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Asborin Inhibits Aldo/Keto Reductase 1A1
Author(s) -
Scholz Matthias,
Steinhagen Max,
Heiker John T.,
BeckSickinger Annette G.,
HeyHawkins Evamarie
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000368
Subject(s) - aldo keto reductase , chemistry , stereochemistry , cyclooxygenase , reductase , aspirin , serine , synthon , enzyme , residue (chemistry) , biochemistry
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.