Isolation and characterization of mimosine degrading enzyme from Arthrobacter sp. Ryudai-S1.

Leucaena leucocephala growing in the tropics and subtropics serves as potential forage for livestock because its foliage is rich in protein, fiber, and minerals. However, its use for livestock feed has been hindered by toxic nonprotein amino acid mimosine. Therefore, it is necessary to develop a method to reduce or eliminate mimosine from foliage. A previous study found that the fermentation of L. leucocephala foliage reduced the mimosine content and prompted the authors to isolate potent mimosine degrading microorganisms and characterize the mimosinase for the complete elimination of mimosine in the L. leucocephala foliage. The soil screening of the L. leucocephala tree surroundings led to the isolation of Arthrobacter sp. Ryudai-S1, which can degrade and assimilate mimosine as a nitrogen and carbon source. Mimosinase in this strain was found to be thermostable and showed strong activity. Docking model's inspection and the interaction energy calculation between mimosine-pyridoxal-5'-phosphate (PLP) complex and the active site of this enzyme identified 11 important amino acid residues that stabilized the binding. Of these amino acid residues, mutation experiment suggested that Tyr-263' and Phe-34 stabilizes the substrate binding and play a critical role in guiding the substrate to proper positions to accomplish high catalytic efficacy and selectivity. These observations suggest that Arthrobacter sp. Ryudai-S1 could be potentially useful for the development of L. leucocephala feed with reduced mimosine content.

Methods of Mimosine Extraction from Leucaena leucocephala (Lam.) de Wit Leaves.

Mimosine is a nonprotein amino acid biosynthesized from OAS (O-acetylserine) and 3H4P (3-hydroxy-4-pyridone or its tautoisomer 3,4-dihydroxypyridine). This amino acid constitutively occurs in all parts of Leucaena leucocephala (Lam.) de Wit plants and is found at higher concentrations in seeds and leaves. This metabolite has several useful activities, such as antioxidant, allelochemical, insecticidal, antimicrobial, metal chelating, and antitumor. Mimosine is well studied in biomedical research due its ability to inhibit cells in the late G1 phase and to induce cell apoptosis. Two simple methods of mimosine extraction from leucaena leaves, pulverized and whole maceration, are described herein in detail.

Influence of the Nonprotein Amino Acid Mimosine in Peptide Conformational Propensities from Novel Amber Force Field Parameters.

Mimosine is a nonprotein amino acid derived from plants known for its ability to bind to divalent and trivalent metal cations such as Zn2+, Ni2+, Fe2+, or Al3+. This results in interesting antimicrobial and anticancer properties, which make mimosine a promising candidate for therapeutic applications. One possibility is to incorporate mimosine into synthetic short peptide drugs. However, how this amino acid affects the peptide structure is not well understood, reducing our ability to design effective therapeutic compounds. In this work, we used computer simulations to understand this question. We first built parameters for the mimosine residue to be used in combination with two classical force fields of the Amber family. Then, we used atomistic molecular dynamics simulations with the resulting parameter sets to evaluate the influence of mimosine in the structural propensities for this amino acid. We compared the results of these simulations with homologous peptides, where mimosine is replaced by either phenylalanine or tyrosine. We found that the strong dipole in mimosine induces a preference for conformations where the amino acid rings are stacked over more extended conformations. We validated our results using quantum mechanical calculations, which provide a robust foundation for the outcome of our classical simulations.

Metal self-assembly mimosine peptides with enhanced antimicrobial activity: towards a new generation of multitasking chelating agents.

Mimosine is a non-protein amino acid with various properties, such as antibacterial, anti-inflammatory, anti-cancer and anti-virus among others. Due to its structural similarity with deferiprone (DFP), mimosine is a potential excellent metal chelator. In the present work, we combine experimental and theoretical (DFT) approaches in order to investigate the properties of mimosine peptides. Six different peptides were synthesized and their complex stoichiometry and stability were characterized by means of UV-Vis spectrophotometry. Then, the binding mode and self-assembly features of the peptides were evaluated using a DFT approach, taking into account different number of mimosine amino acids and varying the length of the spacer between the mimosine residues, and there was good agreement between experimental data and computational calculations. Further elucidations of the structural properties of these peptides allowed us to propose improvements in the structure of the mimosine moiety which can lead to enhanced affinity for high-valent metals. Moreover, we demonstrate that these peptides show an anti-microbial activity against Gram positive bacteria that is enhanced by the formation of a complex with iron(iii) ions. The mimosine peptides could be an alternative to antimicrobial peptides (AMPs), which are expensive and susceptible to proteolytic degradation. In summary, in the present work, we propose a new generation of multipurpose mimosine-based peptides as new metal self-assembly chelators which could be a turning point in biomedical and nanotechnological applications.

