In vivo evaluation of phosphorous-containing derivatives of dodecahydro-closo-dodecaborate for boron neutron capture therapy of gliomas and sarcomas.

The in vivo uptake of dodecahydro-closo-dodecaborate derivatives substituted with phosphate- and bisphosphonate groups was evaluated in two different experimental tumor model systems and compared to other boronated and non-boronated compounds. These phosphorous-containing boron clusters may have potential for use in boron neutron capture therapy, a chemoradiotherapeutic form of cancer treatment. Using the F98 rat glioma as a brain tumor model in syngeneic Fischer rats, there was selective tumor uptake of the phosphate derivative with 21.5 micrograms boron/g tumor versus 5.2 micrograms/g normal brain and a tumor:blood ratio of 2.7. However, this compound was toxic to test animals and lethal at relatively low doses. The uptake of the bisphosphonate by the murine K8 osteosarcoma was approximately 18 micrograms boron/g tumor with a T:Bl ratio of 7.6 and a tumor:bone ratio of 1.5. This compound was non toxic to the test animals. The results indicate that phosphate- and bisphosphonate derivatives of dodecahydro-closo-dodecaborate may have potential for BNCT of gliomas and osteosarcomas, respectively.

Reduction of inner sulfonium salts, thioethers, and sulfones derived from closo-[B12H12]2- by lithium in methylamine: a new route to mercaptododecaborates.

Anions [Me2SB12H11]- (2) and [MeSB12H11]2- (3) can be reduced by excess lithium in methylamine at -15 degrees C to yield [HSB12H11]2- (1) after workup. Such behavior toward this reducing system is similar to that of alkyl aryl sulfides. The sulfone [MeSO2B12H11]2- (12) also yields 1 as a major boron product upon reduction, while alkyl aryl sulfones produce the corresponding arenes under the same conditions. Similarly, isomers of (Me2S)2B12H10 (4-6) are reduced by lithium in methylamine yielding dithiols [(HS)2B12H10]2- (7-9). The tetrabutylammonium salts of 1 and 7-9 are obtained in 80-90% yields and characterized by multinuclear NMR and mass spectrometry, the latter three compounds being isolated and characterized for the first time. The reduction reaction provides access to dithiols 7-9 for biological evaluation and use in synthesis. Thus, 2 and 4-6 can be easily converted to [R2SB12H11]- and (R2S)2B12H10 in a two-step reduction-alkylation procedure. 1,2-(Bn2S)2B12H10 (13) obtained by alkylation of the reduction product of 4 by benzyl chloride was characterized by single-crystal X-ray diffraction analysis. Crystal data for 1,2-(Bn2S)2B12H10.CD3CN: C2/c (No. 15), a = 13.666(1) A, b = 16.978(1) A, c = 14.667(1) A, beta = 91.08(1) degrees, Z = 4.

Synthesis and characterization of sulfide, sulfide-sulfonium, and bissulfide derivatives of [B12H12]2-. Additivity of Me2S and MeS- substituent effects in 11B NMR spectra of disubstituted icosahedral boron clusters.

The 1,2-, 1,7-, and 1,12-isomers of (Me2S)2B12H10 (O, M, and P) react with potassium phthalimide in DMF or EtSNa in CH3CN/EtOH upon reflux producing the corresponding isomers of [(MeS)(Me2S)B12H10]- (O1-, M1-, P1-). If excess of either nucleophile is used, [Me2SB12H11]- (1) and O, M, P can be converted into dianions [MeSB12H11]2- (2) and [(MeS)2B12H10]2- (O2-, M2-, P2-). The use of EtSNa is recommended since it facilitates the isolation of products compared to the potassium phthalimide method. When 1 or O, M, P are treated with an excess of an alkali metal (Na, K) in liquid ammonia at -40 degrees C, sulfide 2 or bissulfide dianions O2-, M2-, P2- are obtained cleanly and almost instantly. While both the nucleophilic substitution and alkali metal reduction methods are useful for the synthesis of dianions 2, O2-, M2-, and P2-, only the former method is suitable for the synthesis of the sulfide-sulfonium anions O1-, M1-, P1-. The analysis of the 11B NMR spectra of 1, O, M, P and anions derived from them demonstrated that the spectra of the disubstituted species can be predicted qualitatively, keeping in mind the simple substituent effects obtained from the spectra of monosubstituted anions 1 and 2. Some evidence is found for small partial double bond character of the B-SMe bonds in anions. [MePPh3]+ salts of [MeSB12H11]2- (2) and [1-(MeS)-7-(Me2S)B12H10]- (M1-) are structurally characterized by single-crystal X-ray diffraction analysis. Crystal data: [MePPh3]2[MeSB12H11], P2(1) (No. 4), a = 9.243(1) A, b = 18.272(1) A, c = 12.548(1) A, beta = 103.17(1) degrees, Z = 2; [MePPh3][1-(MeS)-7-(Me2S)B12H10], P1 (No. 2), a = 9.278(2) A, b = 12.003(5) A, c = 14.819(7) A, alpha = 112.18(4) degrees, beta = 105.61(3) degrees, gamma = 92.91(3) degrees, Z = 2.