Issue 23, 2006
From the journal:

Organic & Biomolecular Chemistry

DFT study on hydroxy acid–lactone interconversion of statins: the case of fluvastatin†

Tomasz Grabarkiewicz,a   Pawel Grobelny,b   Marcin Hoffmann*ac  and  Jadwiga Mielcarekb  

* Corresponding authors

a Quantum Chemistry Group, Faculty of Chemistry, A. Mickiewicz University, Grunwaldzka 6, Poznan, Poland
E-mail: grabar@man.poznan.pl

b Department of Inorganic and Analytical Chemistry, University of Medical Sciences, Grunwaldzka 6, Poznan, Poland

c BioInfoBank Institute, Limanowskiego 24A, Poznan, Poland
E-mail: mmh@bioinfo.pl

Abstract

Fluvastatin is a member of the HMG-CoA reductase inhibitor family of drugs, commonly referred to as statins. It is generally known that, under physiological conditions, statins are susceptible to pH-dependent interconversion between their active (hydroxy acid) and inactive (lactone) forms. The mechanism of this interconversion, under both acidic and basic conditions, was investigated theoretically using the density functional theory (DFT) method. Regardless of the conditions, the lactone form was always higher in energy by 6–19 kcal mol−1. However, under basic conditions, the activation barrier for the hydrolysis was significantly lower (9 kcal mol−1) than for the reverse reaction (28 kcal mol−1), making the lactone form unstable. The activation barriers under acidic conditions were of comparable height in both directions (22 and 28 kcal mol−1), making the occurrence of both forms equally probable. Due to the high activation barrier (>40 kcal mol−1), a one-step, direct interconversion between the two forms turned out to be unfavourable. Moreover, the potential energy surface of fluvastatin was briefly inspected, revealing relatively small energetic differences (<5 kcal mol−1) between the key conformers.

Graphical abstract: DFT study on hydroxy acid–lactone interconversion of statins: the case of fluvastatin

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Article information

DOI
https://doi.org/10.1039/B612999B
Article type
Paper
Submitted
07 Sep 2006
Accepted
10 Oct 2006
First published
25 Oct 2006

Org. Biomol. Chem., 2006,4, 4299-4306

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DFT study on hydroxy acid–lactone interconversion of statins: the case of fluvastatin

T. Grabarkiewicz, P. Grobelny, M. Hoffmann and J. Mielcarek, Org. Biomol. Chem., 2006, 4, 4299 DOI: 10.1039/B612999B

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