Interactions of Phenylalanine Derivatives with Human Tyrosinase: Lessons from Experimental and Theoretical tudies.

The pigmentation of the skin, modulated by different actors in melanogenesis, is mainly due to the melanins (protective pigments). In humans, these pigments' precursors are synthetized by an enzyme known as tyrosinase (TyH). The regulation of the enzyme activity by specific modulators (inhibitors or activators) can offer a means to fight hypo- and hyper-pigmentations responsible for medical, psychological and societal handicaps. Herein, we report the investigation of phenylalanine derivatives as TyH modulators. Interacting with the binuclear copper active site of the enzyme, phenylalanine derivatives combine effects induced by combination with known resorcinol inhibitors and natural substrate/intermediate (amino acid part). Computational studies including docking, molecular dynamics and free energy calculations combined with biological activity assays on isolated TyH and in human melanoma MNT-1 cells, and X-ray crystallography analyses with the TyH analogue Tyrp1, provide conclusive evidence of the interactions of phenylalanine derivatives with human tyrosinase. In particular, our findings indicate that an analogue of L-DOPA, namely (S)-3-amino-tyrosine, stands out as an amino phenol derivative with inhibitory properties against TyH.

Chromium-Thiolate Complex Undergoing C-S Bond Cleavage.

The cleavage of C-S bonds represents a crucial step in fossil fuel refinement to remove organosulfur impurities. Efforts are required to identify alternatives that can replace the energy-intensive hydrodesulfurization process currently in use. In this context, we have developed a series of bis-thiolato-ligated CrIII complexes supported by the L2- ligand (L2- = 2,2'-bipyridine-6,6'-diyl(bis(1,1-diphenylethanethiolate), one of them displaying desulfurization of one thiolate of the ligand under reducing and acidic conditions at ambient temperature and atmospheric pressure. While only 5-coordinated complexes were previously isolated by reaction of L2- with 3d metal MIII ions, both 5- and 6-coordinated mononuclear complexes have been obtained in the case of CrIII, viz., [CrIIILCl], [CrIIILCl2]-, and [CrIIILCl(CH3CN)]. The investigation of the reactivity of [CrIIILCl(CH3CN)] under reducing conditions led to a dinuclear [CrIII2L2(µ-Cl)(µ-OH)] compound and, in the presence of protons, to the mononuclear CrIII complex [CrIII(LN2S)2]+, where LN2S- is the partially desulfurized form of L2-. A desulfurization mechanism has been proposed involving the release of H2S, as evidenced experimentally.

Novel Synthesis of IMC-48 and Affinity Evaluation with Different i-Motif DNA Sequences.

During the last decade, the evidence for the biological relevance of i-motif DNA (i-DNA) has been accumulated. However, relatively few molecules were reported to interact with i-DNA, and a controversy concerning their binding mode, affinity, and selectivity persists in the literature. In this context, the cholestane derivative IMC-48 has been reported to modulate bcl-2 gene expression by stabilizing an i-motif structure in its promoter. In the present contribution, we report on a novel, more straightforward, synthesis of IMC-48 requiring fewer steps compared to the previous approach. Furthermore, the interaction of IMC-48 with four different i-motif DNA sequences was thoroughly investigated by bio-layer interferometry (BLI) and circular dichroism (CD) spectroscopy. Surprisingly, our results show that IMC-48 is a very weak ligand of i-DNA as no quantifiable interaction or significant stabilization of i-motif structures could be observed, stimulating a quest for an alternative mechanism of its biological activity.

Synthesis of Redox-Active Photochromic Phenanthrene Derivatives.

A phenanthrene unit has been functionalized by several methylthiophene units in order to bring it a photochromic behavior. These compounds were characterized by NMR, absorption and emission spectroscopies, theoretical calculations as well as cyclic voltammetry. The association of a phenanthrene group with a photochromic center could open the door to a new generation of organic field-effect transistors.

Enantioselective Approach for Expanding the Three-Dimensional Space of Tetrahydroquinoline to Develop BET Bromodomain Inhibitors.

