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Online ISSN: 1860-7187
October 26, 2010
VIP: Asborin Inhibits Aldo/Keto Reductase 1A1
Matthias Scholz, Max Steinhagen, John T. Heiker, Annette G. Beck-Sickinger, Evamarie Hey-Hawkins*
Acetylsalicylic acid (aspirin) exerts its anti-inflammatory and pain-relieving effects through inhibition of cyclooxygenase (COX) enzymes. It arrests COX activity by acetylating a specific active site serine residue. As aspirin is a rather well-characterized drug, Hey-Hawkins and colleagues at the University of Leipzig in Germany used it as a template for their research into ortho-carbaborane derivatives.
Because they can be modified very easily at either the carbon or boron atoms, the icosahedrally shaped carbaboranes have gained popularity in recent years as substitutes for phenyl rings in known drugs; this allows a straightforward determination of their pharmacological profile. Hey-Hawkins' team found that asborin, the carbaborane-containing analogue of aspirin, also inhibits COX enzymes, albeit more weakly and through a different mechanism of action: by acetylating surface-exposed lysine residues. Asborin was instead found to be a potent inhibitor of aldo/keto reductase (AKR) 1A1, and lysine acetylation was found to be crucial for this. AKR1A1 is one of a large family of reductases, and other members have been shown to play important roles in a variety of cancers and neurological disorders. Asborin holds promise as a lead structure for AKR inhibition because the carbon/boron cluster allows further chemical modification; steric bulk and acetyl group activation can be fine-tuned for other AKR targets.
Received September 1, 2010; published online October 21, 2010, DOI: 10.1002/cmdc.201000368.