Synthesis and Evaluation of a Boronated Nitroimidazole for Boron Neutron Capture Therapy

Abstract

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.

Metal Complexes as Photo- and Radiosensitizers

“…The resulting boranated acylmetronidazole was, however, unstable at pH 6.0. A more stable thioether linkage was prepared (Scheme ) via the reaction of 1,2-dibromoethane with 2-methyl-5-NO 2 Im ( 319) to yield 1-(2-bromoehtyl)-2-methyl-5-NO 2 Im ( 378 ), which upon Cs salt coupling with BSH gave the desired 1-[2[(undecahydro- closo -dodecaborato)thio]ethyl)-2-methyl-5-NO 2 Im ( 379 ) 58 …”

Preparation of dendritic carboranyl glycoconjugates as potential anticancer therapeutics

“…4,24 Several attempts have been made so far to develop glycoconjugates of carboranes as drugs for successful treatment of cancer via boron neutron capture therapy (BNCT). [25][26][27][28][29][30][31][32] However, a thorough investigation of cytotoxicities of carboranyl glycoconjugates towards cancer cell lines vis-a-vis normal cells is necessary to access their efficacy for cancer therapy. In the present work, we describe the synthesis of a series of watersoluble dendritic glycoconjugates of carborane containing three and six glucose and galactose moieties via Cu(I)-catalyzed azide-alkyne click cycloaddition reaction.…”

Synthesis, molecular modeling, and biological evaluation of cinnamic acid metronidazole ester derivatives as novel anticancer agents

“…12,16 Recently, Swenson et al synthesized a 10 B-enriched nitroimidazole by coupling the Cs salt of BSH (Cs 2 -10 B 12 -H 11 SH) with 1-(2-bromoethyl)-2-methyl-5-nitroimidazole and used for boron neutron capture therapy of cancer. 17 As a novel class of bioreductively activated nitroimidazole compounds, we designed and synthesized a series of cinnamic acid metronidazole ester derivatives. We chose cinnamoyl moiety as it was found in a variety of biologically active substances.…”