The pharmaceutical industry has a pervasive need for chiral specific molecules with optimal affinity for their biological targets. However, the mass production of such compounds is currently limited by conventional chemical routes, that are costly and have an environmental impact. Here, we propose an easy access to obtain new tetrahydroquinolines, a motif found in many bioactive compounds, that is rapid and cost effective. Starting from simple raw materials, the procedure uses a proline-catalyzed Mannich reaction followed by the addition of BF3 ⋅ OEt2 , which generates a highly electrophilic aza-ortho-quinone methide intermediate capable of reacting with different nucleophiles to form the diversely functionalized tetrahydroquinoline. Moreover, this enantioselective one-pot process provides access for the first time to tetrahydroquinolines with a cis-2,3 and trans-3,4 configuration. As proof of concept, we demonstrate that a three-step reaction sequence, from simple and inexpensive starting compounds and catalysts, can generate a BD2-selective BET bromodomain inhibitor with anti-inflammatory effect.

Functionalizing Carbon Nanotubes with Bis(2,9-dialkyl-1,10-phenanthroline)copper(II) Complexes for the Oxygen Reduction Reaction.

A new ligand, namely, 2-(5-(pyren-1-yl)pentyl)-9-methyl-1,10-phenanthroline, as well as new bis(2,9-dialkyl-1,10-phenanthroline)copper(II) complexes were designed, which were immobilized on multiwalled carbon nanotube (MWCNT) electrodes. These complexes show a high tendency of autoreduction into their copper(I) form according to electrochemical and EPR experiments. These complexes exhibit strong interactions with MWCNT sidewalls either with or without anchor functions such as the pyrene moiety. The pyrene-modified derivative can be electropolymerized on glassy carbon and MWCNT electrodes to form a poly-[bis(2-(5-(pyren-1-yl)pentyl)-9-methyl-1,10-phenanthroline)copper(II)] metallopolymer film. Furthermore, these MWCNT-supported bis(2,9-dialkyl-1,10-phenanthroline)copper complexes demonstrate a low overpotential for a 4H+/4e- oxygen reduction reaction at pH 5 with an onset potential of 0.86 V versus RHE. Integration of these functionalized MWCNTs at gas-diffusion electrodes of H2/air fuel cells led to a high open-circuit voltage of 0.84 V and a maximum current density of 1.77 mW cm-2 using a Pt/C anode.

Synthesis of a Negative Photochrome with High Switching Quantum Yields and Capable of Singlet-Oxygen Production and Storage.

A dimethyldihydropyrene (DHP) photochromic unit has been functionalized by donor (triphenylamine group) and acceptor (methylpyridinium) substituents. This compound was characterized by NMR, absorption and emission spectroscopies as well as cyclic voltammetry, and its properties were rationalized by theoretical calculations. The incorporation of both electron-donor and -withdrawing groups at the photochromic center allows i) an efficient photo-isomerization of the system when illuminated at low energy (quantum yield: Φc-o =13.3 % at λex =660 nm), ii) the reversible and quantitative formation of two endoperoxyde isomers when illuminated under aerobic conditions at room temperature, and iii) the storage and production of singlet oxygen. The photo-isomerization mechanism was also investigated by spin-flip TD-DFT (SF-TD-DFT) calculations.

Synthesis and Characterization of Bis-1,2,3-Triazole Ligand and its Corresponding Copper Complex for the Development of Electrochemical Affinity Biosensors.

The bis-triazole ligand and its corresponding copper complexes were synthesized and characterized for the first time and proposed as new labels for the development of electrochemical aptasensors. The bis-triazole ligand was prepared from methyl 1,6-heptadiyne-4-carboxylate and 2-(azidomethyl)phenol using classical CuAAC in presence of different copper salts. The X-ray structure of bis-triazole showed a symmetry center (C1). UV-Vis and X-band EPR spectra showed that the coordination capacity of the bis-triazole ligand was improved in the presence of triethylamine due to deprotonation of the triazole and phenolate moieties. After complexation with copper, the obtained complex was successfully attached to an anti-estradiol aptamer through thiol-maleimide coupling, and the resulting labelled aptamer was immobilized on a carbon screen-printed electrode by carbodiimide coupling. The electrochemical response of the resulting sensor was shown to decrease in the presence of estradiol, demonstrating that the developed complexes can be applied for the development of aptasensors.

