Heterocyclic derivatives of all-trans retinoic acid: in vitro effects on fibroblast/keratinocyte growth and differentiation, and in vivo effects on guinea-pig skin.
We investigated the biological effects of five all-trans retinoic acid derivatives, bearing heterocyclic ring systems in the side chain. Growth assays performed on submerged human fibroblast and keratinocyte cultures revealed that (E)4-[2-(5-terbuthyl-thiophen-2-yl)propenyl]benzoic acid (compound 5) is the best compound among the studied derivatives for it exhibits a weaker antiproliferative activity and induces, like all-trans retinoic acid does, a significant increase in fibroblast and keratinocyte growth. The morphological and morphometrical analyses of submerged human fibroblast cultures and human epidermis reconstructed in vitro showed that the compound 5 behaves similarly to all-trans retinoic acid: it induces a decrease in all the cell parameters of submerged fibroblast cultures, and modulates the differentiation of keratinocytes in in vitro reconstructed epidermis. Compound 5 induces thickening of epidermis in vivo, one of the most remarkable pharmacological effects of retinoids on skin, but compared to all-trans retinoic acid, it induces a weaker irritation on guinea-pig skin in terms of both erythema and scaling. Compound 5 could then represent a promising candidate for the treatment of certain dermatological diseases.
Parnigotto
P P
PP
Interdepartmental Centre for the Study of Keratinocytes: Pharmaceutical and Clinical Applications, University of Padua, Italy.
Conconi
M T
MT
Bortoletto
C
C
Manfredini
S
S
Montesi
F
F
Schiavon
M
M
Cancellotti
F M
FM
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002675:Child, Preschool; D004396:Coloring Agents; D005347:Fibroblasts / Q000187:drug effects / Q000648:ultrastructure; D005455:Fluorescent Antibody Technique; D006168:Guinea Pigs; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D007223:Infant; D007536:Isomerism; D015603:Keratinocytes / Q000187:drug effects* / Q000648:ultrastructure; D007641:Keratolytic Agents / Q000494:pharmacology*; D012867:Skin / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development* / Q000648:ultrastructure; D013778:Tetrazolium Salts; D013844:Thiazoles; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000494:pharmacology*
D004396:Coloring Agents; D006571:Heterocyclic Compounds; D007641:Keratolytic Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D014212:Tretinoin; C022616:thiazolyl blue