Asborin inhibits Aldo/Keto reductase 1A1.
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.
Scholz
Matthias
M
Institut für Anorganische Chemie der Universität Leipzig, Germany.
Steinhagen
Max
M
Heiker
John T
JT
Beck-Sickinger
Annette G
AG
Hey-Hawkins
Evamarie
E
D000085:Acetates / Q000494:pharmacology; D000107:Acetylation; D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000449:Aldehyde Reductase; D000074408:Aldo-Keto Reductases; D000595:Amino Acid Sequence; D001241:Aspirin / Q000494:pharmacology; D001895:Boron / Q000737:chemistry*; D001896:Boron Compounds / Q000494:pharmacology; D020134:Catalytic Domain; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data
D000085:Acetates; D001896:Boron Compounds; D016861:Cyclooxygenase Inhibitors; C542329:asborin; D000429:Alcohol Oxidoreductases; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D001895:Boron; D001241:Aspirin