Synthesis and Biological Activity of Novel Retinamide and Retinoate Derivatives

Abstract

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.

Acyclic retinoid, a novel synthetic retinoid, induces growth inhibition, apoptosis, and changes in mRNA expression of cell cycle- and differentiation-related molecules in human colon carcinoma cells

“…These values are similar to those of our previous studies demonstrating 10-40 μM IC 50 in human hepatoma, esophageal SCC or HNSCC cell lines (21,22). Previous studies using ATRA, 4-HPR or novel synthetic retinoid derivative 4-amino-2-(butyrylamino)phenyl-(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6trimethyl-1-cyclohexenyl)-2,4,6,8-nonatetraenoate (ABPN or CBG41) evaluated concentrations that show significant growth inhibition in the range of approximately 0.6-20 μM, when HCT116, HT29, or DLD-1 human colon carcinoma cells were grown in culture conditions similar to those in our studies (32,33). These retinoids also display growth inhibitory activity in other types of human carcinoma cell lines (33).…”

The Retinoic Acid Receptor-α mediates human T-cell activation and Th2 cytokine and chemokine production

“…Like 13- cis RA, the ability of 4-HPR to bind and transactivate RARs or RXRs is a matter of controversy [ 43 - 46 ]. In studies examining 4-HPR interactions with these receptors, 4-HPR appears to bind to and transactivate RAR-β and RAR-γ but not RAR-α and RXRs [ 47 ]. 4-HPR does not undergo appreciable transformation to retinoids such as ATRA [ 42 ].…”

Synthesis, structure, antioxidant activity, and water solubility of trolox ion conjugates

“…This method was used to study organic ammonium salts, but pseudomolecular ions of the cation type [(A − B + ) + H] + have not been observed before now (Kalariya et al, 2014, Wang and Cole, 1996). There are only few examples where pseudomolecular ions of the anion type [(A − B + ) − H] − have been observed by ESI-MS analysis, which include the ICs of retinoid amine derivatives with dicarboxylic acids (Um et al, 2004).…”