Biocatalysis in the Preparation of the Statin Side Chain

Liljeblad, Arto; Kallinen, Annukka; Kanerva, Liisa T.

doi:10.2174/157017909789108738

Cited by 42 publications

(24 citation statements)

References 70 publications

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“…As the chiral 3,5-dihydroxyheptanoic acid derivatives represent the key pharmacophore in all of the super-statins [8], major efforts of the academic and industrial communities have been made for their efficient preparation [38][39][40][41][42][43][44][45][46]. In the course of time, biocatalysis [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] evolved as an important platform for greener and more efficient and stereoselective synthesis of 3,5-dihydroxyheptanoic (heptenoic) acid precursors [63][64][65][66][67][68][69][70][71][72][73][74][75].…”

Section: Structure Of Advanced Super-statin Lateral Chain Precursorsmentioning

confidence: 99%

Recent Progress in the Synthesis of Super-Statins

Časar

2015

Topics in Heterocyclic Chemistry

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Super-statins now represent a mature class of marketed drugs that faces the patent cliff, as has already occurred for fluvastatin and atorvastatin and is approaching for rosuvastatin and pitavastatin. However, they continue to trigger huge scientific interest in terms of their efficient preparation. This is not surprising, as easier accessibility of super-statins will promote even bigger demand in the market and consequently the need for higher rates of the production and productivity. Therefore, the stimulus for the development of even more efficient synthetic approaches to the heterocyclic moieties of super-statins and their chiral lateralchain precursors is at a peak, as also for the assembly of the these two parts into super-statins. The present report summarizes recent developments in the field of the synthesis of super-statins published from 2010 to 2015. Emphasis is given to the analysis of novel approaches to the formation of the chiral statin lateral chain, with detailed discussion of the development of new routes to respective heterocyclic cores and the assembly of these key units into the final super-statin structure.

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Section: Structure Of Advanced Super-statin Lateral Chain Precursorsmentioning

confidence: 99%

Recent Progress in the Synthesis of Super-Statins

Časar

2015

Topics in Heterocyclic Chemistry

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“…Two pathways have been reported for the bioconversion of nitriles to their corresponding carboxylic acids: the direct pathway using nitrilase as a biocatalyst and the indirect pathway using nitrile hydratase and amidase with amides as intermediates (Liljeblad et al 2009;Yeom et al 2007). In the case of (R)-3, although the direct pathway has been described by Dong et al (2010), the indirect pathway remains ambiguous.…”

Section: Biotransformation and Biotransformation Pathway Analysismentioning

confidence: 99%

“…Statins are effective cholesterol-lowering drugs (Liljeblad et al 2009). The third-generation statin, rosuvastatin, elicits good response in therapy for patients with coronary artery disease (Tsutamoto et al 2009).…”

Section: Introductionmentioning

confidence: 99%

“…The third-generation statin, rosuvastatin, elicits good response in therapy for patients with coronary artery disease (Tsutamoto et al 2009). Statins contain a 3,5-dihydroxyheptanoate side chain or its inactive lactone form, which plays an important role in inhibiting the key enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase during cholesterol biosynthesis (Liljeblad et al 2009). The 3,5-dihydroxyheptanoate side chain in rosuvastatin is derived from (R)-ethyl-3-hydroxyglutarate, (R)-3, so the preparation of (R)-3 with stereochemical purity has been a topical issue (Dong et al 2010).…”

Section: Introductionmentioning

confidence: 99%

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Bioconversion of ethyl (R)-4-cyano-3-hydroxybutyate into (R)-ethyl-3-hydroxyglutarate via an indirect pathway by Rhodococcus boritolerans

et al. 2012

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(R)-Ethyl-3-hydroxyglutarate, (R)-3, is an intermediate in the synthesis of the statin side chain. Here, a new two-step, indirect biotransformation pathway involving the formation of ethyl (R)-4-carbamoyl-3-hydroxybutanoate, (R)-2, as an intermediate for (R)-3 production was developed using Rhodococcus boritolerans with ethyl (R)-4-cyano-3-hydroxybutyate, (R)-1, as substrate. Maximum conversion was with 10 g (R)-1/l, 7 g cells/l (dry wt), pH 7.5 and 25°C. A yield of 98 ± 0.5% (w/w) was attained within 8 h.

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“…The stereochemical purity of the two chiral centers belonging to the pharmacophore of statins is critical to their bioactivity, as exemplified by atorvastatin and rosuvastatin (see Scheme 1), which are top-selling cholesterol-lowering drugs throughout the world with Bblockbusterŝ tatus. Considerable research efforts have been devoted to the development of novel strategies for the stereoselective synthesis of the chiral side chain of statins (Liljeblad et al 2009;Muller 2005;Patel 2009). tert-Butyl (S)-6-chloro-5-hydroxy-3-Electronic supplementary material The online version of this article (doi:10.1007/s00253-015-6675-1) contains supplementary material, which is available to authorized users.…”

Section: Introductionmentioning

confidence: 99%

Highly efficient enzymatic synthesis of tert-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate with a mutant alcohol dehydrogenase of Lactobacillus kefir

Chen

et al. 2015

Appl Microbiol Biotechnol

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tert-Butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate ((S)-CHOH) is a valuable chiral synthon, which is used for the synthesis of the cholesterol-lowering drugs atorvastatin and rosuvastatin. To date, only the alcohol dehydrogenases from Lactobacillus brevis (LbADH) and Lactobacillus kefir (LkADH) have demonstrated catalytic activity toward the asymmetric reduction of tert-butyl 6-chloro-3,5-dioxohexanoate (CDOH) to (S)-CHOH. Herein, a tetrad mutant of LkADH (LkTADH), A94T/F147L/L199H/A202L, was screened to be more efficient in this bioreduction process, exhibiting a 3.7- and 42-fold improvement in specific activity toward CDOH (1.27 U/mg) over LbADH (0.34 U/mg) and wild-type LkADH (0.03 U/mg), respectively. The molecular basis for the improved catalytic activity of LkTADH toward CDOH was investigated using homology modeling and docking analysis. Two major issues had a significant impact on the biocatalytic efficiency of this process, including (i) the poor aqueous stability of the substrate and (ii) partial substrate inhibition. A fed-batch strategy was successfully developed to address these issues and maintain a suitably low substrate concentration throughout the entire process. Several other parameters were also optimized, including the pH, temperature, NADP(+) concentration and cell loading. A final CDOH concentration of 427 mM (100 g/L) gave (S)-CHOH in 94 % yield and 99.5 % e.e. after a reaction time of 38 h with whole cells expressing LkTADH. The space-time yield and turnover number of NADP(+) in this process were 10.6 mmol/L/h and 16,060 mol/mol, respectively, which were the highest values ever reported. This new approach therefore represents a promising alternative for the efficient synthesis of (S)-CHOH.

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Biocatalysis in the Preparation of the Statin Side Chain

Cited by 42 publications

References 70 publications

Recent Progress in the Synthesis of Super-Statins

Recent Progress in the Synthesis of Super-Statins

Bioconversion of ethyl (R)-4-cyano-3-hydroxybutyate into (R)-ethyl-3-hydroxyglutarate via an indirect pathway by Rhodococcus boritolerans

Highly efficient enzymatic synthesis of tert-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate with a mutant alcohol dehydrogenase of Lactobacillus kefir

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