Tyrosinase is a multi-copper enzyme which is widely distributed in different organisms and plays an important role in the melanogenesis and enzymatic browning. Therefore, its inhibitors can be attractive in cosmetics and medicinal industries as depigmentation agents and also in food and agriculture industries as antibrowning compounds. For this purpose, many natural, semi-synthetic and synthetic inhibitors have been developed by different screening methods to date. This review has focused on the tyrosinase inhibitors discovered from all sources and biochemically characterised in the last four decades.

https://northumbria-test.eprints-hosting.org/id/document/268389

A comprehensive review on tyrosinase inhibitors.

Natural product libraries contain specialized metabolites derived from plants, animals, and microorganisms that play a pivotal role in drug discovery due to their immense structural diversity and wide variety of biological activities. The strategies to greatly extend natural product scaffolds through available biological and chemical approaches offer unique opportunities to access a new series of natural product analogues, enabling the construction of diverse natural product-like libraries. The affordability of these structurally diverse molecules has been a crucial step in accelerating drug discovery. This review provides an overview of various approaches to exploit the diversity of compounds for natural product-based drug development, drawing upon a series of examples to illustrate each strategy.

Strategies to diversify natural products for drug discovery.

A novel fluorescence biosensor for sensitivity detection of tyrosinase and acid phosphatase based on nitrogen-doped graphene quantum dots

Effect-directed fingerprints of 77 botanical extracts via a generic high-performance thin-layer chromatography method combined with assays and mass spectrometry.

Imine synthesis has enjoyed a long history as the dynamic covalent reaction of choice for the construction of purely covalent molecular architectures. In organic solvents, the formation of imine bonds is reversible but leads to thermodynamically stable products. In the presence of water, however, imine bonds are labile, a fact which limits their utility as mediators of self-assembly in aqueous and biological media. In this Review, we discuss water-compatible dynamic covalent bonds based on N-substituted imine derivatives, namely hydrazones and oximes, for the self-assembly of metal-free organic architectures with well-defined structures. The reasons why hydrazones and oximes are more robust in water than their parent imines are explained. Recent progress in the self-assembly, characterization, and design principles of a variety of complex molecules including macrocycles, cages, catenanes, and knots in aqueous media is highlighted. Emerging applications for these molecules, including guest recognition and separations, are also discussed.

Self-Assembly in Water with N-Substituted Imines

Introduction

Autographic methods are useful tools to detect bioactive compounds in complex matrixes. Experimental design and optimisation techniques were implemented for the development of an autographic assay suitable for the detection of tyrosinase inhibitors.



Objectives

To develop an autographic assay to detect tyrosinase inhibitors using gel entrapped enzyme, experimental design and response surface methodology (RSM) to optimise conditions with a minimum number of experiments.



Methods

Gel entrapment was used for the assay and the effects of four factors on the sensitivity and the detection limit for known inhibitors of the enzyme were evaluated. The factors were: tyrosinase amount (TA), L-tyrosine amount (LTA), incubation time and incubation temperature.



Results

The assay allowed the detection of kojic acid in an extract of Calamagrostis viridiflavescens (Poir.) Steud spiked with 0.1% w/w.



Conclusion

The developed assay is able to detect tyrosinase inhibitors present in complex matrixes in a reproducible way. Copyright © 2015 John Wiley & Sons, Ltd.

Multiresponse Optimisation Applied to the Development of a TLC Autography for the Detection of Tyrosinase Inhibitors.

Introduction
Reverse phase chromatography and bioautographic assays are key tools for natural product bioguided isolation; however, their direct coupling has not been fully achieved.

Objectives
To develop a bioautographic assay to detect tyrosinase inhibitors present in complex matrices sorbed on reverse phase (RP) TLC-plates that can be used for bioguided isolation of bioactive compounds.

Methods
Enzyme gel entrapment with an amphiphilic copolymer was used for assay development. The gel turns into a brown “skin like” colour due to tyrosinase catalysed oxidation of l-tyrosine. The inhibitors are visualised as clear spots against a brown coloured background.

Results
The assay was able to localise cinnamaldehyde in Cinnamomum cassia essential oil, as its main constituent with known tyrosinase inhibition properties. The assay allowed the detection of 0.03% (w/w) of kojic acid co-spotted with a methanolic extract of Sphaeralcea bonariensis and chromatographed on RP-TLC.

Conclusion
The developed assay is able to detect, with high sensitivity, tyrosinase inhibitors present in complex matrices that were chromatographed in RP-TLC. Results can be easily read by colour change, inhibitors appear as clear spots in a darker background. Copyright © 2016 John Wiley & Sons, Ltd.

Reverse Phase Compatible TLC‐Bioautography for Detection of Tyrosinase Inhibitors

The generation of fluorinated essential oils as a source of bioactive compounds is described. Most of the components of the natural mixtures were altered, leading to the discovery of a new fluorinated tyrosinase inhibitor.

A New Fluorinated Tyrosinase Inhibitor from a Chemically Engineered Essential Oil.

A set of chemically engineered essential oils has been generated through chemical diversification by reaction with bromine. The impact of the reaction over the chemical composition of the mixtures was qualitatively demonstrated through GC-MS and utilizing multivariate analysis of 1H NMR and GC-MS. Most of the components of the essential oils are transformed by the reaction expanding the chemical diversity of the mixtures. Biological changes between essential oils and brominated essential oils were demonstrated through image analysis of xanthine oxidase autography profiles. The highest biological activity increase was obtained for the Foeniculum vulgare Mill essential oil. Coupling of xanthine oxidase autography with the BIOMSID strategy allowed the identification of the molecular formula of the active compound. Bioguided fractionation of the mixture led to the isolation of (RS)-2-bromo-1-(4-methoxyphenyl) propan-1-one for being responsible for the observed bioactivity. This xanthine oxidase inhibitor could have been formed from the inactive natural component anethole. The inhibitory potency of this semisynthetic compound was in the same order of magnitude as allopurinol, the most used inhibitor.

Chemical diversification of essential oils, evaluation of complex mixtures and identification of a xanthine oxidase inhibitor

Target-directed dynamic combinatorial chemistry (DCC) has emerged as a strategy for the identification of inhibitors of relevant therapeutic targets. In this contribution, we use this strategy for the identification of a high-affinity binder of a parasite target, the Trypanosoma cruzi bromodomain-containing protein TcBDF3. This protein is essential for viability of T. cruzi, the protozoan parasite that causes Chagas disease. A small dynamic library of acylhydrazones was prepared from aldehydes and acylhydrazides at neutral pH in the presence of aniline. The most amplified library member shows (a) high affinity for the template, (b) interesting antiparasitic activity against different parasite forms, and (c) low toxicity against Vero cells. In addition, parasites are rescued from the compound toxicity by TcBDF3 overexpression, suggesting that the toxicity of this compound is due to the TcBDF3 inhibition, i.e., the binding event that initially drives the molecular amplification is reproduced in the parasite...

/pdf/discovery-of-a-biologically-active-bromodomain-inhibitor-by-2umlu3oc0j.pdf

Paula García

Papers

Multiresponse Optimisation Applied to the Development of a TLC Autography for the Detection of Tyrosinase Inhibitors.

Reverse Phase Compatible TLC‐Bioautography for Detection of Tyrosinase Inhibitors

A New Fluorinated Tyrosinase Inhibitor from a Chemically Engineered Essential Oil.

Chemical diversification of essential oils, evaluation of complex mixtures and identification of a xanthine oxidase inhibitor

Discovery of a Biologically Active Bromodomain Inhibitor by Target-Directed Dynamic Combinatorial Chemistry