Sultan Ullah

Tyrosinase inhibitors: a patent review (2011-2015)

ABSTRACT Introduction: Tyrosinase is responsible for melanin production. The overproduction of melanin causes many skin disorders. The inhibition of tyrosinase activity would appear to be the most rational and explicit way of overcoming these issues. Areas covered: Thirty eight patents on synthetic tyrosinase inhibitors issued since 2011 were reviewed. Inhibitors were categorized by chemical structure and assigned to eight classes. Information on potent inhibitors in each class is provided. Expert opinion: Many tyrosinase inhibitors of natural or synthetic origin have been identified, but very few are qualified for clinical use. Thus medicinal scientists have to work more on the identification of potent and safe tyrosinase inhibitors. Various chemical scaffolds have been explored. Among them, the scaffolds such as resorcinol, biaryl, imidazolethione, β-phenyl-α,β-unsaturated carbonyl, and some double strand oligonucleotides have shown high tyrosinase inhibition, low toxicities, and great potencies. Detail structure activity relationship studies of these potential scaffolds could provide directions for a new and potent tyrosinase inhbitors. Furthermore new trends, such as the use of synergistic phenomena, salt formation, drug repositioning and designing of multi-targeted tyrosinase inhibitors could expand search areas for much improved tyrosinase inhibitors.

(E)-2-Cyano-3-(substituted phenyl)acrylamide analogs as potent inhibitors of tyrosinase: A linear β-phenyl-α,β-unsaturated carbonyl scaffold.

In this study, we synthesized (E)-2-cyano-3-(substituted phenyl)acrylamide (CPA) derivatives which possess a linear β-phenyl-α,β-unsaturated carbonyl scaffold and examined their inhibitory activities against tyrosinase. CPA analogs exerted inhibitory activity against mushroom tyrosinase. Results from the docking simulation indicated that CPA2 could bind directly to the active site of mushroom tyrosinase and the binding affinity of CPA2 for tyrosinase might be higher than that of kojic acid, a well-known potent tyrosinase inhibitor. In B16F10 cells, CPA2 significantly suppressed tyrosinase activity and melanogenesis in a dose-dependent manner. At the concentration of 25μM, CPA2 exhibited tyrosinase inhibitory activity comparable to that of kojic acid with no cytotoxic effect. Results from the present study suggest that CPA2 bearing a linear β-phenyl-α,β-unsaturated carbonyl scaffold may be the potential candidate for treatment of diseases associated with hyperpigmentation and that a linear β-phenyl-α,β-unsaturated carbonyl scaffold might be closely related to potent tyrosinase inhibition.

A novel synthetic compound, (Z)-5-(3-hydroxy-4-methoxybenzylidene)-2-iminothiazolidin-4-one (MHY773) inhibits mushroom tyrosinase

Abstract As part of continued efforts for the development of new tyrosinase inhibitors, (Z)-5-(substituted benzylidene)-2-iminothiazolidin-4-one derivatives (1a – 1l) were rationally synthesized and evaluated for their inhibitory potential in vitro. These compounds were designed and synthesized based on the structural attributes of a β-phenyl-α,β-unsaturated carbonyl scaffold template. Among these compounds, (Z)-5-(3-hydroxy-4-methoxybenzylidene)-2-iminothiazolidin-4-one (1e, MHY773) exhibited the greatest tyrosinase inhibition (IC50 = 2.87 μM and 8.06 μM for monophenolase and diphenolase), and outperformed the positive control, kojic acid (IC50 = 15.59 and 31.61 μM). The kinetic and docking studies demonstrated that MHY773 interacted with active site of tyrosinase. Moreover, a melanin quantification assay demonstrated that MHY773 attenuates α-melanocyte-stimulating hormone (α-MSH) and 3-isobutyl-1-methylxanthine (IBMX)-induced melanin contents in B16F10 melanoma cells. Taken together, these data suggest that MHY773 suppressed the melanin production via the inhibition of tyrosinase activity. MHY773 is a promising for the development of effective pharmacological and cosmetic agents for skin-whitening. Binding mode and affinity of MHY773 with tyrosinase was investigated by enzyme kinetics and docking simulations. MHY773 showed potent tyrosinase inhibitory activity.

Design, synthesis, and anti-melanogenic effects of (E)-2-benzoyl-3-(substituted phenyl)acrylonitriles.

Background Tyrosinase is the most prominent target for inhibitors of hyperpigmentation because it plays a critical role in melaninogenesis. Although many tyrosinase inhibitors have been identified, from both natural and synthetic sources, there remains a considerable demand for novel tyrosinase inhibitors that are safer and more effective. Methods (E)-2-Benzoyl-3-(substituted phenyl)acrylonitriles (BPA analogs) with a linear β-phenyl-α,β-unsaturated carbonyl scaffold were designed and synthesized as potential tyrosinase inhibitors. We evaluated their effects on cellular tyrosinase activity and melanin biosynthesis in murine B16F10 melanoma cells and their ability to inhibit mushroom tyrosinase activity. Results BPA analogs exhibited inhibitory activity against mushroom tyrosinase. In particular, BPA13 significantly suppressed melanin biosynthesis and inhibited cellular tyrosinase activity in B16F10 cells in a dose-dependent manner. A docking study revealed that BPA13 had higher binding affinity for tyrosinase than kojic acid. Conclusion BPA13, which possesses a linear β-phenyl-α,β-unsaturated carbonyl scaffold, is a potential candidate skin-whitening agent and treatment for diseases associated with hyperpigmentation.

