Synthesis of a novel nitroimidazole-spermidine derivative as a tumor-targeted hypoxia-selective cytotoxin.
A four-step synthesis of (R,S)-N(4)-[3-(2-nitro-1-imidazolyl)-2-hydroxypropyl]-spermidine trihydrochloride (4) is described and the utilization of the polyamine active transport system for the uptake of this compound in cells is demonstrated. Thus, V79 cells pretreated with an inhibitor of spermidine biosynthesis, alpha-difluoromethylornithine (DFMO), are ca. 2-fold more sensitive to 4 under hypoxic conditions, compared to untreated cells. Similarly, radiosensitization of hypoxic V79 cells by 4 is improved in DFMO-pretreated cells.
Evanston Northwestern Healthcare, Department of Radiation Medicine, Evanston, IL 60201, USA. m-papadopoulou@northwestern.edu
Maria V
MV
Papadopoulou
Howard S
HS
Rosenzweig
William D
WD
Bloomer
D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D013095:Spermidine / Q000138:chemical synthesis* / Q000494:pharmacology
D009593:Nitroimidazoles; D013095:Spermidine