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Issue 29, 2012
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Serendipitous fragment-based drug discovery: ketogenic diet metabolites and statins effectively inhibit several carbonic anhydrases

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Abstract

Acetoacetic acid and R-3-hydroxy-butyric acid (BHB) are “ketone bodies”, metabolites produced during the ketogenic diet. We discovered that they inhibit in the submicromolar–micromolar range several carbonic anhydrase (CA, EC 4.2.1.1) isoforms involved in relevant physiologic processes such as lipogenesis and tumorigenesis. The BHB fragment is also present in the molecules of most statins, widely used drugs for inhibiting cholesterol biosynthesis through the 3-hydroxy-3-methyl-glutaryl-CoA reductase pathway. Three such statins, atorvastatin, fluvastatin and rosuvastatin, showed submicromolar–low nanomolar inhibition of the fifteen human isoforms hCA I–XIV. Our data point out that in addition to their cholesterol lowering properties, these drugs may exert a therapeutic effect by inhibiting lipogenesis through mitochondrial CA inhibition. The statins are also low nanomolar inhibitors of the tumor-associated isoforms CA IX and XII. Based on the BHB/statin scaffolds, antiepileptic, antiobesity and antitumor compounds with higher affinity for the various CA isoforms involved in epileptogenesis (CA VA, VB, VII), lipogenesis (CA III, CA VA, CA VB) and tumorigenesis (CA IX and CA XII) may be designed.

Graphical abstract: Serendipitous fragment-based drug discovery: ketogenic diet metabolites and statins effectively inhibit several carbonic anhydrases

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Publication details

The article was received on 16 Jan 2012, accepted on 16 Feb 2012 and first published on 17 Feb 2012


Article type: Communication
DOI: 10.1039/C2CC30359K
Chem. Commun., 2012,48, 3551-3553

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    Serendipitous fragment-based drug discovery: ketogenic diet metabolites and statins effectively inhibit several carbonic anhydrases

    S. Parkkila, D. Vullo, A. Maresca, F. Carta, A. Scozzafava and C. T. Supuran, Chem. Commun., 2012, 48, 3551
    DOI: 10.1039/C2CC30359K

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