Synthesis and preliminary chemotherapeutic evaluation of the fully C-linked glucuronide of N-(4-hydroxyphenyl)retinamide.
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.
Walker
Joel R
JR
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
Alshafie
Galal
G
Nieves
Nirca
N
Ahrens
Jamie
J
Clagett-Dame
Margaret
M
Abou-Issa
Hussein
H
Curley
Robert W
RW
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000818:Animals; D001943:Breast Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D005260:Female; D017313:Fenretinide / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020719:Glucuronides / Q000737:chemistry*; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley
D020719:Glucuronides; D017313:Fenretinide; D015127:9,10-Dimethyl-1,2-benzanthracene