M. Frederick Hawthorne

Multidentate carborane-containing Lewis acids and their chemistry: mercuracarborands

Abstract Macrocyclic Lewis acidic hosts with structures incorporating electron-withdrawing icosahedral carboranes and electrophilic mercury centers bind a variety of electron-rich guests. These compounds, the so-called mercuracarborands, are synthesized by a kinetic halide ion template effect that affords tetrameric cycles or in the absence of halide ion templates, cyclic trimers. Both types of mercuracarborands form stable host–guest complexes with anionic and neutral electron-rich molecules. The multidentate structure of mercuracarborand hosts has made these unique molecules ideal for catalytic and ion-sensing applications as well as for the assembly of supramolecular architectures.

A critical assessment of boron target compounds for boron neutron capture therapy

SummaryBoron neutron capture therapy (BNCT) has undergone dramatic developments since its inception by Locher in 1936 and the development of nuclear energy during World War II. The ensuing Cold War spawned the entirely new field of polyhedral borane chemistry, rapid advances in nuclear reactor technology and a corresponding increase in the number to reactors potentially available for BNCT. This effort has been largely oriented toward the eradication of glioblastoma multiforme (GBM) and melanoma with reduced interest in other types of malignancies. The design and synthesis of boron-10 target compounds needed for BNCT was not channeled to those types of compounds specifically required for GBM or melanoma. Consequently, a number of potentially useful boron agents are known which have not been biologically evaluated beyond a cursory examination and only three boron-10 enriched target species are approved for human use following their Investigational New Drug classification by the US Food and Drug Administration; BSH, BPA and GB-10. All ongoing clinical trials with GBM and melanoma are necessarily conducted with one of these three species and most often with BPA. The further development of BNCT is presently stalled by the absence of strong support for advanced compound evaluation and compound discovery driven by recent advances in biology and chemistry. A rigorous demonstration of BNCT efficacy surpassing that of currently available protocols has yet to be achieved. This article discusses the past history of compound development, contemporary problems such as compound classification and those problems which impede future advances. The latter include means for biological evaluation of new (and existing) boron target candidates at all stages of their development and the large-scale synthesis of boron target species for clinical trials and beyond. The future of BNCT is bright if latitude is given to the choice of clinical disease to be treated and if a recognized study demonstrating improved efficacy is completed. Eventually, BNCT in some form will be commercialized.

New horizons for therapy based on the boron neutron capture reaction

Boron neutron capture therapy (BNCT) is currently undergoing clinical trials in the USA, Japan and The Netherlands with patients afflicted with deadly brain cancer (glioblastoma multiforme) or melanoma. This therapy relies on a binary process in which the capture of a slow neutron by a 10B nucleus leads to an energetic nuclear fission reaction, with the formation of 7Li3+ and 4He2+ and accompanied by about 2.4 MeV of energy. The fleeting 7Li3+ and 4He2+ travel a distance of only about the diameter of one cell, and they are deadly to any cell in which they have been produced. Research in progress is concerned with the development of advanced boron agents and neutron sources, other than nuclear reactors, for the treatment of a variety of cancer types using novel 10B delivery methods. Non-malignant diseases such as rheumatoid arthritis offer additional opportunities for BNCT. The entire BNCT area awaits commercialization.

Synthesis and evaluation of transthyretin amyloidosis inhibitors containing carborane pharmacophores

Carboranes represent a potentially rich but underutilized class of inorganic and catabolism-inert pharmacophores. The regioselectivity and ease of derivatization of carboranes allows for facile syntheses of a wide variety of novel structures. The steric bulk, rigidity, and ease of B- and C-derivatization and lack of π-interactions associated with hydrophobic carboranes may be exploited to enhance the selectivity of previously identified bioactive molecules. Transthyretin (TTR) is a thyroxine-transport protein found in the blood that has been implicated in a variety of amyloid related diseases. Previous investigations have identified a variety of nonsteroidal antiinflammatory drugs (NSAIDs) and structurally related derivatives that imbue kinetic stabilization to TTR, thus inhibiting its dissociative fragmentation and subsequent aggregation to form putative toxic amyloid fibrils. However, the cyclooxygenase (COX) activity associated with these pharmaceuticals may limit their potential as long-term therapeutic agents for TTR amyloid diseases. Here, we report the synthesis and evaluation of carborane-containing analogs of the promising NSAID pharmaceuticals previously identified. The replacement of a phenyl ring in the NSAIDs with a carborane moiety greatly decreases their COX activity with the retention of similar efficacy as an inhibitor of TTR dissociation. The most promising of these compounds, 1-carboxylic acid-7-[3-fluorophenyl]-1,7-dicarba-closo-dodecaborane, showed effectively no COX-1 or COX-2 inhibition at a concentration more than an order of magnitude larger than the concentration at which TTR dissociation is nearly completely inhibited. This specificity is indicative of the potential for the exploitation of the unique properties of carboranes as potent and selective pharmacophores.

Symmetry and dynamics of molecular rotors in amphidynamic molecular crystals

Rotary biomolecular machines rely on highly symmetric supramolecular structures with rotating units that operate within a densely packed frame of reference, stator, embedded within relatively rigid membranes. The most notable examples are the enzyme FoF1 ATP synthase and the bacterial flagellum, which undergo rotation in steps determined by the symmetries of their rotators and rotating units. Speculating that a precise control of rotational dynamics in rigid environments will be essential for the development of artificial molecular machines, we analyzed the relation between rotational symmetry order and equilibrium rotational dynamics in a set of crystalline molecular gyroscopes with rotators having axial symmetry that ranges from two- to fivefold. The site exchange frequency for these molecules in their closely related crystals at ambient temperature varies by several orders of magnitude, up to ca. 4.46 × 108 s-1.