Deferoxamine but Not Dimethyloxalylglycine, L-Mimosine, or Cobalt Dichloride Can Interfere with the MTT Assay.

Hypoxia mimetic agents (HMAs) have been shown to have a positive influence on cellular functions in a multitude of tissue regenerative strategies. Novel experimental approaches use biomaterials as carriers for controlled delivery of these HMAs. Here, the cytotoxic aspects of biocompatibility are of key relevance. The MTT assay is widely used to evaluate cytotoxicity and proliferation. Based on the implications from the proceeding research we hypothesized that specific HMAs such as deferoxamine at high concentrations can interfere with the MTT assay. Thus, the aim of this study was to test the repercussions of the HMAs dimethyloxalylglycine, deferoxamine, L-mimosine, and CoCl2 on the validity of the MTT assay. Murine MC3T3-E1 cells were cultured in serum-free alphaMEM and in alphaMEM supplemented with 10 % fetal bovine serum with the HMAs dimethyloxalylglycine, deferoxamine, L-mimosine, and CoCl2, respectively, at 3 mM-0.3 mM for 24 h (experimental groups). Cells without HMAs served as control (control groups). The same experiments were performed with medium and phosphate buffered saline (PBS) without cells. In all settings MTT solution was added to PBS-washed or unwashed culture plates for the last two hours of the incubation period. Then MTT solution was removed and dimethyl sulfoxide was added to dissolve the formazan crystals and absorption was measured. Our data show that the presence of deferoxamine can interfere with the MTT assay if not removed before the addition of MTT. This is particularly important when evaluating cell viability in setups where deferoxamine-loaded biomaterials are used.

Attenuation of prostaglandin E1­induced osteoprotegerin synthesis in osteoblasts by normoxic HIF inducers.

Mimosine, which is a natural plant amino acid present in the Leucaena genus, is able to induce hypoxia­inducible factors (HIFs). Previous evidence has indicated that HIF regulates angiogenesis­osteogenesis coupling in bone metabolism, and it has previously been reported that mimosine inhibits prostaglandin (PG)F2α­induced osteoprotegerin (OPG) synthesis without affecting interleukin­6 (IL­6) production in osteoblast­like MC3T3­E1 cells. In addition, PGE1 has been demonstrated to induce OPG synthesis via activation of p38 mitogen­activated protein (MAP) kinase and stress­activated protein kinase/c­Jun N­terminal kinase (SAPK/JNK) in these cells, and PGE1 stimulates IL­6 production via the activation of protein kinase A. In the present study, the effects of mimosine on the PGE1­stimulated synthesis of OPG and IL­6 were investigated in osteoblast­like MC3T3­E1 cells. The concentrations of OPG and IL­6 were measured using relevant ELISA kits. OPG mRNA was measured by semi­quantitative reverse transcription polymerase chain reaction. The phosphorylation of p38 MAP kinase and SAPK/JNK was analyzed by western blotting. Mimosine significantly reduced PGE1­induced release of OPG and OPG mRNA expression levels without affecting the release of IL­6. In addition, deferoxamine, which is also a normoxic HIF inducer, significantly inhibited PGE1­induced OPG release and OPG mRNA expression levels; however, it had little effect on IL­6 release. Furthermore, mimosine and deferoxamine failed to affect PGE1­stimulated phosphorylation of p38 MAP kinase or SAPK/JNK. These results strongly suggest that normoxic HIF inducers attenuate PGE1­stimulated OPG synthesis without affecting IL­6 production in osteoblasts.

The Chemistry and Biological Activities of Mimosine: A Review.

