Asborin: The Carbaborane Analogue of Aspirin

Abstract

Aspirin, the acetyl ester of salicylic acid, was first discovered in the late 1800s and became one of the most world-renowned drugs. Its fame is rooted in its ability to treat a wide range of symptoms such as fever, inflammation, and pain. Aspirin represents an advancement of the previously applied salicylic acid, which was obtained from myrtle leaf decoction or willow bark extract, but was found to be less active and to cause serious gastrointestinal irritation.[1] Later on, other chemical modifications of aspirin were investigated with the aim of improving its pharmacological profile. The influence of additional substituents on the phenyl ring and modification of the acetoxy and carboxy groups were studied, [2] and even the phenyl core of aspirin was replaced by the organometallic ferrocene moiety. [3] However, none of these derivatives could substitute for aspirin. We have now modified aspirin by replacing the phenyl ring with a three-dimensional and highly hydrophobic carbaborane cluster.Carbaboranes are already known in medicinal chemistry as phenyl group mimetics, and analogues of tamoxifen, [4] trimethoprim, [5] and transthyretin amyloidosis inhibitors derived from flufenamic acid and diflunisal, [6] two nonsteroidal anti-inflammatory drugs (NSAIDs), have been presented.The focal point of our research was a high-yield synthesis of asborin, the carbaborane analogue of aspirin, and the study of its pharmacological behavior. Asborin is obtained in three steps (Scheme 1) starting from ortho-dicarba-closo-dodecaborane(12) (1). In the first step one of the carbaborane carbon atoms is hydroxylated according to a protocol described by Endo and co-workers.[7] The monolithiated carbaborane is treated with trimethyl borate to give a carbaboranyl boronic ester in situ. The ester is then oxidized with peracetic acid. The second step is carboxylation of the second cluster carbon atom. Both the OH proton and the remaining carbaborane CH proton of 2 can be removed with n-butyllithium, and reaction of the resulting dilithium salt with gaseous carbon dioxide gives 1-hydroxy-1,2-dicarba-closo-dodecaborane(12)-2-carboxylic acid (3) in greater than 99 % yield after acidic workup. Compound 3, with an ortho arrangement of hydroxy and carboxy groups, is the carbaborane analogue of salicylic acid. Finally, 1-acetoxy-1,2-dicarba-closo-dodecaborane(12)-2-carboxylic acid (asborin, 4) is obtained quantitatively simply by stirring 3 in acetyl chloride. The use of acetyl chloride rather than acetic anhydride is advantageous, as it can easily be removed under reduced pressure due to its lower boiling point of 52 8C. Crystals of 4 suitable for X-ray crystallography ( Figure 1) were obtained from chloroform; hydrogen-bonded dimers are formed via the carboxy groups.Asborin, with its hydrophobic cluster framework and hydrophilic carboxy group, is remarkably amphiphilic: It dissolves in water and nonpolar organic solvents.Aspirin is one of the smallest members of the NSAID family. These compounds are structurally very diverse, but all of the...

Asborin Inhibits Aldo/Keto Reductase 1A1

“…Asborin was capable of decreasing COX activity, but to a lesser extent than aspirin. [4] However, in the case of AKR1A1, asborin performed far better, and in fact, the cluster was the basis of inhibition. Salicylic acid and aspirin showed only very poor AKR1A1 inhibition, but the cluster analogues were active inhibitors.…”

“…We previously reported the synthesis of asborin, the carbaborane analogue of aspirin. [4] Asborin inhibits both cyclooxygenase (COX) isozymes, the major pharmaceutical targets of aspirin identified so far. Asborin also proved to acetylate COX-1 and COX-2, but in a completely different manner than aspirin.…”

Imitation and modification of bioactive lead structures via integration of boron clusters

“…Asborin, the carbaborane analogue of aspirin, has a highly hydrophobic cluster framework and hydrophilic carboxyl group and is remarkably amphiphilic: It dissolves in water and nonpolar organic solvents. The pharmacological behavior of asborin was studied [49]. COX inhibition was studied with an enzyme-linked immunosorbent assay (ELISA)-based COX inhibitor screening assay with the free enzymes of COX-1 and COX-2.…”

Synthesis, characterization and radiolabeling of carborane-functionalized tetrazines for use in inverse electron demand Diels–Alder ligation reactions

“…Dicarba-closo-dodecaboranes are attractive synthons for developing inorganic pharmaceuticals [1][2][3][4][5][6][7][8], radiopharmaceuticals [9], fluorophores [10], and boron neutron capture therapy (BNCT) [11][12][13][14][15] or synovectomy (BNCS) agents [16,17]. Carboranes are biocompatible, resistant to enzymatic modification, and can be linked to or incorporated within a variety of different targeting vectors.…”