A Brief Summary of Current Projects in the Hawthorne Research Group

         The element boron neighbors carbon in the periodic table, exists in plentiful supply throughout the Universe and reaches a long arm across the periodic table in order to form stable compounds with a wide variety of other elements. The most important chemical property shared by carbon and boron is the ability of both these elements to form large families of discrete structures by bonding to themselves. Thus, boron atoms form stable bonds to other boron atoms when forming polyhedral borane clusters. Carbon, of course, adopts the same behavior while creating organic chemistry. Rapid advances made during the past fifty years have now established such boron clusters as the basis of a nearly infinite number of new species containing elements from throughout the periodic table. This new science supports an ever increasing scope of molecular structures having extraordinary chemical, biological, thermal and photochemical stabilities. Such properties provide unique applications not possible with other elements including carbon. While borane and hydrocarbon derivatives share many related structural features and functions, borane species are apparently stable in the presence of enzyme systems which have supported the evolution of life (at least on this planet) and they appear, at this time, to be inert to enzymatic degradation reactions. Another unique feature of boron is its isotopic distribution of 10B (20%) and 11B (80%) accompanied by the very great propensity of 10B to capture a slow neutron and fission to cytotoxic 4He and 7Li nuclei. This process is accompanied by the liberation of about 2.4 MeV of kinetic energy and a 0.5 MeV gamma-photon (the boron neutron capture reaction). This nuclear reaction provides the basis of boron neutron capture therapy of cancer (BNCT) and the nonmalignant disease, arthritis.

          The research projects pursued by, and the members of, the Hawthorne Research Group are as diverse and eclectic as the field of polyhedral borane and carborane cluster chemistry. Of specific interest to the group are new structures and reactions which find applications in supramolecular chemistry, nanotechnology, molecular recognition and biomedicine. A separate link is provided for the latter subject entitled, "Biomedical Polyhedral Borane Chemistry."

Biomedical Polyhedral Borane Chemistry

       Biomedical polyhedral borane chemistry is a new field which combines polyhedral borane chemistry with organic chemistry and aspects of biomedicine. New structures and reactions commonplace in the broad area of polyhedral organoborane chemistry provide the bases of novel derivatives and reactions designed for use in the medically important areas of disease diagnosis and therapy, drug delivery, pharmaceutical discovery and biosensors. It should be pointed out that nearly all of the chemical research under way in the Hawthorne Group is in some way applicable to biomedical science.

Functional Assemblies of Carborane-containing Modules

          "Functional assemblies of carborane-containing modules" can be further subdivided into two categories. These are rod-like assemblies (carborods) and cyclic assemblies (carboracycles and mercuracarborands).
          We are currently evaluating the rod-like constructs for application as Langmuir-Blodgett films, ordered functional monolayers on solid surfaces, and as liquid-crystalline materials. A variety of different linear groups for use between the carborane cages and carborane cage substituents are under investigation in order to control the length, rigidity, shape, reactivity and solubility of these materials. These rods carry an assortment of versatile terminal substituents which can be adapted to a variety of applications.
           The cyclic assemblies under investigation are composed of two different types of cycles, depending on the type of linker used to join the carborane modules. When electrophilic mercury is used as the bridge between the carborane modules, mercuracarborands are formed. These species provide the basis of a variety of unique applications including anion complexation, a very robust and sensitive microelectrode for the determination of serum chloride ion in real time, electrophilic catalysts for organic reactions such as Diels-Alder and, when complexed with chloride ion, the resulting complex is a weakly-coordinating anion potentially useful in Ziegler-Natta catalysis of alkene polymerization. Another macrocyclic assembly is formed if the linkage is based upon a bifunctional arylene or alkylene hydrocarbon segments with or without ancillary functional groups. These carboracycles are being evaluated as hosts for host-guest chemistry in both organic and aqueous solvent environments. An assortment of linking groups is being investigated to adjust the size of the interior cavity, cavity functionality, and solubility properties. The carborane modules incorporated in carboracycles may also be converted to metallacarborane components by well-known reactions with transition metals, lanthanides, and main group metals.