Mimosine [ß-[N-(3-hydroxy-4-oxypyridyl)]-α-aminopropionic acid] is a non-protein amino acid found in the members of Mimosoideae family. There are a considerable number of reports available on the chemistry, methods for estimation, biosynthesis, regulation, and degradation of this secondary metabolite. On the other hand, over the past years of active research, mimosine has been found to have various biological activities such as anti-cancer, antiinflammation, anti-fibrosis, anti-influenza, anti-virus, herbicidal and insecticidal activities, and others. Mimosine is a leading compound of interest for use in the development of RAC/CDC42-activated kinase 1 (PAK1)-specific inhibitors for the treatment of various diseases/disorders, because PAK1 is not essential for the growth of normal cells. Interestingly, the new roles of mimosine in malignant glioma treatment, regenerative dentistry, and phytoremediation are being emerged. These identified properties indicate an exciting future for this amino acid. The present review is focused on the chemistry and recognized biological activities of mimosine in an attempt to draw a link between these two characteristics. Copyright © 2016 John Wiley & Sons, Ltd.

Insecticidal and Nematicidal Activities of Novel Mimosine Derivatives.

Mimosine, a non-protein amino acid, is found in several tropical and subtropical plants, which has high value for medicine and agricultural chemicals. Here, in continuation of works aimed to development of natural product-based pesticidal agents, we present the first significant findings for insecticidal and nematicidal activities of novel mimosine derivatives. Interestingly, mimosinol and deuterated mimosinol (D-mimosinol) from mimosine had strong insecticidal activity which could be a result of tyrosinase inhibition (IC50 = 31.4 and 46.1 µM, respectively). Of synthesized phosphoramidothionate derivatives from two these amino alcohols, two compounds (1a and 1b) showed high insecticidal activity (LD50 = 0.5 and 0.7 µg/insect, respectively) with 50%-60% mortality at 50 µg/mL which may be attributed to acetylcholinesterase inhibition. Compounds 1a and 1b also had strong nematicidal activity with IC50 = 31.8 and 50.2 µM, respectively. Our results suggest that the length of the alkyl chain and the functional group at the C5-position of phosphoramidothionates derived from mimosinol and d-mimosinol are essential for the insecticidal and nematicidal activities. These results reveal an unexplored scaffold as new insecticide and nematicide.

Mimosine Dipeptide Enantiomsers: Improved Inhibitors against Melanogenesis and Cyclooxygenase.

Melanogenesis plays an important role in the protection of skin against UV through production of melanin pigments, but abnormal accumulation of this pigment causes unaesthetic hyperpigmentation. Much effort is being made to develop effective depigmenting agents. Here, we show for the first time that a small library of mimosine dipeptide enantiomers (Mi-L/D-amino acid) inhibit the melanogenesis in B16F10 melanoma cells by down-regulating the cellular tyrosinase with little effect on their growth or viability. Two of them, Mi-D-Trp and Mi-D-Val, turned out to be the most potent inhibitors on melanin content and cellular tyrosinase in B16F10 melanoma cells. In addition, most of the mimosine dipeptides were more potent than mimosine for inhibiting cyclooxygenase 1 (COX-1) with IC50 of 18-26 µM. Among them, Mi-L-Val and Mi-L-Trp inhibited cyclooxygenase 2 (COX-2) more potently than indomethacin, with IC50 values of 22 and 19 µM, respectively. Taken together, our results suggest the possibility that mimosine dipeptides could be better candidates (than mimosine) for anti-melanogenic (skin hyperpigmentation treatment) and cyclooxygenase (COX) inhibition.

A carbon-nitrogen lyase from Leucaena leucocephala catalyzes the first step of mimosine degradation.

The tree legume Leucaena leucocephala contains a large amount of a toxic nonprotein aromatic amino acid, mimosine, and also an enzyme, mimosinase, for mimosine degradation. In this study, we isolated a 1,520-bp complementary DNA (cDNA) for mimosinase from L. leucocephala and characterized the encoded enzyme for mimosine-degrading activity. The deduced amino acid sequence of the coding region of the cDNA was predicted to have a chloroplast transit peptide. The nucleotide sequence, excluding the sequence for the chloroplast transit peptide, was codon optimized and expressed in Escherichia coli. The purified recombinant enzyme was used in mimosine degradation assays, and the chromatogram of the major product was found to be identical to that of 3-hydroxy-4-pyridone (3H4P), which was further verified by electrospray ionization-tandem mass spectrometry. The enzyme activity requires pyridoxal 5'-phosphate but not α-keto acid; therefore, the enzyme is not an aminotransferase. In addition to 3H4P, we also identified pyruvate and ammonia as other degradation products. The dependence of the enzyme on pyridoxal 5'-phosphate and the production of 3H4P with the release of ammonia indicate that it is a carbon-nitrogen lyase. It was found to be highly efficient and specific in catalyzing mimosine degradation, with apparent Km and Vmax values of 1.16×10(-4) m and 5.05×10(-5) mol s(-1) mg(-1), respectively. The presence of other aromatic amino acids, including l-tyrosine, l-phenylalanine, and l-tryptophan, in the reaction did not show any competitive inhibition. The isolation of the mimosinase cDNA and the biochemical characterization of the recombinant enzyme will be useful in developing transgenic L. leucocephala with reduced mimosine content in the future.