MHY451 induces cell cycle arrest and apoptosis by ROS generation in HCT116 human colorectal cancer cells

Colorectal cancer (CRC) is the third most frequently diagnosed cancer and cause of cancer-related deaths. Despite advancements in conventional therapeutic approaches to CRC, most patients with CRC die of their disease. There is a need to develop novel therapeutic agents for this malignancy. Therefore, the present study aimed to examine the anticancer effects and elucidate the underlying mechanism of MHY451 in HCT116 human colorectal cancer cells. Treatment with MHY451 inhibited cell growth in a time- and concentration-dependent manner. MHY451 increased the accumulation of cell cycle progression at the G2/M phase. This agent decreased the protein level of cyclin B1 and its activating partners, Cdc25c and Cdc2, whereas it increased the cell cycle inhibitor p21WAF/CIP. The induction of apoptosis was observed by decreased viability, cleavage of poly(ADP-ribose) polymerase (PARP), alteration in the ratio of Bax/Bcl-2 protein expression and reduction of procaspase-8 and -9. Pretreatment with Z-VAD-FMK, a pan-caspase inhibitor, inhibited MHY451-induced apoptosis, indicating that apoptotic cell death by MHY451 was mediated through caspases. Moreover, the apoptotic effect of MHY451 was reactive oxygen species (ROS)-dependent, evidenced by the inhibition of MHY451-induced PARP cleavage and ROS generation by N-acetylcysteine-induced ROS scavenging. Taken together, these results demonstrate that MHY451 exerts anticancer effects by regulating the cell cycle, inducing apoptosis through caspase activation and generating ROS. These results suggest that MHY451 has considerable potential for chemoprevention or treatment of CRC or both.

Tyrosinase Inhibitory Effect of (E)-2-(substituted benzylidene)-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-one Derivatives

The inhibition of tyrosinase, a key enzyme in mammalian melanin synthesis, plays an important role in preventing skin pigmentation and melanoma. Therefore, tyrosinase inhibitors are very important in the fields of medicine and cosmetics. However, only a few tyrosinase inhibitors are currently available because of their toxic effects on skin or lack of selectivity and stability. Therefore, we synthesized a novel series of (E)-2-(substituted benzylidene)-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-one derivatives and evaluated their inhibitory effects on mushroom tyrosinase, with the aim of discovering a novel tyrosinase inhibitor. Among 19 derivatives, MHY3655 (IC50 = 0.1456 μM) showed the strongest inhibitory effect on tyrosinase activity compared to kojic acid (IC50 = 17.2 μM), a well-known tyrosinase inhibitor. In addition, MHY3655 showed competitive inhibition on Lineweaver-Burk plots. We confirmed that MHY3655 strongly interacts with mushroom tyrosinase residues through the docking simulation. Substitutions with a hydroxy group at both R2 and R4 in the phenyl ring indicated that these groups play a major role in the high binding affinity to tyrosinase. Further, MHY3655 did not show cytotoxicity at the concentrations tested in B16F10 melanoma cells. In conclusion, the novel compound MHY3655 potentially shows tyrosinase inhibitory activity, and it could be used as an ingredient in whitening cosmetics.

Design, synthesis, and antimelanogenic effects of (2-substituted phenyl-1,3-dithiolan-4-yl)methanol derivatives

The authors designed and synthesized 17 (2-substituted phenyl-1,3-dithiolan-4-yl) methanol (PDTM) derivatives to find a new chemical scaffold, showing excellent tyrosinase-inhibitory activity. Their tyrosinase-inhibitory activities were evaluated against mushroom tyrosinase at 50 μM, and five of the PDTM derivatives (PDTM3, PDTM7–PDTM9, and PDTM13) were found to inhibit mushroom tyrosinase more than kojic acid or arbutin, the positive controls. Of seventeen PDTMs, PDTM3 (half-maximal inhibitory concentration 13.94±1.76 μM), with a 2,4-dihydroxyphenyl moiety, exhibited greatest inhibitory effects (kojic acid half-maximal inhibitory concentration 18.86±2.14 μM). Interestingly, PDTM compounds with no hydroxyl group, PDTM7–PDTM9, also had stronger inhibitory activities than kojic acid. In silico studies of interactions between tyrosinase and the five PDTMs suggested their binding affinities were closely related to their tyrosinase-inhibitory activities. Cell-based experiments performed using B16F10 mouse-skin melanoma cells showed that PDTM3 effectively inhibited melanogenesis and cellular tyrosinase activity. A cell-viability study conducted using B16F10 cells indicated that the antimelanogenic effect of PDTM3 was not attributable to its cytotoxicity. Kinetic studies showed PDTM3 competitively inhibited tyrosinase, indicating binding to the tyrosinase-active site. We found that PDTM3 with a new chemical scaffold could be a promising candidate for skin-whitening agents, and that the 1,3-dithiolane ring could be used as a chemical scaffold for potent tyrosinase inhibition.

