Discovery of Benzylidenebenzofuran-3(2H)-one (Aurones) as Inhibitors of Tyrosinase Derived from Human Melanocytes

Abstract

Tyrosinase is a copper-dependent enzyme which converts l- tyrosine to dopaquinone and is involved in different biological processes such as melanogenesis and skin hyperpigmentation. The purpose of this study was to investigate naturally occurring aurones (Z-benzylidenebenzofuran-3(2H)-one) and analogues as human tyrosinase inhibitors. Several aurones bearing hydroxyl groups on A-ring and different substituents on B-ring were synthesized and evaluated as inhibitors of human melanocyte-tyrosinase by an assay which measures tyrosinase-catalyzed l-Dopa oxidation. We found that unsubstituted aurones were weak inhibitors; however, derivatives with two or three hydroxyl groups preferably at 4,6 and 4' positions are able to induce significant tyrosinase inhibition. The most potent aurone was found to be the naturally occurring 4,6,4'-trihydroxyaurone which induces 75% inhibition at 0.1 mM concentration and is highly effective when compared to kojic acid, one of the best tyrosinase inhibitors known so far (the latter is completely inactive at such concentrations). Active aurones are devoid of toxic effects as shown by in vivo studies.

2-Hydroxypyridine-N-oxide-Embedded Aurones as Potent Human Tyrosinase Inhibitors

“…34 Embedding this small moiety in an aurone backbone generated "hybrid" aurone 1a, which showed a TyM1 inhibition activity in the same range as HOPNO ( Figure 1). 32 We report herein the synthesis of three hybrid aurones, whose A-ring substitution patterns were selected reminiscently of our previous results on human melanocytes, 31 along with their biological evaluation through in vitro assays using (1) purified recombinant TyH (from Homo sapiens) and (2) human MNT-1 melanoma cells. The interactions of the most active hybrid aurone with TyH were then rationalized by combining QM/MM dynamics and noncovalent interaction (NCI) analysis, using the recent homology model of TyH mentioned above.…”

“…17,31,32 The B-ring of aurones, as it interacts directly with the active site, completely determined their general behavior toward TyM1 and TyB3. Indeed, aurones I and II act as alternative substrates, aurones III and IV as activators (for TyM1) or weak inhibitors (for TyB3), and aurones V as mixed inhibitors (Figure 1).…”

Quantitative Structure–Cytotoxicity Relationship of Aurones

“…[7], (2Z)-6-methoxy-2-(phenylmethylene)-3(2H)-benzofuranone [8], (2Z)-6-methoxy-2-[(4-methoxyphenyl)methylene]-3(2H)-benzofuranone [9], (2Z)-2-[(3,4-dimethoxyphenyl)methylene]-6-methoxy-3(2H)-benzofuranone [10] and (2Z)-2-[(4-bromophenyl)methylene]-6-methoxy-3(2H)-benzofuranone [11] were synthesized by the oxidative cyclization of 2'-hydroxychalcone derivatives, according to previous methods (13). Also, (2Z)-2-[(3,4-dimethoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone [12], (2Z)-2-[(4-fluorophenyl)methylene]-6-hydroxy-3(2H)-benzofuranone [13] [16] and (2Z)-2-[(3,4-dihydroxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone [17] were synthesized by the condensation of 6-hydroxy-3(2H)-benzofuranone with selected benzaldehyde derivatives, according to previous methods (14). All compounds were dissolved in DMSO at 40 mM and stored at -20˚C before use.…”

Boronic-aurone Derivatives as Anti-Tubercular Agents: Design, Synthesis and Biological Evaluation

“…Adapting published protocols [22], synthesis of all four boronic aurones ( Figure 1) were carried out using microwave assisted ClaisenSchmidt condensation reaction as shown in Scheme 1. To a solution of substituted benzofuran-3(2H)-one 1 (1 equiv) dissolved in 95% ethanol (10 mL) was added aqueous solution of sodium hydroxide (10 mol%).…”