Synthesis and biological evaluation of 5‐substituted‐4‐nitroimidazole ribonucleosides

Abstract

Abstract The imidazole nucleosides, 4(5)‐bromo‐5(4)‐nitro‐1‐β‐D‐ribofuranosylimidazoles, have been prepared via glycosylation of the trimethylsilylated aglycone, 4(5)‐bromo‐5(4)‐nitroimidazole, with tetra‐ O ‐acetyl‐β‐D‐ribo‐furanose followed by removal of the acetyl protecting groups. The 5‐bromo‐4‐nitro‐1‐β‐D‐ribofuranosylimidazole nucleoside was acetonated to produce 5‐bromo‐4‐nitro‐1‐(2,3‐ O ‐isopropylidene‐β‐D‐ribofuranosyl)‐imidazole which was cyclized to provide the corresponding anhydronucleoside 5,5′‐anhydro‐4‐nitro‐5‐oxo‐1‐(2,3‐ O ‐isopropylidene‐β‐D‐ribofuranosyl)imidazole. Sodium hydrosulfide treatment of 5‐bromo‐4‐nitroimidazole nucleoside provided 5‐mercapto‐4‐nitro‐1‐β‐D‐ribofuranosylimidazole 5‐sodium salt which was alkylated with E ‐1,5‐diiodopent‐1‐ene to yield 5‐( E ‐1‐iodo‐1‐penten‐5‐yl)thio‐4‐nitro‐1‐β‐D‐ribofuranosylimidazole. The corresponding iodine‐125‐labeled compound was prepared similarly using radiolabeled diiodopentene. The 5‐bromo‐4‐nitroimidazole, 5‐mercapto‐4‐nitroimidazole, and 5‐iodopentenylthio‐4‐nitroimidazole nucleosides were cytotoxic to Molt‐3 cells in vitro at concentrations higher than 10 μg/mL. The radiolabeled 5‐iodopentenylthio‐4‐nitroimidazole nucleoside showed 2‐fold higher uptake in a rapidly growing tumor as compared to uptake in a relatively slower growing tumor in mice.