Ditopic Chelators of Dicopper Centers for Enhanced Tyrosinases Inhibition.

Tyrosinase enzymes (Tys) are involved in the key steps of melanin (protective pigments) biosynthesis and molecules targeting the binuclear copper active site on tyrosinases represent a relevant strategy to regulate enzyme activities. In this work, the possible synergic effect generated by a combination of known inhibitors is studied. For this, derivatives containing kojic acid (KA) and 2-hydroxypyridine-N-oxide (HOPNO) combined with a thiosemicarbazone (TSC) moiety were synthetized. Their inhibition activities were evaluated on purified tyrosinases from different sources (mushroom, bacterial, and human) as well as on melanin production by lysates from the human melanoma MNT-1 cell line. Results showed significant enhancement of the inhibitory effects compared with the parent compounds, in particular for HOPNO-TSC. To elucidate the interaction mode with the dicopper(II) active site, binding studies with a tyrosinase bio-inspired model of the dicopper(II) center were investigated. The structure of the isolated adduct between one ditopic inhibitor (KA-TSC) and the model complex reveals that the binding to a dicopper center can occur with both chelating sites. Computational studies on model complexes and docking studies on enzymes led to the identification of KA and HOPNO moieties as interacting groups with the dicopper active site.

Substituent Effects in Carbon-Nanotube-Supported Copper Phenolato Complexes for Oxygen Reduction Reaction.

Unprotected mononuclear pyrene-modified (bispyridylaminomethyl)methylphenol copper complexes were designed to be immobilized at multiwalled carbon nanotube (MWCNT) electrodes and form dinuclear bis(µ-phenolato) complexes on the surface. These complexes exhibit a high oxygen reduction reaction activity of 12.7 mA cm-2 and an onset potential of 0.78 V versus reversible hydrogen electrode. The higher activity of these complexes compared to that of mononuclear complexes with bulkier groups is induced by the favorable early formation of a dinuclear catalytic species on MWCNT.

Study of a phosphorescent cationic iridium(III) complex displaying a blue-shift in crystals.

We report the synthesis and the characterization of a new cationic iridium(III) complex featuring two 1-(p-methoxyphenyl)-5-methoxybenzimidazole cyclometallating ligands and a dimethylbipyridine ancillary ligand. The complex has been fully characterized by 1D and 2D NMR (1H, 13C, 19F and 31P), elemental analysis and high-resolution mass spectrometry (HRMS). The photoluminescence studies performed in a solution, on amorphous powder and on crystals revealed an unexpected behavior. Indeed, the emission spectra observed in both solution (CH2Cl2) and amorphous powder samples are centered at around 580 nm, whereas in crystals the emission displays a large hypsochromic shift of ∼800 cm-1 (λem = 558 nm). X-ray diffraction experiments, photophysical studies and DFT calculations allow for rationalizing the hypsochromic shift.

Improved Visible Light Absorption of Potent Iridium(III) Photo-oxidants for Excited-State Electron Transfer Chemistry.

Three iridium photosensitizers, [Ir(dCF3ppy)2(N-N)]+, where N-N is 1,4,5,8-tetraazaphenanthrene (TAP), pyrazino[2,3-a]phenazine (pzph), or benzo[a]pyrazino[2,3-h]phenazine (bpph) and dCF3ppy is 2-(3,5-bis(trifluoromethyl-phenyl)pyridine), were found to be remarkably strong photo-oxidants with enhanced light absorption in the visible region. In particular, judicious ligand design provided access to Ir-bpph, with a molar absorption coefficient, ε = 9800 M-1 cm-1, at 450 nm and an excited-state reduction potential, E(Ir+*/0) = 1.76 V vs NHE. These complexes were successful in performing light-driven charge separation and energy storage, where all complexes photo-oxidized seven different electron donors with rate constants (0.089-3.06) × 1010 M-1 s-1. A Marcus analysis provided a total reorganization energy of 0.7 ± 0.1 eV for excited-state electron transfer.

Effect of Distortions on the Geometric and Electronic Structures of One-Electron Oxidized Vanadium(IV), Copper(II), and Cobalt(II)/(III) Salen Complexes.

