Jonas Malmquist

Chemistry and biology of some low molecular weight boron compounds for Boron Neutron Capture Therapy

Boronated DNA targeting agents are especially attractive candidatesfor BNCT because they may deliver boron-10 tothe nuclei of tumor cells. Numerous boron-containing analogshave been synthesized and some have shown promisingresults in initial biological tests. One of themost challenging tasks in this special field ofresearch remains the finding of suitable targeting strategiesfor the selective delivery of boron rich DNA-intercalator/alkylatorto tumor cells. Synthetic and biological studies ofboron compounds suitable for DNA-binding are reviewed.The amino acid p-boronophenylalanine (BPA) is presently ofconsiderable clinical interest. Other boronated amino acids mightalso be candidates for BNCT either per se,as part of part of tumor-seeking peptides orconjugated to targeting macromolecules. A large number ofboronated L- and D-amino acids with varying liphophicilityand sterical requirements are now available for evaluation.Recent synthetic and biological studies of aromatic boronoaminoacids, carboranylamino acids and carboranyl amines are alsoreviewed.

Asymmetric Synthesis of p-Carboranylalanine(p-Car) and 2-Methyl-o-Carboranylalanine(Me-o-Car).

Abstract Two new α-amino acids containing the 1,2- and the 1,12-dicarba- closo -dodecaborane(12) cages, namely p -carboranylalanine ( 1 ), and 2-methyl- o -carboranylalanine ( 2 ), were prepared using Oppolzers sultam methodologies.

Determination of enantiomeric purity of (S)-carboranylalanine using capillary column supercritical fluid chromatography

Abstract Carboranylalanine, the o -carborane analogue of phenylalanine, is a potential candidate for boron neutron capture therapy of cancer. In this paper a method is described for the determination of enantiomeric purity of ( S )-carboranylalanine as the ( N - trifluoroacetyl)propylester using open tubular column supercritical fluid chromatography with a chiral stationary phase consisting of permethyl-β-cyclodextrin methyloctylsiloxane.

Synthesis of para- and nido-carboranyl phenanthridinium compounds for neutron capture therapy

Abstract The syntheses of two novel para -carboranyl and two novel nido -carboranyl phenanthridinium compounds as potential boron delivery agents for Neutron Capture Therapy are described

In vitro determination of toxicity, binding, retention, subcellular distribution and biological efficacy of the boron neutron capture agent DAC-1

In boron neutron capture therapy (BNCT), 10B is delivered selectively to the tumour cells and the nuclide then forms high-LET radiation (4He2+ and 7Li3+) upon neutron capture. Today much research is focused on development of a variety of boron compounds aimed for BNCT. The compounds must be thoroughly analysed in preclinical tests regarding basic characteristics such as binding and subcellular distribution to enable accurate estimations of dose-modifying factors. DAC-1,2-[2-(3-amino-propyl)-1,2-dicarba-closo-dodecaboran (12)-1-yl-methoxy]- 1,3-propanediol was synthesized at our laboratories and the human colon carcinoma cells LS-174T were used as an in vitro model. The boron compound showed a remarkable intracellular accumulation, 20-100 times higher than the boron content in the culture medium, in cultured cells and was not removed by extensive washes. Approximately half of the boron taken up also remained within the cells for at least 4 days. The DAC-1 compound alone was not toxic at boron concentrations below 2.5 micrograms B/g. The intracellular distribution of the boron compound was investigated by subcellular fractionation experiments and low pH treatments. It is possible that DAC-1 binds to some intracellular molecules or to membranes connected with organelles in the cytoplasm or even to the inside of the outer cell membrane. Another possibility is that the compound, due to the somewhat lipophilic properties, is embedded in the membranes. Thermal neutron irradiations were carried out at the Brookhaven Medical Research Reactor (BMRR). At a survival level of 0.1, DAC-1 + thermal neutrons were about 10.5 times more effective in cell inactivation than the thermal neutrons alone. Monte Carlo calculations gave a mean value of the 10B-dependent specific energy, the dose, of 0.22 Gy. The total physical dose during irradiation of DAC-1-containing cells with a neutron fluence of 0.18 x 10(12) n/cm2 was 0.39 Gy. The dose-modifying factor, at survival level 0.1, when comparing irradiation with thermal neutrons with and without DAC-1 was 3.4, while the dose-modifying factor when comparing neutron irradiations of cells with DAC-1 and irradiation of the cells with 60Co-gamma was 7.3. The results are encouraging and in vivo tests of tissue distributions and tumour uptake should now be carried out.

Uptake, toxicity and radiation effects of the boron compounds DAAC-1 and DAC-1 in cultured human glioma cells

PURPOSE To study the uptake, toxicity and radiation effects in vitro of a diol-amino acid-carborane (DAAC-1) and make comparisons with the previously studied diol-amine-carborane (DAC-1). MATERIALS AND METHODS Toxicity and radiation effects were studied with clonogenic survival, uptake by measuring the cellular boron content and the subcellular distribution was investigated after organelle separation with centrifugation. The studied cell line was human glioma U343. RESULTS DAAC-1 showed an accumulation of 1-1.5 times, compared with the culture medium, and was non-toxic up to 47 microg boron/ml. The accumulation of DAC-1 was about 90 times, but toxic effects were detectable already at the concentration 5 microg boron/ml. None of the compounds was localized in the cell nucleus. Following irradiation with thermal neutrons, DAC-1 was about 2.5 times more effective than DAAC-1 and about 4.9 times more effective than neutrons alone, at the survival level 0.2. The dose modifying factors, when compared with the neutron beam alone, were for both DAAC-1 and DAC-1 about 1.5 and about 5 when compared with 60Co-gamma-radiation. CONCLUSIONS DAAC-1 was less toxic than DAC-1 but gave less accumulation of boron. Both substances gave significant boron-dependent cell inactivation when the test cells were exposed to thermal neutrons.

Asymmetric Synthesis of o- and p-Carboranyl Amino Acids

The amino acid p-boronophenylalanine (BPA) containing one boron atom is presently of considerable clinical interest for use in BNCT of cancer. Amino acids, substituted with polyhedral boron clusters, could also be of interest for BNCT.1a–k We have recently reported the synthesis of some amines and optically active amino acids, containing the lipophilic o-carborane cage1b,e In this contribution we describe the synthesis of the hydrophilically substituted o-carborane derivatives, the diolamine 3 (DAC-1) and the diolamino acid 7 (DAAC-1) as well as the asymmetric synthesis of the highly lipophilic amino acid p-carboranylalanine 14. A method for determination of enantiomeric purities of o-carboranylalanine using supercritical fluid chromatography (SFC) on a β-cyclodextrin based stationary phase is reported.

Synthesis and Initial Biological Evaluation of Carborane-Containing Phenanthridinium Derivatives

The radiobiological effectiveness of the neutron capture reaction is 2–5 times greater when it occurs in the cell nucleus rather than in the cytoplasm.1 One class of compounds which may be suitable agents to achieve high and selective boron concentrations in tumor cell nuclei are boronated derivatives of nucleic acid building blocks.2 Another type of compounds may be boronated DNA intercalator. Only a few boron-containing DNA-ligands have been prepared so far.3–5