2-Aryl-1,3-thiazolidines as masked sulfhydryl agents for inhibition of melanogenesis.
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 concentration 2-(2'-hydroxyphenyl)-1,3-thiazolidine-4-carboxylic acid (Th2), as well as the descarboxy 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 maximum centered at 305 nm. HPLC analysis of the final incubation mixture revealed the presence of a major product (lambda max 306 nm), ninhydrin and ferric chloride positive, 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)]al anine (DBA) by 1H-NMR spectroscopy. Attempts to isolate the intermediate with lambda max 400 nm were hampered by its marked instability under the usual chromatographic conditions. However, the nature of the chromophore, coupled with mechanistic considerations, suggested for the compound the Schiff base-containing 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 observed 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 containing 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.
Napolitano
A
A
Department of Organic and Biological Chemistry, University of Naples, Italy.
d'Ischia
M
M
Prota
G
G
Havens
M
M
Tramposch
K
K
D000409:Alanine / Q000031:analogs & derivatives / Q000378:metabolism; D002264:Carboxylic Acids / Q000494:pharmacology*; D002850:Chromatography, Gel; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D006868:Hydrolysis; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008543:Melanins / Q000096:biosynthesis*; D015394:Molecular Structure; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors; D013053:Spectrophotometry; D013843:Thiazines / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
D002264:Carboxylic Acids; D008543:Melanins; D013843:Thiazines; D013844:Thiazoles; C068154:7-(3-carboxy-5-hydroxy-3,4-dihydro-2H-1,4-benzothiazinyl)alanine; D014443:Tyrosine; D004295:Dihydroxyphenylalanine; D014442:Monophenol Monooxygenase; D000409:Alanine