Efficacy validation of synthesized retinol derivatives In vitro: stability, toxicity, and activity

• Published in: Bioorganic & medicinal chemistry 2003-08, Vol.11 (17), p.3839-3845
• Main Authors: Han, Hye-Sook, Kwon, Youn-Ja, Park, Myoung-Soon, Park, Si-Ho, Cho, So-Mi Kim, Rho, Young-Soy, Kim, Jin-Wou, Sin, Hong-Sig, Um, Soo-Jong
• Format: Article
• Language: English
• Subjects: Adult; Biological and medical sciences; Collagenases - metabolism; Diseases of the skin. Cosmetics; Drug Stability; Fibroblasts - drug effects; Fibroblasts - metabolism; Genes, jun; Humans; Medical sciences; Pharmacology. Drug treatments; Photolysis; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects); Receptors, Retinoic Acid - drug effects; Retinoic Acid Receptor alpha; Skin, nail, hair, dermoskeleton; Vitamin A - analogs & derivatives; Vitamin A - standards; Vitamin A - toxicity
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(03)00334-1

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 μM, 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 μM treatment, like retinol, derivatives 3 and 4 were specifically active for RARα out of six retinoid receptors (RAR/RXRα, β, γ). Dose-dependent analysis confirmed that derivative 4 was as active as retinol and the other two derivatives were less active for RARα. 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 RARα activity (possibly indicating reduced side effects), and similar effect on collagenase expression. Synthesis and in vitro evaluation of three retinol derivatives are described.