The present application relates to borane cluster chemistry and the method of making such clusters. More specifically, the present invention relates to borane dianions which are precursors for use in boron, neutron capture therapy of cancer.
There has been renewed interest in boron neutron capture therapy of cancer. Neutron capture therapy is an effective therapy for cancer treatment, specifically the treatment of malignant tumors. The method involves capture of a thermalized neutron which is usually from a nuclear reactor with special moderators and ports. This is accomplished by an appropriate nucleus having a large neutron capture cross-section. The subsequent decay emits energetic particles, alpha particles, which kill nearby tumor cells. Since the energetic and cytotoxic alpha particles travel only about one cell diameter in tissue, specificity of the cell type to be destroyed can be obtained by placing the alpha particle precursors only on and within the tumor cells.
Generally, boron neutron capture therapy (BNCT) is based on the nuclear reaction which occurs when a stable isotope, B-10 (present in 19.8% natural abundance) is irradiated with thermal neutrons to produce the alpha particle and a Li-7 nucleus.
Historically, boron neutron capture therapy was first employed for the treatment of glioblastoma (a fatal form of brain tumor) and other brain tumors at a time when tumor specific substances were almost unknown. Problems with previous inorganic boron therapy methods is that the boron reached both targeted and non-targeted areas. Accordingly, when the boron was irradiated, healthy cells as well as cancer cells were destroyed.
More recently, boron neutron capture therapy has been extended to other cancers, spurred on by the discovery of a number of tumor localizing substances, including tumor-targeting monoclonal antibodies.
Considerable activities have recently occurred in the preparation of larger polyhedral boranes and carboranes that have the ability to form a variety of exo-polyhedrally linked biomolecules (1). The importance of synthons to such molecules are the boron-10 enriched neutral decaborane (14), B10H14, and the dianionic dodecaborate cluster, (B12H12)2xe2x88x92. Although both of these compounds can be efficiently synthesized directly from pentaborane (9), B5H9, that has been stockpiled in U.S. Government inventory (2), the 10B-enriched species are being prepared by readily available sodium borohydride, NaBH4(3).
The simplified method of Dunks and coworkers for decaborane from sodium borohydride via the (B11H14)xe2x88x92 ion has an obvious appeal (4).
Since the decaborane (14) was previously produced only in the optimum yield of 50%, it was speculated that the oxidation step in the procedure could lead to a coupling reaction between two (B11H14)xe2x88x92 ions by losing two protons with concomitant page degradation to yield B10H14 (4). Although the oxidation of the (B11H11)xe2x88x92 ion in the presence of FeCl3 using anhydrous conditions failed to produce the desired coupled species, (B22H24)2xe2x88x92 ion, on one occasion the addition of Me3NHCl to the aqueous mixture of (B11H14)xe2x88x92 ion subsequent to its oxidation with hydrogen peroxide yielded a white precipitate. The analytical and spectroscopic data of this white precipitate were consistent with the formula, (B22H24)2xe2x88x92 in which the B10-cage is singly bonded to a B12-unit in the (B10H13xe2x80x94B12H11)2xe2x88x92 cluster (4).
Although such a cluster formation could have resulted from the initial disproportionation reaction of (B11H14)xe2x88x92 ion forming 0.5 mole each of (B12H12)2xe2x88x92 ion and a neutral B10H14 followed by the oxidative coupling of these cages, it was clear that more synthetic and structural work was warranted in order to prove this hypothesis. Further work in this area led to the reinvestigation of the work of Dunks and coworkers with a particular interest in establishing reactivity and structural patterns in this large cage.
There has also been investigation into the synthesis and pharmacological properties of boron analogs of biologically important molecules. Many of these molecules are isoelectronic and isostructural with their naturally occurring carbon counterparts. Based upon 4-coordinate boron, these molecules generally possess sufficient hydrolytic and oxidative stability to be used in biological studies. They can be used to probe fundamental biochemical events at the molecular level as well as providing entirely new classes of compounds for potential medical value. These compounds also prove valuable in boron neutron capture therapy. For example, potential biological activity has been found for various of these new species, such as boronated nucleosides and nucleotides (3C). Amino acid analogs have ranged from simple glycine and N-methyl substituted glycines to analogs of more complex amino acids, such as alanine. Other amides of common amino acids have likewise been prepared and these derivatives as well as many other related precursors and derivatives of simple glycines including peptides are now commercially available (3C).
It is desirable to establish reactivity and structural patterns in large cage systems. Such systems are envisioned to be precursors for selected biomolecules that can be used in boron neutron capture therapy of cancer.
In accordance with the present invention there is provided a polyhedral borane cluster consisting of a fused polyhedron including an open (nido) decaborane cage fused to a closed (closo) dodecaborane cluster wherein borane atoms are not integral parts of the cluster vertices. The present invention also provides a method for synthesizing a polyhedral borane cluster by fusing an open (nido) decaborane cage to a closed (closo) dodecaborane cluster. Also, the present invention provides a neutron capture reagent consisting essentially of the polyhedral borane cluster including the open decaborane cage fused to the closed dodecaborane cluster, the polyhedral borane cluster being conjugated to a biomolecule.
USPTO Backgrounds
USPTO Backgrounds