Asborin Inhibits Aldo/Keto Reductase 1A1

Abstract

Asborin is the carbaborane analogue of aspirin. Replacement of the phenyl ring in aspirin by ortho-carbaborane was found to change the pharmacological profile of the compound remarkably. Unlike aspirin, asborin cannot selectively acetylate a single serine residue in the active site of cyclooxygenase, and as a result inhibitory potency is reduced. Activation of the acetyl group and the presence of the hydrophobic and bulky cluster therefore did not meet the requirements for cyclooxygenase inhibition. Both features, however, match perfectly for inhibition of the aldo/keto reductase family. Herein, we describe the identification of aldo/keto reductase (AKR) 1A1 as an enzymatic target of asborin, which is inhibited in the low micromolar range. The detailed mode of inhibition was studied and is discussed with respect to the cluster properties. The results shed light on how ortho-carbaborane can be used as a drug synthon, as well as on the development of carbaborane-based inhibitors of other aldo/keto reductases.

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

“…However, asborin proved to be a highly potent aldo/keto reductase 1A1 (AKR1A1) inhibitor instead [51]. Salborin, the deacetylated version of asborin, was also a competitive AKR1A1 inhibitor, while the phenyl analogues, salicylic acid and aspirin, showed only very poor AKR1A1 inhibition [51].…”

“…Salborin, the deacetylated version of asborin, was also a competitive AKR1A1 inhibitor, while the phenyl analogues, salicylic acid and aspirin, showed only very poor AKR1A1 inhibition [51]. Asborin's mode of action is unique, as it irreversibly acetylates lysine residues first and thereby eliminates salborin, which in addition is a competitive AKR1A1 inhibitor.…”

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.…”

Carborane-Based Carbonic Anhydrase Inhibitors: Insight into CAII/CAIX Specificity from a High-Resolution Crystal Structure, Modeling, and Quantum Chemical Calculations

“…Incorporation of carborane cages into the structures of certain substances of medicinal interest can enhance hydrophobic interactions between the boron cluster-coupled pharmaceuticals and their protein targets, increase in vivo stability, and facilitate uptake through cellular membranes [ 14 , 15 ]. The successful use of boron clusters as hydrophobic pharmacophores has recently been increasing [ 16 , 17 ]. Examples of carborane pharmacophores include boron-containing antifolates [ 18 ], HIV protease inhibitors [ 19 , 20 ], and estrogen receptor agonists and antagonists [ 21 ], among others [ 16 , 22 , 23 ].…”