Contribution of condensed tannins and mimosine to the methane mitigation caused by feeding Leucaena leucocephala.

Leucaena (Leucaena leucocephala), a leguminous shrub promising to cope with feed scarcity in the tropics, may help in mitigating ruminal methane (CH4) emission in the tropics as well. Two experiments were conducted to evaluate the effect of Leucaena and major secondary compounds of this plant in ruminants. At first, effects of Leucaena tannins and mimosine on ruminal CH4 and nutrient degradability were tested in vitro. Incubations were made with Leucaena without or with polyethylene glycol (PEG) to exclude the tannins effects, as well as with Bermuda grass (Tifton) and lucerne hays, both either untreated or supplemented with mimosine at the same concentration that has been provided by the tested Leucaena (6.52 mg/g DM). Furthermore, in an in vivo experiment a control diet (per kg DM 700 g Tifton hay) and Leucaena diets (per kg DM 350 g Tifton hay and 350 g Leucaena), either with or without 20 g PEG/d per head, were evaluated in six Santa Inês sheep following a double Latin square design. In vitro, Leucaena resulted in the lowest (p < 0.05) gas and CH4 production and the highest (p < 0.05) partitioning factor, a measure for microbial efficiency, whereas the amount of truly degraded organic matter (TDOM) was lowest (p < 0.05) with Tifton among the experimental forage plants. Mimosine addition to lucerne and Tifton as well as PEG addition to Leucaena had no effect on ruminal CH4 and TDOM. In vivo Leucaena, compared to the Tifton diet, enhanced (p < 0.05) intake, faecal nitrogen excretion, body nitrogen retention and the excretion of urinary purine derivatives as an indicator for microbial protein synthesis and availability. This was independent of PEG addition. Leucaena also decreased (p < 0.001) CH4 emission per unit of digested organic matter by 14.1% and 10.8%, without and with PEG, respectively. No significant diet differences were observed in total-tract nutrient digestibility. The study demonstrated efficiency of Leucaena to mitigate in vivo methane emission of sheep, but did not reveal which constituent of Leucaena was primarily responsible for that since no clear efficiency of either tannins or mimosine could be demonstrated.

Preparative scale isolation, purification and derivatization of mimosine, a non-proteinogenic amino acid.

Focusing on drug discovery non-proteinogenic amino acids have often been used as important building blocks for construction of compound libraries in the filed of combinatorial chemistry and chemical biology. Highly homogeneous L: -mimosine, α-amino-ß-(3-hydoxy-4-oxo-1,4-dihydropyridin-1-yl)-propanoic acid, a non-proteinogenic amino acid, has been successfully isolated and purified on an industrial scale from wild leaves of Leucaena (Leucaena leucocephala de Wit) which is a widely distributed legume in Okinawa, a sub-tropical island in Japan. Optical purity determinations used for quality control have been established through diastereomer formation. Physico-chemical properties and biological properties of purified mimosine have been clarified. Mimosine is sparingly soluble in water and organic solvents but can be dissolved in aqueous alkaline solution. The tyrosinase pathway is of particular interest in the cosmetic field, since mimosine is an analog of tyrosine. Thus the present purified mimosine have been tested in tyrosinase inhibitory assays. The IC50 for tyrosinase inhibitory activity of purified Mim was compared with kojic acid. Mimosine shows significant inhibition of melanin production in murine melanoma cells. The derivatization of mimosine has been investigated with a focus on its use in conventional peptide syntheses to generate mimosyl peptides. N-(9-Fluorenylmethoxycarbonyloxy)-mimosine and resin-bound mimosine for solid-phase syntheses have also been performed. Highly homogeneous Mim is a useful material for the development of functional cosmetics or active pharmaceutical ingredients.