The ligands N,N'-bis(3-tert-butyl-5-methoxysalicylidene)-1,2-ethanediamine and N,N'-bis(3-tert-butyl-5-methoxysalicylidene)-1,3-propanediamine were chelated to V(IV)═O (1, 2), Cu(II) (3, 4), Co(II) (5), and Co(III) (6). The X-ray crystal structures of 1-6 were solved. The vanadium center in 1-2 resides in square pyramidal geometry, with an axially bound oxo ligand, whereas the metal ion displays a tetrahedrally distorted square planar geometry in 3-5. The extent of distortion is correlated to the length of the diamine spacer: The longer the linker, the larger the tetrahedral distortions. Complex 6 is octahedral with a bidentate acetate molecule that completes the coordination sphere. All the complexes were characterized by UV-vis and EPR spectroscopies, as well as DFT calculations and electrochemistry. Complexes 1-6 exhibit a reversible one-electron oxidation wave in the range -0.11-0.26 V vs Fc+/Fc. The cations 1+ and 2+ were structurally characterized, showing an octahedral V(V) ion with one oxo and one water molecule coordinated in axial positions. Their vis-NIR spectra are dominated by a band at 727 and 815 nm, respectively, which is assigned to a phenolate-to-vanadium(V) charge transfer (CT) transition. The crystal structures of 3+ and 4+ are congruent with Cu(II)-radical species, wherein the metal center remains four-coordinated. Both feature a Class II (Robin-Day classification scale) IVCT transition at around 1200 nm (ε > 1 mM cm-1), indicative of partial localization of the radical. The structure of 5+ displays a square pyramidal cobalt ion, where the fifth (axial) coordination is occupied by a water molecule. It displays a NIR feature at 1244 nm and is described as intermediate between high spin Co(III) and Co(II) radical. In the presence of acetate the dimer [(5)2(µ-OAc)]+ forms, which was structurally characterized and shows a blue shift and lowering in intensity of the NIR absorption band in comparison to 5+. Complex 6+ is a genuine Co(III) radical complex, wherein the phenoxyl moiety is localized on one side of the molecule.

O2 Activation by Non-Heme Thiolate-Based Dinuclear Fe Complexes.

Iron centers featuring thiolates in their metal coordination sphere (as ligands or substrates) are well-known to activate dioxygen. Both heme and non-heme centers that contain iron-thiolate bonds are found in nature. Investigating the ability of iron-thiolate model complexes to activate O2 is expected to improve the understanding of the key factors that direct reactivity to either iron or sulfur. We report here the structural and redox properties of a thiolate-based dinuclear Fe complex, [FeII2(LS)2] (LS2- = 2,2'-(2,2'-bipyridine-6,6'-iyl)bis(1,1-diphenylethanethiolate)), and its reactivity with dioxygen, in comparison with its previously reported protonated counterpart, [FeII2(LS)(LSH)]+. When reaction with O2 occurs in the absence of protons or in the presence of 1 equiv of proton (i.e., from [FeII2(LS)(LSH)]+), unsupported µ-oxo or µ-hydroxo FeIII dinuclear complexes ([FeIII2(LS)2O] and [FeIII2(LS)2(OH)]+, respectively) are generated. [FeIII2(LS)2O], reported previously but isolated here for the first time from O2 activation, is characterized by single crystal X-ray diffraction and Mössbauer, resonance Raman, and NMR spectroscopies. The addition of protons leads to the release of water and the generation of a mixture of two Fe-based "oxygen-free" species. Density functional theory calculations provide insight into the formation of the µ-oxo or µ-hydroxo FeIII dimers, suggesting that a dinuclear µ-peroxo FeIII intermediate is key to reactivity, and the structure of which changes as a function of protonation state. Compared to previously reported Mn-thiolate analogues, the evolution of the peroxo intermediates to the final products is different and involves a comproportionation vs a dismutation process for the Mn and Fe derivate, respectively.

A Non-Heme Diiron Complex for (Electro)catalytic Reduction of Dioxygen: Tuning the Selectivity through Electron Delivery.