Metallocarboranes That Exhibit Novel Chemical Features: A virtually unlimited variety of structural and dynamic features are observed in metallocarborane chemistry

Among the myriad transition metal and main group complexes of ligands derived from carboranes, some exhibit unique structural variations and novel dynamic behavior.

Frontiers in neutron capture therapy

Frontiers in Neutron Capture Therapy Contents of Volume I: Medicine and Physics. Preface. In Memoriam. Acknowledgments. Introductory Overviews. Clinical Experiences. Treatment Planning and Clinical Considerations. Reactor Neutron Sources and Facilities. Accelerators and Other Neutron Sources. Dosimetry. Fast Neutron Studies. Author Index, Vol. I. Keyword Index, Vol. I. Frontiers in Neutron Capture Therapy Contents of Volume II: Chemistry and Radiobiology. Chemistry and Synthesis. Imaging and Analysis of Nuclides. Pharmacology and Compound Evaluation. Tissue Targeting. Preclinical Dosimetry. Preclinical Radiobiology. Future Directions and Emerging Applications. Author Index, Vol. II. Keyword Index, Vol. II. List of Symposium Participants.

Liposomes as drug delivery vehicles for boron agents.

The successful treatment of cancer by boron neutroncapture therapy (BNCT) requires the selective concentration ofboron-10 within malignant tumors. The potential of liposomesto deliver boron-rich compounds to tumors has beenassessed by examination of the biodistribution of borondelivered by liposomes in tumor-bearing mice. Small unilamellarvesicles have been found to stably encapsulate highconcentrations of water-soluble ionic boron compounds. Alternatively, lipophilicboron-containing species have been embedded within the phospholipidbilayer of liposomes, and both hydrophilic and lipophilicboron compounds have been incorporated within the sameliposome formulation.The biodistribution of boron was determined at severaltime points over 48 hr after i.v. injection ofliposomal suspensions in BALB/c mice bearing EMT6 tumors.The tumor-selective delivery of boron by the liposomeswas demonstrated as tumor-boron concentrations increased for severalhours post-injection. Even at the low injected dosesemployed (6–18 mg boron/kg body weight) therapeutic tumor boronconcentrations were observed (>30 μg boron/g tissue) andhigh tumor/blood ratios were achieved (>5). The mostfavorable results were obtained with the polyhedral boraneNa3[a2-B20H17NH2CH2CH2NH2]. Liposomes encapsulating this species produced a tumorboron concentration of 45 μg/g tissue at 30hr post-injection,at which time the tumor/blood boron ratio was9.3.

Ten Years of Metallocarboranes

Publisher Summary Metallocarboranes are only been known for ten years, and research into their synthesis and characterization has involved a small number of workers. Practical applications of these unique compounds are not been rapidly forthcoming. Recent work has shown catalytic activity in certain of these compounds and may signify future commercial value and industrial importance of metallocarboranes. The preparative methods of metallocarboranes are discussed in this chapter, for the synthesis of all the known metallocarboranes has been accomplished by one or more of these routes. This chapter focuses on the synthesis, structures, properties, and reactions of η-bonded metallocarboranes. Complexes of 2-carbon carboranes and species that have between nine and fourteen total polyhedral vertices are described in the chapter. The approach to the subject has been to divide the metallocarboranes according to the size of the polyhedron–starting with twelve-vertex compounds, which constitute the majority of the effort, to the larger polyhedral, so far unknown in the B n H n 2 - and C 2 B n-2 H, series, and then to the lower polyhedral. Further subdivisions within each polyhedral size include synthesis, structures, and properties of monometallic complexes, reactions of monometallic, bimetallic preparations and reactions, and, in two instances, trimetallic compounds. This catalyst systemis extremely stable and may be recovered quantitatively from alkene isomerizations and hydrogenation reactions.

Boron neutron capture therapy demonstrated in mice bearing EMT6 tumors following selective delivery of boron by rationally designed liposomes

The application of boron neutron capture therapy (BNCT) following liposomal delivery of a 10B-enriched polyhedral borane and a carborane against mouse mammary adenocarcinoma solid tumors was investigated. Unilamellar liposomes with a mean diameter of 134 nm or less, composed of an equimolar mixture of cholesterol and 1,2-distearoyl-sn-glycero-3-phosphocholine and incorporating Na3[1-(2′-B10H9)-2-NH3B10H8] in the aqueous interior and K[nido-7-CH3(CH2)15-7,8-C2B9H11] in the bilayer, were injected into the tail veins of female BALB/c mice bearing right flank EMT6 tumors. Biodistribution studies indicated that two identical injections given 24 h apart resulted in tumor boron levels exceeding 67 µg/g tumor at 54 h—with tumor/blood boron ratios being greatest at 96 h (5.68:1; 43 µg boron/g tumor)—following the initial injection. For BNCT experiments, tumor-bearing mice were irradiated 54 h after the initial injection for 30 min with thermal neutrons, resulting in a total fluence of 1.6 × 1012 neutrons per cm2 (±7%). Significant suppression of tumor growth was observed in mice given BNCT vs. control mice (only 424% increase in tumor volume at 14 d post irradiation vs. 1551% in untreated controls). In a separate experiment in which mice were given a second injection/irradiation treatment 7 d after the first, the tumor growth was vastly diminished (186% tumor volume increase at 14 d). A similar response was obtained for mice irradiated for 60 min (169% increase at 14 d), suggesting that neutron fluence was the limiting factor controlling BNCT efficacy in this study.