Solid-phase synthesis of mimosine tetrapeptides and their inhibitory activities on neuraminidase and tyrosinase.

Neuraminidase is a rational target for influenza inhibition, and the search for neuraminidase inhibitors has been intensified. Mimosine, a nonprotein amino acid, was for the first time identified as a neuraminidase inhibitor with an IC(50) of 9.8 ± 0.2 µM. It was found that mimosine had slow, time-dependent competitive inhibition against the neuraminidase. Furthermore, a small library of mimosine tetrapeptides (M-A(1)-A(2)-A(3)) was synthesized by solid-phase synthesis and was assayed to evaluate their neuraminidase and tyrosinase inhibitory properties. Most of the tetrapeptides showed better activities than mimosine. Mimosine-FFY was the best compound, and it exhibited 50% neuraminidase inhibition at a low micromolar range of 1.8 ± 0.2 µM, whereas for tyrosinase inhibition, it had an IC(50) of 18.3 ± 0.5 µM. The kinetic studies showed that all of the synthesized peptides inhibited neuraminidase noncompetitively with K(i) values ranging from 1.9 -to 7.2 µM. These results suggest that mimosine could be used as a source of bioactive compounds and may have possibilities in the design of drugs as neuraminidase and tyrosinase inhibitors.

Daboia russelli venom hyaluronidase: purification, characterization and inhibition by ß-3-(3-hydroxy-4-oxopyridyl) α-amino-propionic Acid.

The present study describes the purification and characterization of a hyaluronidase (DRHyal-II) from Daboia/Vipera russelli venom and its inhibition by ß-3-(3-hydroxy-4-oxopyridyl) α-amino-propionic acid, the mimosine. Gel permeation and ion exchange chromatography were employed to isolate DRHyal-II. The molecular mass by MALDITOF mass spectrometry was found to be 28.3 kDa. Single band in reduced SDS-PAGE suggested the monomeric nature. It was optimally active at pH 5.5 and at 37C and require 150 mM NaCl in the reaction mixture. It was specific to hyaluronan substrate and belongs to class-I or the neutral active enzymes. DRHyal-II was non-toxic by itself but, it potentiated the myotoxicity of VRV-PL-VIII myotoxin and hemorrhagic activity of hemorrhagic complex (HC). In in vitro experiments, mimosine inhibited the activity of DRHyal-II and the hyaluronidase activity of whole venom dose dependently. In in vivo experiments, mimosine inhibited the DRHyal-II potentiated myotoxicity of VRV-PL-VIII myotoxin and hemorrhagic activity of HC. The inhibition was due to the formation of DRHyal-II-mimosine inhibitory complex that resulted in significant structural changes at secondary and tertiary levels as evidenced by fluorescence emission and CD spectral studies. Hence, in this study an attempt was made to establish the possible role of hyaluronidase activity in the pathology of Daboia/Vipera russelli venom and the beneficial effects of its inhibition with special emphasis on the management of local toxicity.

Kinetic properties of hexameric tyrosinase from the crustacean Palinurus elephas.

Tyrosinases catalyze hydroxylation of monophenols to o-diphenols and their subsequent oxidation to o-quinones, whereas catecholoxidases catalyze only the latter reaction. Both enzymes occur in all organisms and are Type 3 copper proteins that perform the first steps of melanin formation. In arthropods, they play an essential role in the sclerotization of the exoskeleton. Very few phenoloxidases are characterized structurally or kinetically and the existence of an actual tyrosinase activity has not been demonstrated in most cases. Here we present for the first time a complete kinetic characterization of a tyrosinase from a crustacean (Palinurus elephas) including the influence of inhibitors. In contrast to most tyrosinases which are monomeric or dimeric, this tyrosinase occurs as a hexamer. However, the data did not indicate cooperativity in steady-state kinetics for the two substrates used, the monophenol tyramine and the diphenol dopamine. Mimosine as well as phenylthiourea (PTU) inhibited both monophenolhydroxylase and diphenoloxidase activity. Inhibition by mimosine was competitive, whereas PTU was a noncompetitive inhibitor. Furthermore, for the diphenolase activity substrate inhibition was observed, which was apparently abolished by adding PTU. These observations lead to the hypothesis that a secondary, allosteric binding site exists, which binds dopamine and PTU and reduces the catalytic activity.

