As a part of an ongoing project aimed at developing new skin depigmenting agents, the ability of variously substituted 2-aryl-1,3-thiazolidines to inhibit melanogenesis in vitro was investigated. At 0.2 mM concn. 2-(2'-hydroxyphenyl)-1,3-thiazolidine-4-carboxylic acid (Th2), as well as the decarboxy analog (Th1) and, to a lower extent, the 4'-hydroxy isomer (Th3) all proved capable of preventing the tyrosinase catalyzed conversion of 0.2 mM L-tyrosine to melanin. Spectrophotometric monitoring of the reaction course in the presence of Th2 showed the initial formation of a yellow chromophore (.lambda.max 400 nm) which slowly decayed, being eventually replaced by a new absorption max. centered at 305 nm. HPLC anal. of the final incubation mixt. revealed the presence of a major product (.lambda.max 306 nm), ninhydrin and ferric chloride pos., which was isolated by gel filtration on Sephadex G-10 and was identified as .beta.-[7-(3-carboxy-5-hydroxy-3,4-dihydro-2H-1,4-benzothiazinyl)]alanine (DBA) by 1H-NMR spectroscopy. Attempts to isolate the intermediate with .lambda.max 400 nm were hampered by its marked instability under the usual chromatog. conditions. However, the nature of the chromophore, coupled with mechanistic considerations, suggested for the compd. the Schiff base-contg. structure 3,4-dihydroxy-5-S-(N-salicylidenecysteinyl)phenylalanine (salcysdopa). This was substantiated by: (i) the formation of a zinc complex (.lambda.max 349 nm) analogous to that obsd. with the model Schiff base N-salicylidene leucine; and (ii) detection by 1H-NMR of a Schiff base resonance at .delta. 8.1 during the yellow chromophoric phase of the reaction. It was concluded that 1,3-thiazolidines inhibit melanin formation by a mechanism that involves the trapping of enzymically generated dopaquinone by the -SH contg. Schiff base arising by cleavage of the thiazolidine ring. The salcysdopa adduct thus formed undergoes hydrolysis and subsequent ring closure to give eventually the colorless DBA.

2-Aryl-1,3-thiazolidines as masked sulfhydryl agents for inhibition of melanogenesis

NAPOLITANO, ALESSANDRA;D'ISCHIA, MARCO;PROTA, GIUSEPPE;
1991

Abstract

As a part of an ongoing project aimed at developing new skin depigmenting agents, the ability of variously substituted 2-aryl-1,3-thiazolidines to inhibit melanogenesis in vitro was investigated. At 0.2 mM concn. 2-(2'-hydroxyphenyl)-1,3-thiazolidine-4-carboxylic acid (Th2), as well as the decarboxy analog (Th1) and, to a lower extent, the 4'-hydroxy isomer (Th3) all proved capable of preventing the tyrosinase catalyzed conversion of 0.2 mM L-tyrosine to melanin. Spectrophotometric monitoring of the reaction course in the presence of Th2 showed the initial formation of a yellow chromophore (.lambda.max 400 nm) which slowly decayed, being eventually replaced by a new absorption max. centered at 305 nm. HPLC anal. of the final incubation mixt. revealed the presence of a major product (.lambda.max 306 nm), ninhydrin and ferric chloride pos., which was isolated by gel filtration on Sephadex G-10 and was identified as .beta.-[7-(3-carboxy-5-hydroxy-3,4-dihydro-2H-1,4-benzothiazinyl)]alanine (DBA) by 1H-NMR spectroscopy. Attempts to isolate the intermediate with .lambda.max 400 nm were hampered by its marked instability under the usual chromatog. conditions. However, the nature of the chromophore, coupled with mechanistic considerations, suggested for the compd. the Schiff base-contg. structure 3,4-dihydroxy-5-S-(N-salicylidenecysteinyl)phenylalanine (salcysdopa). This was substantiated by: (i) the formation of a zinc complex (.lambda.max 349 nm) analogous to that obsd. with the model Schiff base N-salicylidene leucine; and (ii) detection by 1H-NMR of a Schiff base resonance at .delta. 8.1 during the yellow chromophoric phase of the reaction. It was concluded that 1,3-thiazolidines inhibit melanin formation by a mechanism that involves the trapping of enzymically generated dopaquinone by the -SH contg. Schiff base arising by cleavage of the thiazolidine ring. The salcysdopa adduct thus formed undergoes hydrolysis and subsequent ring closure to give eventually the colorless DBA.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/365482
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