Synthesis and preliminary chemotherapeutic evaluation of the fully C-linked glucuronide of N-(4-hydroxyphenyl)retinamide

Abstract

All-trans retinoic acid analogues such as N-(4-hydroxyphenyl)retinamide (4-HPR) are effective chemopreventive and chemotherapeutic agents but their utility has been hampered by dose-limiting side effects. The glucuronide derivatives of 4-HPR, the oxygen-linked 4-HPROG and the carbon-linked 4-HPRCG, have been found to be more effective agents. The synthetic route to the fully C-linked analogue of 4-HPROG (4-HBRCG), which employs Suzuki coupling and Umpolung chemistries as key methodologies, is shown. The results of this study show 4-HBRCG to be an effective chemotherapeutic agent in a rat mammary tumor model while being devoid of classical retinoid toxicities.

4-Hydroxyphenylretinamide (4HPR) derivatives regulate aromatase activity and expression in breast cancer cells

“…Further studies exhibit that compound 7 and 20 also stimulate CYP19 gene expression in these cells. It has been well studied that RA is a potent retinoic acid receptor agonist and stimulates aromatase expression in placental cells [8,13]. In addition, other RXR and RAR ligands dramatically stimulate aromatase in MCF-7 breast cancer cells [14], which proves that the retinoic acid receptor plays an important role in regulating aromatase expression in breast cancer cells.…”

“…Retinoids bind to retinoic acid receptors (RAR) and retinoid X receptors (RXR), which bind to specific DNA sequences to regulate gene expression [7]. However, as a synthetic retinoid analog, 4HPR minimally binds RXR receptors and seems to have only moderate affinity for both the RAR␤ and RAR␥ receptor compared to all-trans retinoic acid (RA) [8,9]. This result points to a mode of action of 4HPR that is at least partially independent of the RAR or RXR.…”

Improved synthesis of the C-glucuronide/glycoside of 4-hydroxybenzylretinone (4-HBR)

“…Therefore, we prepared 4-HBR- C -glucuronide (4-HBRCG; 7 ). [16] This synthesis allowed us to prepare a modest amount of 7 and preliminary experiments showed it to be relatively non-toxic and effective in mammary tumor chemotherapy. [16] We also prepared a small amount of the C -glucoside analog 8 as a model compound.…”

Synthesis and Biological Evaluation of 9Z-Retinoic Acid Analogs Having 2-Substituted Benzo[b]furan

“…3,4) Much effort has been directed toward for the preparation of receptor-selective retinoids in order not only to define the functions of each receptor but also to develop therapeutic agents. [5][6][7][8][9][10][11][12] We have also studied the stereoselective synthesis [13][14][15][16] and structure-activity relationship of retinoid analogs. 1,[17][18][19] Recently, we showed that the 9Z-retinoic acid analog 3, in which the cyclohexene ring and adjacent double bond in retinoic acid (2) were replaced by 2-benzo[b]furan, had no biological effects such as antiproliferative, differentiation-inducing, and apoptosis-inducing activities in HL-60 cells.…”