Camouflaged Carboranes and Polyhedral Boranes

          Thus far, "camouflaged carboranes and polyhedral boranes" are comprised of derivatives of the three isomers of carboranes (1,2- or ortho-, 1,7- or meta-, and 1,12- or para-carborane) and the icosahedral B12H122- anion. The term "camouflaged" carborane or polyhedral borane describes a molecule in which all, or very nearly all, the B-H vertices have been substituted by hydrophobic alkyl or hydrophilic hydroxyl groups. The resulting polyhedral borane derivative, which has a borane core stabilized by multicenter electron delocalization, is shrouded by a sheath of substituents which display characteristic properties. Hence, camouflaged polymethylated carboranes and B12H122- species demonstrate physical and chemical properties representative of both the thermally and chemically stable carboranes or polyhedral boranes and the versatile aliphatic hydrocarbons. These unprecedented structures appear at first sight to be either a hydrophobic hydrocarbon (methyl groups on the icosahedral surface) or a hydrophilic sugar (hydroxyl groups on the icosahedral surface). Such camouflaged species are currently being investigated as modules for the formation of the functional assemblies discussed above. Also, both of these unusual families may be derivatized and incorporated in new pharmaceuticals, employed as dendrimer (closomer) precursors, as drug delivery vehicles and in various aspects of nanotechnology. Structural variations, including stereochemistry, are unlimited and the uses to which new materials may be put are similarly broad. Another useful feature of the polyhedral boranes and carboranes is again emphasized: their inertness to enzymatic attack in marked contrast to purely organic species.

Oligomeric Phosphate Diesters

          A wide variety of boron-rich molecules have been synthesized for use as boron-delivery agents to provide target atoms for the boron neutron capture therapy (BNCT) of cancer. This promising method for the treatment of various types of cancer is dependent upon the ability of boron-containing compounds to preferentially accumulate in tumor tissue. Selective tumor cell penetration followed by nuclear localization of boron-rich agents will greatly enhance the efficiency of this potential therapy. A family of promising nuclear delivery agents is the carborane-containing oligomeric phosphate diesters (OPDs). These boron-rich molecules mimic the primary structure of DNA: instead of nucleosides connected by phosphodiester linkages, OPDs consist of closo- or nido- carborane modules connected by phosphodiester linkages. The nido-OPD derivatives have been demonstrated to localize and persist inside cell nuclei (109 boron atoms/cell) without incurring cell death. The observed intracellular binding of dinegative nido-OPD modules may be the result of their coulombic interaction with positively charged histones in the cell nuclei. This important discovery opens new opportunities for improving BNCT and provides a new vehicle for delivering molecules such as toxins or fragments of DNA to cell nuclei. Other non-cytotoxic enzyme-resistant nuclear delivery systems are unknown. In order to utilize OPDs in selective cell-killing, the OPDs must first be directed to the targeted cells. This may be accomplished by attaching the OPDs to biomolecules which are themselves selectively targeted for cancer cells. These OPD-biomolecule conjugates will then accumulate within the targeted tumor cells. Alternatively, OPDs can be selectively localized in tumor cells using liposomes as delivery vehicles, as discussed below.

Exploratory Liposome Research

          One of the most challenging problems facing the successful application of BNCT is the development of effective drug-targeting strategies which provide tumor-selective delivery of therapeutic quantities of boron or neutrons. The simplest approach is to use a tumor-targeted high energy neutron beam and global agents, small boron-containing molecules with little tumor-selectivity. Such agents are easy to prepare, relatively non-toxic, and they can be administered in large doses. At the other end of the spectrum are big, complex, boron-rich molecules such as tumor-cell targeting biomolecule conjugates of OPDs which potentially exhibit greater tumor-selectivity while carrying large quantities of boron per molecule. However, species of this sort have always fallen short of expectations and they no longer are considered as viable delivery vehicles. Consequently, another type of agent was explored.
          In terms of cell selectivity and delivery capability, unilamellar liposomes lie somewhere between the extremes of global and tumor-selective delivery and combine some of the more attractive qualities of both methods. As employed here, liposomes are small spheroidal phospholipid vesicles which can be used to transport a variety of boron-containing compounds into the interior of tumor cells. Since significant tumor cell-selectivity is provided by the liposome vehicle, the boron species employed may be relatively simple and dissolved in the aqueous core of the vesicle, embedded within the phospholipid bilayer, or both. The observed selectivity is due in part to the small size of the liposome nanoparticle (50-100 nm), but this is quite large in molecular terms. Consequently, the vesicle may carry a large boron dose. In addition, encapsulation of the boron species within a liposome attenuates potential systemic toxicity and provides an extended circulation lifetime in vivo. Very promising results have been obtained from investigations with boron-laden liposomes in animal tumor models evaluated for us in other laboratories.

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