Efficacy validation of synthesized retinol derivatives In vitro: stability, toxicity, and activity.
Retinol (vitamin A) is used as an antiwrinkle agent in the cosmetics industry. However, its photo-instability makes it unsuitable for use in general cosmetic formulations. To improve the photo-stability of retinol, three derivatives (3, 4, and 5) were synthesized and their biological activities were analyzed. 1H NMR and HPLC analysis indicated that derivatives 3 and 5 were much more stable than retinol under our sunlight exposure conditions. When human adult fibroblasts were treated, the IC(50) of derivative 3 was 96 microM, which is similar to that of retinol, as determined by the MTT assay. Derivatives 4 and 5 were 2.5 and 8 times more toxic than retinol, respectively. At 1 microM treatment, like retinol, derivatives 3 and 4 were specifically active for RARalpha out of six retinoid receptors (RAR/RXRalpha, beta, gamma). Dose-dependent analysis confirmed that derivative 4 was as active as retinol and the other two derivatives were less active for RARalpha. The effect of our derivatives on the expression of collagenase, an indicator of wrinkle formation, was measured using the transient co-expression of c-Jun and RT-PCR in HaCaT cells. Collagenase promoter activity, which is increased by c-Jun expression, was reduced 42% by retinol treatment. The other derivatives inhibited collagenase promoter activity similarly. These results were further confirmed by RT-PCR analysis of the collagenase gene. Taken together, our results suggest that retinol derivative 3 is a promising antiwrinkle agent based on its higher photo-stability, lower RARalpha activity (possibly indicating reduced side effects), and similar effect on collagenase expression.
Han
Hye-Sook
HS
Department of Bioscience and Biotechnology/Institute of Bioscience, Sejong University, 143-747, Seoul, South Korea.
Kwon
Youn-Ja
YJ
Park
Myoung-Soon
MS
Park
Si-Ho
SH
Cho
So-Mi Kim
SM
Rho
Young-Soy
YS
Kim
Jin-Wou
JW
Sin
Hong-Sig
HS
Um
Soo-Jong
SJ
D000328:Adult; D017364:Collagenases / Q000378:metabolism; D004355:Drug Stability; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D016758:Genes, jun; D006801:Humans; D010782:Photolysis; D018168:Receptors, Retinoic Acid / Q000187:drug effects; D000072482:Retinoic Acid Receptor alpha; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000592:standards / Q000633:toxicity
C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014801:Vitamin A; D017364:Collagenases