Synthesis and evaluation of transthyretin amyloidosis inhibitors containing carborane pharmacophores

Abstract

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 ofinteractions 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.amyloid ͉ cyclooxygenase ͉ nonsteroidal antiinflammatory drug ͉ fibril T he dicarba-closo-dodecaboranes (carboranes) are icosahedral carbon-containing boron clusters with extraordinary characteristic properties (such as resistance to catabolism, kinetic inertness to reagents, strong hydrophobicity, and wellestablished chemistry) that afford the opportunity for their exploitation as novel hydrophobic pharmacophores. The three isomeric dicarbon carboranes, closo-1,2-C 2 B 10 H 12 , closo-1,7-C 2 B 10 H 12 , and closo-1,12-C 2 B 10 H 12 , commonly known as ortho-, meta-, and para-carborane, respectively, share approximately the same volume as a rotated phenyl ring. This, as well as their structural integrity, ease of substitution, and delocalized bonding, suggests their description as three-dimensional analogs of aromatic hydrocarbons (1), allowing their facile substitution for phenyl rings as rigid scaffolding in pharmacological agents. This rigid scaffolding can be easily and selectively derivatized through deprotonation of the slightly acidic C-H vertices by a strong base (alkyllithium reagents, Grignard reagents, etc.) affording a strongly nucleophilic carboranyl anion capable of reaction with a wide range of electrophiles, inclu...

Synthesis and Characterization of New Fluorescent Styrene‐Containing Carborane Derivatives: The Singular Quenching Role of a Phenyl Substituent

“…[5] These properties have made them suitable for potential application in the fields of catalysis, [6] material science such as heat-stable polymer or hybrid materials, [7] and especially in medicine. [8] Due to the versatility of o-carboranes to be chemically modified, [1c, 9] they have been an ideal group for the preparation of stable, agile, and suitable building blocks that can be subsequently attached to a molecule, such as star-shaped systems; [10] dendrons and dendrimers; [11,12] or porphyrins.…”

Polyhedral Boranes for Medical Applications: Current Status and Perspectives

“…Later, carborane analogues of nonsteroidal anti-inflammatory drugs, flufenamic acid, and diflunisal, were synthesized, and some of them were found to be potent inhibitors of transthyretin amyloid formation. [179] The use of carboranes as pharmacophores in the design of new pharmaceuticals was a subject of several re-views.…”

Strategies for Inhibiting Protein Aggregation: Therapeutic Approaches to Protein-Aggregation Diseases

“…Their regioselectivity and ease of derivatization allows for facile syntheses of a wide variety of novel structures. Carboranes were recently used to synthesize NSAID analogues, but lacking the cyclooxygenase-inhibiting activity of NSAIDs (Julius et al 2007). Several carboranes were synthesized, and one of these, 1-carboxylic acid-7-[3-fl uorophenyl]-1,7-dicarba-closo-dodecaborane, bound to TTR and stabilized its tetrameric form, while showing effectively no COX-1 or COX-2 inhibition at concentrations ~10-fold higher than those needed to inhibit TTR dissociation to monomer (Fig.…”