In the oxygen reduction reaction (ORR) domain, the investigation of new homogeneous catalysts is a crucial step toward the full comprehension of the key structural and/or electronic factors that control catalytic efficiency and selectivity. Herein, we report a unique non-heme diiron complex that can act as a homogeneous ORR catalyst in acetonitrile solution. This iron(II) thiolate dinuclear complex, [FeII2(LS)(LSH)] ([Fe2SH]+) (LS2- = 2,2'-(2,2'-bipyridine-6,6'-diyl)bis(1,1-diphenylethanethiolate)) contains a thiol group in the metal coordination sphere. [Fe2SH]+ is an efficient ORR catalyst both in the presence of a one-electron reducing agent and under electrochemically assisted conditions. However, its selectivity is dependent on the electron delivery pathway; in particular, the process is selective for H2O2 production under chemical conditions (up to ∼95%), whereas H2O is the main product during electrocatalysis (less than ∼10% H2O2). Based on computational work alongside the experimental data, a mechanistic proposal is discussed that rationalizes the selective and tunable reduction of dioxygen.

Stable M(II)-Radicals and Nickel(III) Complexes of a Bis(phenol) N-Heterocyclic Carbene Chelated to Group 10 Metal Ions.

The tetradentate ligand based on (1-imidazolium-3,5-di tert-butylphenol) units was prepared and chelated to group 10 metal ions (Ni(II), Pd(II), and Pt(II)), affording complexes 1, 2, and 3, respectively. The X-ray crystal structures of 1-3 show a square planar metal ion coordinated to two N-heterocyclic carbenes and two phenolate moieties. The cyclic voltammetry curves of complexes 1-3 show two reversible oxidation waves in the range 0.11-0.21 V ( E1/21) and 0.55-0.65 V ( E1/22) vs Fc+/Fc, which are assigned to the successive oxidations of the phenolate moieties. One-electron oxidation affords mononuclear ( S = 1/2) systems. Complex 1+·SbF6- was remarkably stable, and its structure was characterized. The coordination sphere is slightly dissymmetric, while the typical patterns of phenoxyl radicals were observed within the ligand framework. Complex 1+ exhibits a rhombic signal at g = 2.087, 2.016, and 1.992, confirming its predominant phenoxyl radical character. The g-values are slightly smaller for 2+ (2.021, 2.008, and 1.983) and larger for 3+ (2.140, 1.999, and 1.885) yet consistent with phenoxyl radical species. The electronic spectra of 1+-3+ display an intervalence charge-transfer (IVCT) transition at 2396, 2600, and 2294 nm, respectively. Its intensity supports the description of cations 1+ and 3+ as mixed-valent (Class II/III) compounds according to the Robin Day classification. Complex 2+ behaves as a mixed-valent class II radical compound. In the presence of pyridine, radical species 1+ is successively converted into stable mono and bis(adducts), which are both Ni(III) complexes. Dications 1+2-3+2 were prepared electrochemically. They are electron paramagnetic resonance (EPR)-silent and do not show IVCT transition in their NIR spectra, consistent with a bis(radical) formulation. The proposed electronic structures are fully supported by density functional theory calculations.

Experimental and Theoretical Identification of the Origin of Magnetic Anisotropy in Intermediate Spin Iron(III) Complexes.

The complexes [FeLN2S2 X] [in which LN2S2 =2,2'-(2,2'-bipryridine-6,6'-diyl)bis(1,1'-diphenylethanethiolate) and X=Cl, Br and I], characterized crystallographically earlier and here (Fe(L)Br), reveal a square pyramidal coordinated FeIII ion. Unusually, all three complexes have intermediate spin ground states. Susceptibility measurements, powder cw X- and Q-band EPR spectra, and zero-field powder Mössbauer spectra show that all complexes display distinct magnetic anisotropy, which has been rationalized by DFT calculations.

Solvent- and Halide-Induced (Inter)conversion between Iron(II)-Disulfide and Iron(III)-Thiolate Complexes.

