fenretinide and 4-aminophenol

Tyrosinase is involved in the synthesis of melanin in the skin and hair as well as neuromelanin in the brain. This rate limiting enzyme catalyzes two critical steps (reactions) in melanogenesis; the hydroxylation of tyrosine to form DOPA and the subsequent oxidation of DOPA into dopaquinone. Several new aminophenol derivatives have been synthesized based on structure-activity relationship studies of N-(4-hydroxyphenyl)retinamide (1), a derivative of retinoic acid. In order to find new tyrosinase inhibitors, we investigated the effects of these p-aminophenols, including p-decylaminophenol (3), on the activity of mushroom tyrosinase. Compound 3 was the most potent agent, showing significant inhibition as compared with control. The inhibitory effects of 3 on tyrosinase activities were greater than seen with kojic acid, a well-known potent inhibitor of tyrosinase activity, which also causes adverse effects, including rash and dermatitis. A Lineweaver-Burk kinetic analysis of inhibition showed that 3 suppresses tyrosinase activity in a non-competitive fashion for both substrates, tyrosine and DOPA. These results suggest that 3 might be a useful alternative to kojic acid as a tyrosinase inhibitor.

Topics: Agaricales; Aminophenols; Enzyme Inhibitors; Kinetics; Monophenol Monooxygenase; Protein Binding; Pyrones; Structure-Activity Relationship; Tretinoin

Fenretinide, N-(4-hydroxyphenyl)retinamide (4-HPR), is a synthetic amide of all-trans-retinoic acid (RA), which inhibits cell growth, induces apoptosis, and is an antioxidant, and cancer chemopreventive and antiproliferative agent. These findings led us to investigate which structural component of 4-HPR contributes to these potent activities. Our approach was to examine 4-aminophenol (4-AP), p-methylaminophenol (p-MAP), and p-acetaminophen (p-AAP). It was found that vitamin E, 4-AP and p-MAP scavenge alpha,alpha-diphenyl-beta-picrylhydrazyl (DPPH) radicals in a 1:2 ratio, in contrast to 4-HPR and p-AAP, for which 1:1 and 1:0.5 ratios were observed relative to DPPH radicals. However, RA was inactive. Lipid peroxidation in rat liver microsomes was reduced by compounds (RA > p-MAP = 4-HPR > 4-AP) in a dose-dependent manner, while p-AAP was inactive. In addition, both p-MAP and 4-HPR are potent inhibitors of cell growth and inducers of apoptosis in HL60 cells. p-MAP exhibits the same level of antiproliferative activity as 4-HPR against HL60R cells, which are a resistant clone against RA, and it inhibits the growth of various cancer cell lines (MCF-7, MCF-7/Adr(R), HepG2, and DU-145) to an extent greater than 4-AP and p-AAP, but is less potent than 4-HPR. Thus, although the antioxidant activity of p-MAP is more potent than that of 4-HPR, p-MAP is less potent than 4-HPR in anticancer activity. These results suggest that both the anticancer and antioxidative activities shown by 4-HPR are due to the structure of p-MAP. The retinoyl residue or long alkyl chain substituent attached to an aminophenol may be significant for anticancer properties.

Topics: Aminophenols; Animals; Antioxidants; Fenretinide; Humans; In Vitro Techniques; Lipid Peroxidation; Male; Rats; Tumor Cells, Cultured

We demonstrate that N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR), a synthetic retinoic acid (RA) derivative, is a potent and selective inducer of apoptosis in malignant T lymphoid cells, but has little effect on normal lymphoid cells of the thymus or spleen. 4-HPR and its stereoisomer, 9-cis-4-HPR, are 50 to > 150 times more potent than 7 other retinoids in killing CEM-C7 human T lymphoblastoid leukemia cells and P1798-C7 murine T lymphoma cells. 4-HPR's apoptotic action requires the intact molecule bearing both the retinoid moiety and the hydroxyphenol ring; 4-HPR remains unmetabolized after uptake into CEM-C7 and P1798-C7 cells for up to 24 hours. We also show that glucocorticoid (GC)-resistant variants are equally susceptible to 4-HPR as are GC-sensitive cells. Thus, 4-HPR may be potentially important as a new chemotherapeutic drug for use as alternative to, or in combination with, conventional drugs for treating lymphoid malignancies.

Topics: Aminophenols; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Division; Cells, Cultured; DNA Fragmentation; Drug Resistance, Neoplasm; Fenretinide; Glucocorticoids; Humans; Leukemia, T-Cell; Lymphocytes; Lymphoma, T-Cell; Mice; Mice, Inbred BALB C; Retinoids; Spleen; Stereoisomerism; Thymus Gland; Tretinoin; Tumor Cells, Cultured