Abstract
1‐(2‐Deoxy‐β‐D‐ribofuranosyl)‐2,4‐difluoro‐5‐iodobenzene (5‐IDFPdR) is one of the several unnatural 1‐(2‐deoxy‐β‐D‐ribofuranosyl)‐2,4‐difluoro‐5‐substituted‐benzenes recently synthesized for evaluation as anticancer, antiviral and diagnostic imaging agents. This class of C‐nucleosides was designed to exploit several potential advantages relative to classical 5‐substituted‐2′‐deoxyuridines, including stability towards phosphorolysis by pyrimidine phosphorylase, increased lipophilicity that may alter their ability to cross the blood–brain‐barrier, and a greater resistance towards catabolism and deiodination.
The physiochemical evaluation of 5‐IDFPdR showed high lipophilicity (log P=2.8), moderately high protein binding (70–75%), stability towards phosphorolysis (e.g. no evidence of metabolic deglycosylation) by thymidine phosphorylase, and minimal microsomal metabolism in vitro. Pharmacokinetic studies of 5‐IDFPdR in rat were characterized by a short elimination half‐life (9–12 min), modest urinary elimination in pooled 0–24 h urine specimens (10–14%, including 2% as unconjugated drug) and high oral bioavailability (F=0.96). Both glucuronide and sulfate metabolites were present in urine. Glucuronidation was the predominant conjugation pathway. Copyright © 2002 John Wiley & Sons, Ltd.