Mimosine mitigates oxidative stress in selenium deficient seedlings of Vigna radiata. Part II: mitochondrial uptake of 75selenium and mimosine.

During the growth of selenium (Se)-deficient seedlings of Vigna radiata, exposure to mimosine [2-amino-3-(3-hydroxy-4-oxo-1H-pyridin-1-yl)-propanoic acid], a nonprotein plant amino acid, effectively mitigated stress at 0.1 mM, as reflected in enhancement of growth and efficiency of mitochondrial functions. Since the changes in the seedlings elicited by exposure to mimosine were similar to those effected by Se at an optimal exposure level of 0.75 ppm (Sreekala et al., Biol Trace Elem Res 70:193-207, 1999), the uptake of Se and that of mimosine itself was individually studied in the respiring mitochondria of Se-deficient seedlings (-Se-stressed group) in comparison with those exposed to mimosine during growth at 0.1 mM (Mim 0.1 group). In both groups, the mitochondrial uptake of (75)Se at 10 microM added Na(2)(75)SeO(3), increased linearly up to 2 min, attaining steady-state levels thereafter. Uptake levels were 2.3-fold higher in the Mim 0.1 group than in the -Se-stressed group. Double-reciprocal plots of mitochondrial (75)Se uptake against 2-20 microM Na(2)(75)SeO(3) in the medium were nonlinear and negative cooperative effects during the uptake were confirmed by Scatchard plots, whereas Hill coefficients were 0.8 and 0.85 for the two groups. Mitochondrial uptake of mimosine, at added levels of 25 or 50 microM, increased linearly up to 1 min and decelerated thereafter. Initial uptake levels of mimosine at 1 min were higher by 6.5-fold at 25 microM and 4-fold at 50 microM in the Mim 0.1 group than those in the -Se-stressed group. Initial uptake levels with added mimosine up to 50 or 100 microM yielded nonlinear double-reciprocal plots; and kinetic analyses at 5 to 50 microM revealed the prevalence of positive cooperativity in the -Se-stressed group and negative cooperativity in the Mim 0.1 group. Involvement of active thiol groups in the uptake of both Se and mimosine were indicated by inhibition studies. Evidence presented for mimosine mediated increase in mitochondrial Se uptake and cooperative interactions thereof underscores the metabolic significance of mimosine.

Selective determination of mimosine and its dihydroxypyridinyl derivative in plant systems.

Our observations on the growth stimulatory nature of mimosine, (beta-(3-hydroxy-4-pyridon-1-yl)-L-alanine), the toxic non-protein plant amino acid, in some model experimental systems, warranted sensitive and selective routine estimations. For the determination of both mimosine and DHP, an indirect spectrophotometric method was developed based on their individual reaction with known excess of DZSAM and by estimating the remaining DZSAM with N-(1-naphthyl)ethylene-diamine (NEDA). The resultant decrease in the secondary coupled product was measured at 540 nm. On equimolar basis, DHP had 40% of the reactivity of mimosine while interference from other relevant compounds was 15-35%. The determination of mimosine and DHP in tissue samples under different physiological conditions was effected after paper chromatographic separation of mimosine and DHP with distinctly differing Rf, from other compounds. The indirect method is superior in terms of absolute selectivity, sensitivity and ease of applicability with linear decreases in absorbance, proportional to increasing concentrations of mimosine from 0.1 to 0.75 microM or DHP from 0.2 to 1.5 microM and with recoveries of 99.2 to 100.5%.

Tyrosinase inhibition studies of cycloartane and cucurbitane glycosides and their structure-activity relationships.

In the present paper, tyrosinase inhibition studies and structure-activity relationship of eight cycloartane glycosides and one cucurbitane glycoside and its genin, which were isolated from Astragalus (Leguminoseae) and Bryonia (Cucurbitaceae) plants, have been discussed. The activities are compared with two reference tyrosinase inhibitors, kojic acid and l-mimosine. These studies and the SAR showed that the askendoside B which exhibited highly potent (IC50 =13.95 microM) tyrosinase inhibition could be a possible lead molecule for the development of new medications of several skin diseases related with the over-expression of the enzyme tyrosinase, like hyperpigmentation. The molecule also may be interesting for the cosmetic industries as a skin whitening agent.