Synthesis and evaluation of a boronated nitroimidazole for boron neutron capture therapy.
We postulated that nitroimidazoles, previously used for radiosensitizing solid tumors, may be interesting templates as carriers of 10B for boron neutron capture therapy. To test this hypothesis, we synthesized a 10B-enriched nitroimidazole, 1-2[(undecahydro-closo-dodecaborato)thio]ethyl]-2- methyl-5-nitroimidazole (imidocaptate), by coupling the Cs salt of BSH (Cs2-10B12H11SH) with 1-(2-bromoethyl)-2-methyl-5-nitroimidazole followed by purification of the adduct. Imidocaptate was taken up by V-79 cells in culture and showed no inherent toxicity under euoxic conditions up to 1.05 mM (126 micrograms of 10B/mL of culture medium). Imidocaptate showed a dose-dependent decrease in D0 when the treated cells were irradiated with a thermal neutron beam. At the highest dose tested (126 micrograms of 10B/mL of culture medium), the ratio of control to sample D0 values was 2.6 for both linear quadratic and single-hit multitarget models. At 33 micrograms of 10B/mL, imidocaptate showed a control/treated D0 ration (1.5) equal to that observed with the disulfide form of BSH at 28 micrograms of 10B/mL. Compared to BSH and its disulfide, the reduced toxicity and equipotency of imidocaptate suggest that this agent may be useful for boron neutron capture therapy of cancer.
Swenson
D H
DH
Department of Veterinary Physiology, Pharmacology and Toxicology, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana 70803, USA.
Laster
B H
BH
Metzger
R L
RL
D000818:Animals; D001896:Boron Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D016754:Boron Neutron Capture Therapy; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009369:Neoplasms / Q000532:radiotherapy; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*
D001896:Boron Compounds; D009593:Nitroimidazoles; C100472:imidocaptate