Synthesis and biomedical applications of novel carboranes

Chapter 1. Carboranes represent a potentially rich but underutilized class of inorganic and catabolism-inert pharmacophores. The steric bulk, rigidity, ease of B- and C-derivatization and lack of n-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 non-steroidal anti-inflammatory drugs (NSAIDs), and structurally related derivatives, which imbue kinetic stabilization to TTR thus inhibiting its dissociative fragmentation and subsequent misaggregation. 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 in which the replacement of a phenyl ring in the NSAIDs with a carborane moiety greatly decreases their COX activity while retaining similar efficacy as an inhibitor of TTR dissociation. The most promising of these compounds, 1-carboxylic acid-7-[3-fluoropheny1]-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.;Chapter 2. In continuing research, a mild protocol for the palladium-catalyzed Buchwald-Hartwig amination and amidation of icosahedral dicarbon carboranes has been described. Employing 2-dicyclohexylphosphino-2'-( N, N-dimethylamino)biphenyl as a ligand and K3PO 4 as a base, benzamide, aniline, o-phenylenediamine and trifluoroacetamide were coupled to a series of mono- and diiodo carboranes furnishing the respective carborane derivatives in good to excellent yields. Subsequent base-mediated saponification of the trifluoroacetamide derivatives was shown to provide the free amino-carboranes. The structures eight aminocarborane derivatives have been established through X-ray diffraction studies.;Chapter 3. A novel homotrifunctional conjugation reagent, 1,3,5-tris-(N-maleimidomethyl) benzene, has been synthesized in high yield with minimum purification. The reactivity of this molecule was examined by using L-cysteine as a nucleophile.