing enzyme widely present in plants, bacteria, and humans, where it is involved in biosynthesis of melanin-type pigments. Development of Ty inhibitors is an ...important approach to control the production and the accumulation of pigments in living systems. In this paper, we focused our interest in phenylthiourea (PTU) and phenylmethylene thiosemicarbazone (PTSC) recognized as inhibitors of tyrosinase by combining enzymatic studies and coordination chemistry methods. Both are efficient inhibitors of mushroom tyrosinase and they can be considered mainly as competitive inhibitors. Computational studies verify that PTSC and PTU inhibitors interact with the metal center of the active site. The K IC value of 0.93 μM confirms that PTSC is a much more efficient inhibitor than PTU, for which a K IC value of 58 μM was determined. The estimation of the binding free energies inhibitors/Ty confirms the high inhibitor efficiency of PTSC. Binding studies of PTSC along with PTU to a dinuclear copper(II) complex (Cu2(μ-BPMP)(μ-OH)(ClO4)2 (1); H-BPMP = 2,6-bis-bis(2-pyridylmethyl)aminomethyl-4-methylphenol) known to be a structural and functional model for the tyrosinase catecholase activity, have been performed. Interactions of the compounds with the dicopper model complex 1 were followed by spectrophotometry and electrospray ionization (ESI). The molecular structure of 1-PTSC and 1-PTU adducts were determined by single-crystal X-ray diffraction analysis showing for both an unusual bridging binding mode on the dicopper center. These results reflect their adaptable binding mode in relation to the geometry and chelate size of the dicopper center.
With the aim to develop effective and selective human tyrosinase inhibitors, we investigated aurone derivatives whose B-ring was replaced by a non-oxidizable 2-hydroxypyridine-N-oxide (HOPNO) moiety. ...These aurones were synthesized and evaluated as inhibitors of purified human tyrosinase. Excellent inhibition activity was revealed and rationalized by theoretical calculations. The aurone backbone was especially found to play a crucial role, as the HOPNO moiety alone provided very modest activity on human tyrosinase. Furthermore, the in vitro activity was confirmed by measuring the melanogenesis suppression ability of the compounds in melanoma cell lysates and whole cells. Our study reveals that HOPNO-embedded 6-hydroxyaurone is to date the most effective inhibitor of isolated human tyrosinase. Owing to its low toxicity and its high inhibition activity, it could represent a milestone on the path toward new valuable agents in dermocosmetics, as well as in medical fields where it was recently suggested that tyrosinase could play key roles.
Melanin play a major role in human skin protection and their biosynthesis is vital. Due to their color, they contribute to the skin pigmentation. Tyrosinase is a key enzyme involved in the first ...stage of melanin biosynthesis, it catalyzes the transformation of tyrosine into
l-dopaquinone. The aim of the present study was to study molecules able to inhibit tyrosinase to be used in treating depigmentation-related disorders. In this study, we targeted arylthiosemicarbazone analogs with the aim to contribute to the identification of the optimal aryl ring to be linked to the thiosemicarbazone moiety. The biological activity was evaluated on commercial mushroom tyrosinase which was purified prior use. The results demonstrated that several of our compounds (
1a–
h,
1j,
1r and
5) had more potent inhibitory activities than kojic acid which was used as the reference inhibitor.
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► Arylthiosemicarbazones were investigated as tyrosinase inhibitors. ► We examine the impact of the aryl moiety on the inhibitory activity. ► A phenyl, furanyl or pyrolidinyl rings were found as the most advantageous. ► The distance separating the aryl ring from the thiourea moeity was important.
Tyrosinase is a copper-containing enzyme found in plants and bacteria, as well as in humans, where it is involved in the biosynthesis of melanin-type pigments. Tyrosinase inhibitors have attracted ...remarkable research interest as whitening agents in cosmetology, antibrowning agents in food chemistry, and as therapeutics. In this context, commercially available tyrosinase from mushroom (TyM) is frequently used for the identification of inhibitors. This and bacterial tyrosinase (TyB) have been the subjects of intense biochemical and structural studies, including X-ray diffraction analysis, and this has led to the identification of structural homology and divergence among enzymes from different sources. To better understand the behavior of potential inhibitors of TyM and TyB, we selected the aurone family-previously identified as potential inhibitors of melanin biosynthesis in human melanocytes. In this study, a series of 24 aurones with different hydroxylation patterns at the A- and B-rings were evaluated on TyM and TyB. The results show that, depending on the hydroxylation pattern of A- and B-rings, aurones can behave as inhibitors, substrates, and activators of both enzymes. Computational analysis was performed to identify residues surrounding the aurones in the active sites of both enzymes and to rationalize the interactions. Our results highlight similarities and divergence in the behavior of TyM and TyB toward the same set of molecules.
In this work, the influence of two new dinuclear copper(II) complexes in the viability of melanoma cells (B16F10 and TM1MNG3) was investigated, with the aim of verifying possible correlations between ...their cytotoxicity and their structure. One of the complexes had a polydentate dinucleating amine–imine ligand (complex 2), and the other a tridentate imine and a diamine-bridging ligand (complex 4). The analogous mononuclear copper(II) species (complexes 1 and 3, respectively) were also prepared for comparative studies. Crystal structure determination of complex 2 indicated a square-based pyramidal geometry around each copper, coordinated to three N atoms from the ligand and the remaining sites being occupied by either solvent molecules or counter-ions. Complex 4 has a tetragonal geometry. Interactions of these complexes with human albumin protein (HSA) allowed an estimation of their relative stabilities. Complementary studies of their reactivity towards DNA indicated that all of them are able of causing significant oxidative damage, with single and double strand cleavages, in the presence of hydrogen peroxide. However, nuclease activity of the dinuclear species was very similar and much higher than that of the corresponding mononuclear compounds. Although complex 2, with a more flexible structure, exhibits a much higher tyrosinase activity than complex 4, having a more rigid environment around the metal ion, both complexes showed comparable cytotoxicity towards melanoma cells. Corresponding mononuclear complexes showed to be remarkably less reactive as tyrosinase mimics as well as cytotoxic agents. Moreover, the dinuclear complexes showed higher cytotoxicity towards more melanogenic cells. The obtained results indicated that the structure of these species is decisive for its activity towards the malignant tumor cells tested.
Tyrosinase mimics: possible correlation between its structural features and reactivity towards melanoma cells. Besides causing oxidative damage to DNA, its cytotoxic action could be related to melanogenesis. Display omitted
•Mono- and dinuclear copper complexes thermodynamic stability and tyrosinase activity were compared.•These dinuclear complexes show better nuclease activity than the similar mononuclear ones.•Their cytotoxicity against melanoma cells is much higher against melanogenic cells.•Its alternative mechanism can involve melanogenesis process, in addition to DNA damage.
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