Design of PPAR-γ agonist based on algal metabolites and the endogenous ligand 15-deoxy-Δ12, 14-prostaglandin J2

In a previous study, we synthesized endocyclic enone jasmonate derivatives that function as anti-inflammatory and PPAR-γ-activating entities by using key functional moieties of anti-inflammatory algal metabolites. Herein, we designed additional derivatives containing an exocyclic enone moiety that resembles the key structure of the natural PPAR-γ ligand, 15-deoxy-Δ12, 14-prostaglandin J2 (15 d-PGJ2). The exocyclic enone moiety of 15 d-PGJ2 is essential for covalent bonding with the Cys285 residue in the PPAR-γ ligand-binding domain (LBD). In silico analysis of the designed compounds indicated that they may form hydrogen bonds with key amino acid residues in the PPAR-γ LBD, and thus, secure a position in the bioactive cavity in a similar fashion as does rosiglitazone and 15 d-PGJ2. By a luciferase reporter assay on rat liver Ac2F cells, the synthesized compounds were evaluated for PPAR-γ transcriptional activity. The differential PPAR-γ transcriptional activities of the geometric and enantiomeric isomers of the selected analog were also evaluated; based on our results, the enantiopure compound (+)-(R,E)-6a1 was suggested as a potential PPAR-γ ligand.

Novel SIRT1 activator MHY2233 improves glucose tolerance and reduces hepatic lipid accumulation in db/db mice

The NAD+-dependent deacetylase SIRT1, which is associated with the improvement of metabolic syndromes, such as type 2 diabetes, is a well-known longevity-related gene. Several in vitro and in vivo studies have shown the known protective effects of SIRT1 activators, such as resveratrol and SRT1720, on diabetes- or obesity-induced fatty liver and insulin resistance. Here, we newly synthesized 18 benzoxazole hydrochloride derivatives based on the structure of resveratrol and SRT1720. We performed an in vitro SIRT1 activity assay to identify the strongest SIRT1 activator. The assay confirmed MHY2233 to be the strongest SIRT1 activator (1.5-fold more potent than resveratrol), and docking simulation showed that the binding affinity of MHY2233 was higher than that of resveratrol and SRT1720. To investigate its beneficial effects, db/db mice were orally administered MHY2233 for 1 month, and various metabolic parameters were assessed in the serum and liver tissues. MHY2233 markedly ameliorated insulin signaling without affecting body weight in db/db mice. In particular, the mRNA expression of lipogenic genes, such as acetyl CoA carboxylase, fatty acid synthase, and sterol regulatory element-binding protein, which increased in db/db mice, decreased following oral treatment with MHY2233. In conclusion, the novel SIRT1 activator MHY2233 reduced lipid accumulation and improved insulin resistance. This finding may contribute toward therapeutic approaches for fatty liver disease and glucose tolerance.

Design, synthesis and anti-melanogenic effect of cinnamamide derivatives

Pigmentation disorders are attributed to excessive melanin which can be produced by tyrosinase. Therefore, tyrosinase is supposed to be a vital target for the treatment of disorders associated with overpigmentation. Based on our previous findings that an (E)-β-phenyl-α,β-unsaturated carbonyl scaffold can play a key role in the inhibition of tyrosinase activity, and the fact that cinnamic acid is a safe natural substance with a scaffolded structure, it was speculated that appropriate cinnamic acid derivatives may exhibit potent tyrosinase inhibitory activity. Thus, ten cinnamamides were designed, and synthesized by using a Horner-Emmons olefination as the key step. Cinnamamides 4 (93.72% inhibition), 9 (78.97% inhibition), and 10 (59.09% inhibition) with either a 2,4-dihydroxyphenyl, or 4-hydroxy-3-methoxyphenyl substituent showed much higher mushroom tyrosinase inhibition at 25 µM than kojic acid (18.81% inhibition), used as a positive control. Especially, the two cinnamamides 4 and 9 having a 2,4-dihydroxyphenyl group showed the strongest inhibition. Docking simulation with tyrosinase revealed that these three cinnamamides, 4, 9, and 10, bind to the active site of tyrosinase more strongly than kojic acid. Cell-based experiments carried out using B16F10 murine skin melanoma cells demonstrated that all three cinnamamides effectively inhibited cellular tyrosinase activity and melanin production in the cells without cytotoxicity. There was a close correlation between cellular tyrosinase activity and melanin content, indicating that the inhibitory effect of the three cinnamamides on melanin production is mainly attributed to their capability for cellular tyrosinase inhibition. These results imply that cinnamamides having the (E)-β-phenyl-α,β-unsaturated carbonyl scaffolds are promising candidates for skin-lighting agents.