Synthesis and biological activity of novel retinamide and retinoate derivatives.
Retinoic acid and its amide derivative, N-(4-hydroxyphenyl)retinamide (4-HPR), have been proposed as chemopreventative and chemotherapeutic agents. However, their low cytotoxic activity and water solubility limit their clinical use. In this study, we synthesized novel retinoid derivatives with improved cytotoxicity against cancer cells and increased hygroscopicity. Our syntheses were preceded by selective O-acylation and N-acylation, which led to the production of retinoate and retinamide derivatives, respectively, in one pot directly from aminophenol derivatives and retinoic acid without protection. Transcription assays in COS-1 cells indicated that the N-acylated derivatives (2A-5A) and 4-HPR (1A) were much weaker ligands for all three subtypes of retinoic acid receptor (RAR) than all-trans retinoic acid (ATRA), although they showed some selectivity for RARbeta and RARgamma. In contrast, the O-acylated retinoate derivatives (1B-5B) activated all three RAR isotypes without specificity to an extent similar to ATRA. The cytotoxicity was determined using an MTT assay with HCT116 colon cancer cells, and the IC(50) of N-acylated retinamide derivative 4A and O-acylated retinoate derivative 5B was 1.67 microM and 0.65 microM, respectively, which are about five and 13-fold better than that of 4-HPR (8.21 microM), a prototype N-acylated derivative. When retinoate derivative 5B was coupled to organic acid salts, the resulting salt derivatives 5C and 5D had RAR activation and cytotoxicity similar to those of 5B. These data may delineate the relationship between the structure and function of retinoate and retinamide derivatives.
Um
Soo-Jong
SJ
Department of Bioscience and Biotechnology / Institute of Bioscience, Sejong University, Korea.
Kwon
Youn-Ja
YJ
Han
Hye-Sook
HS
Park
Si-Ho
SH
Park
Myoung-Soon
MS
Rho
Young-Soy
YS
Sin
Hong-Sig
HS
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D017313:Fenretinide / Q000138:chemical synthesis / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*
D018168:Receptors, Retinoic Acid; D017313:Fenretinide; D014212:Tretinoin; C054441:retinamide