Biological activity of p-methylaminophenol, an essential structural component of N-(4-hydroxyphenyl)retinamide, fenretinide.
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.
Takahashi
Noriko
N
Department of Health Chemistry, Faculty of Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo 142-8501. t-noriko@hoshi.ac.jp
Ohba
Toshihiro
T
Togashi
Shin-ichi
S
Fukui
Tetsuya
T
D000627:Aminophenols / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism; D017313:Fenretinide / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D051381:Rats; D014407:Tumor Cells, Cultured
D000627:Aminophenols; D000975:Antioxidants; D017313:Fenretinide; C026729:4-aminophenol