Steric strain and reactivity: electrophilic bromination of trans-(1-methyl-2-adamantylidene)-1-methyladamantane

trans-(1-Methyl-2-adamantylidene)-1-methyladamantane (DMAD, 1b) reacts with Br(2) in chlorinated hydrocarbon solvents to give either a bromonium polybromide ion pair or a substitution product, depending on bromine concentration. The first intermediate is a 1:1 pi-complex having K(f) = 1.85(0.19) x 10(3) M(-)(1) at 25 degrees C, which rapidly evolves to the bromonium tribromide ion pair. At high bromine concentration, which shifts all equilibria involving the counteranion of the ion pair intermediate toward the pentabromide species, this bromonium ion is stable and unable to further evolve into products. Temperature-dependent NMR spectra indicate chemical exchange of Br(+) between the sides of the plane containing the two carbons of the bromonium ion. At very low bromine concentration, no ionic intermediate is detected and the reaction rapidly yields a rearranged substitution product, identified as 10. Under these conditions the disappearance of the pi-complex follows a first-order rate law, and the observed rate constant increases with increasing olefin concentration, showing that product formation implies Br(-) as counteranion of the ionic intermediate, whose formation is a reversible process. A comparison of the results reported here for the bromination of 1b with those previously found for the parent olefin, adamantylideneadamantane (1a), shows that steric strain markedly affects the reactivity of the double bond.

New drugs for BNCT: an experimental approach.

New kinds of boron-containing drugs were developed and tested in several murine tumor models. The boron-containing ether lipid B-Et-11-OMe was injected in mammary carcinoma (AT17) and osteosarcoma (OTS-64) bearing mice. Furthermore boron-substituted ferrocenium derivatives were tested. Two were excessively toxic; the third could be investigated. Boron accumulation and time-dependent biodistribution were determined using alpha-particle sensitive films and inductively coupled plasma-atomic emission pectrometry (ICP-AES) and -mass spectrometry (ICP-MS) of tumors, organs and tissues. Additionally, a new method of boron detection by NMR is in preparation.

Uptake and distribution of the boron-containing ether lipid B-Et-11-OMe in tumor-bearing mice.

Ether lipids in general are accumulated in tumor tissue with a favorable tumor/healthy tissue ratio. The uptake of the boron-containing analog rac-1-(9-o-carboranyl)nonyl-2-methyl-glycero-3-phosphocholine (B-Et-11-OMe) was studied in C3H mice bearing the murine mammary carcinoma AT17 and in BALB/c mice bearing an osteosarcoma. Boron concentrations of tumor, blood, liver and kidney were followed up to 48 h by inductively coupled plasma emission spectrometry and inductively coupled plasma mass spectrometry. Boron concentration in AT17 mamma carcinoma rose up to 2 mg/kg and the tumor/blood ratio rose to 0.5. The bulk was taken up by the liver. Osteosarcoma did not take up B-Et-11-OMe. This result constitutes a significant contrast to the behavior of published (non-boron-containing) analogs. It is interpreted in terms of critical micellar concentration (CMC). Whereas earlier work with ether lipids was done well below CMC, this study was undertaken above. Further studies will concentrate on syntheses of high CMC analogs.

New carborane-based compounds for boron neutron capture therapy: binding and toxicity of ANC-1, DAC-1 and B-Et-11-OMe in cultured human glioma and mouse melanoma cells.

The toxicity and binding of the three new carborane based compounds: 2 (1,2-dicarba-closo-dodecaborane (12)-1(-yl-methoxy)-2-(3-amino-propyl))-1,3-propanediol, called DAC-1; 7-(3-amino-propyl)-7,8-dicarba-nido-undecarborate (-1) called ANC-1; and rac-1-(9-o-carboranyl)-nonyl-2-methyl-glycero-3- phosphocholine, called B-Et-11-OMe, were analyzed with cultured human glioma cells, U-343MGa, and mouse melanoma cells, B16, as biological models. The previously developed compound di-sodium undecahydro-mercapto-closo-dodecarborate (BSH), which is tested for therapy of malignant gliomas, was analyzed for comparison. In the toxicity tests the cells were exposed to the substances at cell culture medium concentrations in the range 0-50 ppm boron for 1 or 20 h and thereafter analyzed regarding growth. Growth-disturbing effects were seen for the two compounds DAC-1 and B-Et-11-OMe at the concentrations corresponding to 15 and 50 ppm boron, respectively. The compounds ANC-1 and BSH showed no growth-disturbing effects at the tested concentrations. In the binding tests, the cells were incubated for 20 h at about the highest compound concentrations that did not cause growth disturbances. The boron content in the cells was then determined by inductively coupled plasma-atomic emission spectrometry (ICP-AES) and in some cases ICP-mass spectrometry (ICP-MS). The most extensive binding was seen for DAC-1 and B-Et-11-OMe, which accumulated boron to about 100 and 60 times, respectively, compared with the concentration in the culture medium. The compound ANC-1 also accumulated boron in the cells but the boron could be easily washed out indicating no or only a weak binding. BSH did not accumulate. Further analysis should be made regarding biological properties such as intracellular compartmentalization, metabolic interference and tumor specificity of the compounds DAC-1 and B-Et-11-OMe.

Utilization of medium-chain triglycerides and octanoic acid by cultured human fibroblasts and lymphoblasts.

Cultured human fibroblasts and lymphoblasts were incubated with emulsions containing 14C-trioctanoin or 14C-tripalmitin. Both cell types were able to hydrolyse the medium-chain triglyceride but not the long-chain triglyceride to the corresponding fatty acids. At the end of a 3 days incubation period, 25-30% of the initial amount of 10 nmol/ml trioctanoin were present as triglyceride. The observed hydrolysis seems to be mediated by an esterase secreted into the culture medium, as was shown by the use of cell-conditioned medium. CO2 production from octanoic acid was below 2 nmol per mg protein and day, demonstrating that these cells have a low capacity to use this substrate for their energy metabolism.

[Building blocks for oligonucleotide syntheses with uniformly fragmentable beta-halogenated protective groups]. / Bausteine für Oligonucleotid-Synthesen mit einheitlich fragmentierbaren beta-halogenierten Schutzgruppen.

5'-Dimethoxytrityl-3'-phosphite amides of deoxynucleosides are synthesized. Phosphite/phosphate is protected by the 2,2,2-trichloro-1,1-dimethyl-ethyl (TCB) group, heterocyclic bases by the 2,2,2-trichloro-2,2-dimethyl-ethoxycarbonyl (TCBOC) group. Deoxyguanosine is also blocked by 6-O-trichloroethyl thus avoiding the difficulties observed with monoprotected guanine residues.