Disulfide/thiolate interconversion controlled by Cu is proposed to be involved in relevant biological processes. In analogy to Cu, it can be envisaged that Fe also participates in the control of similar biological processes. We describe here Fe complexes that undergo FeIII -thiolate/FeII -disulfide (inter)conversion mediated by halide (de)coordination, and by the nature of the solvent. The dinuclear FeII -disulfide complex [FeII2 (LSSL)]2+ ((LS)2- =2,2'-(2,2'-bipyridine-6,6'-diyl)bis(1,1-diphenylethanethiolate), (LSSL)2- =the corresponding disulfide ligand) shows solvent-dependent properties. Whereas in a non-coordinating solvent (CH2 Cl2 ) the dinuclear FeII -disulfide complex is the only stable form, in the presence of coordinating solvents like MeCN or DMF it is partly or fully converted into mononuclear FeIII -thiolate species having a bound solvent molecule ([FeIII (LS)(Solv)]+ , Solv=DMF, MeCN). Addition of Cl- to a CH2 Cl2 solution containing the FeII -disulfide dinuclear complex leads to the fast and quantitative formation of a mononuclear FeIII -thiolate species with a bound Cl- , that is, ([FeIII (LS)Cl]). The reverse reaction can be achieved by addition of Li[[B(C6 F5 )4 ]. In relation to the metal-sulfur electronic distribution, the comparison between the redox properties of the Fe, Mn and Co complexes involved in these MIII -thiolate/MII -disulfide interconversion processes allow one to rationalize their respective efficiency.

New Acridine-Based Tridentate Ligand for Ruthenium(II): Coordination with a Twist.

A new tridentate ligand based on acridine has been synthetized. The central acridine heterocycle bears two pyridine coordinating units at positions 4 and 5. The terdentate 2,7-di- tert-butyl-4,5-di(pyridin-2-yl)acridine (dtdpa) was then coordinated to a ruthenium(II) cation. The corresponding homoleptic complex could only be obtained where both ligands coordinate to the ruthenium in a fac fashion. Thus, a heteroleptic compound (2) was constructed in combination with a terpyridine ligand in order to constrain the ligand to adopt a mer geometry. Such a coordination imposes a dramatic twist on the acridine heterocycle, resulting in an unexpected photophysical behavior. The electrochemical and photophysical properties of both complexes were studied, and the molecular structure of 2 was determined by X-ray diffraction. The two compounds absorb at low energy wavelengths, and a very weak luminescence is detected only for complex 2 in the near-infrared region.

Electronic Structure and Reactivity of One-Electron-Oxidized Copper(II) Bis(phenolate)-Dipyrrin Complexes.

The sterically hindered bis(phenol)-dipyrrin ligands HLH3 and PhLH3 were reacted with 1 equiv of copper(II) under ambient conditions to produce the copper radical complexes [Cu(HL)] and [Cu(PhL)]. Their X-ray crystal structures show relatively short C-O bond distances (mean bond distances of 1.287 and 1.291 Å), reminiscent of mixed pyrrolyl-phenoxyl radical species. Complexes [Cu(HL)] and [Cu(PhL)] exhibit rich electronic spectra, with an intense near-IR (NIR) band (ε > 6 mM-1 cm-1) at 1346 and 1321 nm, respectively, assigned to a ligand-to-ligand charger-transfer transition. Both show a reversible oxidation wave ( E1/21,ox = 0.05 and 0.04 V), as well as a reversible reduction wave ( E1/21,red = -0.40 and -0.56 V versus ferrocenium/ferrocene, respectively). The cations ([Cu(HL)]+ and [Cu(PhL)]+) and anions ([Cu(HL)]- and [Cu(PhL)]-) were generated. They all display an axial ( S = 1/2) signal with a copper hyperfine structure in their electron paramagnetic resonance spectra, consistent with ligand-centered redox processes in both reduction and oxidation. Complex [Cu(HL)](SbF6) was cocrystallized with [Cu(HL)]. Oxidation is accompanied by a slight contraction of both the C-O bonds (mean bond distance of 1.280 Å) and the C-C bonds connecting the peripheral rings to the dipyrrin. The cations show vis-NIR bands of up to 1090 nm due to their quinoidal nature. The anions do not show a significant band above 700 nm, in agreement with their bis(phenolate)-dipyrrin character. The radical complexes efficiently catalyze the aerobic oxidation of benzyl alcohol, 1-phenylethanol, and unactivated 2-phenylethanol in basic conditions.