Immobilization of Cholesterol Esterase for Use in Multiple Batch Biotransformations to Prepare (−)- FTC (Emtricitabine)

Osborne, Andrew P.; Brick, Dean; Ruecroft, Graham; Taylor, Ian N.

doi:10.1021/op050258f

Cited by 14 publications

(2 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The immobilization adsorption rate, in terms of activity (compared with total protein) was greater on octadecyl Sepabeads ( Figure 1(b) ) than on butyl Sepabeads ( Figure 1(a) ). Esterases and lipases have been immobilized on hydrophobic supports in several works [ 9 , 15 , 16 , 18 , 33 , 35 – 37 ]. The use of hydrophobic supports is most promising because these supports mimic the enzymes' natural medium and can often promote hyperactivation, highly selective adsorption, purification, increased enantioselectivity, and strong but reversible immobilization, allowing the support to be reused after the enzyme has been deactivated [ 25 – 27 ].…”

Section: Resultsmentioning

confidence: 99%

Immobilization and Characterization of a Recombinant Thermostable Lipase (Pf2001) from Pyrococcus furiosus on Supports with Different Degrees of Hydrophobicity

et al. 2010

View full text Add to dashboard Cite

We studied the immobilization of a recombinant thermostable lipase (Pf2001Δ60) from the hyperthermophilic archaeon Pyrococcus furiosus on supports with different degrees of hydrophobicity: butyl Sepabeads and octadecyl Sepabeads. The enzyme was strongly adsorbed in both supports. When it was adsorbed on these supports, the enzyme showed 140 and 237% hyperactivation, respectively. The assessment of storage stability showed that the octadecyl Sepabeads immobilized enzyme showed 100% of residual activity after 30 days of storage. However, the greatest stability at 70°C was obtained in butyl Sepabeads immobilized enzyme, which retained 77% activity after 1 hour incubation. The maximum activity of the immobilized preparations was obtained with the pH between 6 and 7, at 70°C. Thus, this study achieved a new extremophilic biocatalyst with greater stability, for use in several biotechnological processes.

show abstract

Section: Resultsmentioning

confidence: 99%

Immobilization and Characterization of a Recombinant Thermostable Lipase (Pf2001) from Pyrococcus furiosus on Supports with Different Degrees of Hydrophobicity

et al. 2010

View full text Add to dashboard Cite

show abstract

“…The hydrolytic ester resolution of racemic (+/-)-2'3'-dideoxy-5-fluoro-3'thiacytidine butyrate (128) was successfully demonstrated using an immobilized cholesterol esterase (accurel PP). In this manner emtricitabine (13) was obtained in high enantioselectivity (98% ee) and good with a good recovery (31%, 2.17 kg) [116]. Such biocatalytic resolutions can be complicated by the SDE phenomenon [117] necessitating controlled SDE assays for the reliable determination of reported enantioselectivity values [118].…”

Section: Emtricitabinementioning

confidence: 99%

Next generation organofluorine containing blockbuster drugs

Han

Remete

Dobson

et al. 2020

Journal of Fluorine Chemistry

231

View full text Add to dashboard Cite

The role of organo-fluorine compounds in modern health, food and energy related 2 industries is widely-appreciated. The unique properties that fluorine imparts to organic molecules, stemming from its high electronegativity and stability when bound to carbon, finds it increasing being used in the development of new bioactivities. Around 25% of the current blockbuster drugs contain fluorine and this number is increasing to well above 30% for recent FDA approvals. In this Review we highlight a selection of the most successful organo-fluorine drugs, that have achieved blockbuster status, namely, sitagliptin (diabetes), sofosbuvir (hepatitis C), emtricitabine (HIV), glecaprevir/pibrentasvir (hepatitis C), elvitegravir (HIV), dolutegravir (HIV), bictegravir (HIV), efavirenz (HIV), enzalutamide (prostate cancer), aubagio (immunomodulatory) and paliperidone palmitate (schizophrenia). For each compound we discuss their discovery, their relevant disease state and how they are made, emphasizing the source of fluorine-containing moieties, and where known, their mode of action. Scheme 7. Synthesis of intermediate 23 for the preparation of sitagliptin (4). The synthesis of β-amino acid 28 was shown in Scheme 8. An asymmetric Ru-catalyzed reduction of the carbonyl group on β-ketoester 24 is another illustration of the contribution of Noyori's asymmetric methodology to the development of pharmaceutical processes. This asymmetric reduction is followed by ester hydrolysis to generate intermediate 25. A coupling reaction between carboxylic acid 25 and BnONH2 in the presence of EDC-HCl afforded hydroxamate 26, which was subjected to an intramolecular cyclization reaction to generate lactam 27. The treatment of lactam 27 with HCl and then a hydrolysis under basic conditions, provided the key intermediate 28. Triazole 23 was then coupled to amino acid 28 in the presence of EDC-HCl and N-methylmorpholine (NMM) to afforded intermediate 29, which was finally converted into sitagliptin ( 4) via a Pd-catalyzed hydrogenation. It should be noted that Soloshonok and co-workers applied their chiral Ni-complex approach to the synthesis of sitagliptin (4) [33].

show abstract

Chiral Alcohols by Enzymatic Preparation

Borup

Daußmann²,

Collier³

2010

Encyclopedia of Industrial Biotechnology

View full text Add to dashboard Cite

Biocatalytic processes are of increasing importance in the production of chiral alcohols which are important building blocks in the synthesis of chemical catalysts, liquid crystals, agrochemicals and pharmaceuticals. Methods for the synthesis of chiral alcohols can be subdivided into three general classes: traditional (such as classic racemic resolution, chromatography, chiral pool synthesis), asymmetric chemical, and biological (enzymes, whole microbial cells) methods. The last can also be applied to the more traditional methods. Enzymatic techniques are attracting a growing interest as green catalysts because of the different advantages they offer, as compared to other methods: high selectivity, high product purity, mild reaction conditions, competitive production costs, and excellent catalyst availability. In this contribution we give an overview of the biocatalytic approaches for the manufacture of chiral alcohols. To our knowledge there are currently about five major enzyme groups applied for the synthesis of chiral alcohols. The first one reduces carbonyl functional groups (ketones) to enantiopure secondary alcohols (dehydrogenases or reductases). The second group forms alcohols by introduction of molecular oxygen with concomitant one or two electron reduction (mono‐ and dioxygenases). The third group forms alcohols by addition of water to unsaturated carbon carbon double bonds (hydratases) whereas the fourth one forms alcohols by nucleophilic addition of small molecules such as HCN at carbonyl groups which usually also results in a new C–C bond formation (hydroxynitrile lyases and aldolases). The last major group of enzymes discussed herein belongs to the traditional methods mentioned above and resolves racemic chiral alcohols by reacting with only one enantiomer in a racemic mixture (hydrolases). In a selection of case studies we demonstrate the high level of importance that biocatalytic processes have already gained in the industrial manufacture of chiral alcohols. There are numerous processes available that have been or still are operated in multi‐tonne scale. By solving the drawback of cofactor requirements and regeneration for a range of enzymes, especially in the area of asymmetric reduction, the dehydrogenases and oxygenases are now commonly used for commercial processes and are in several cases superior to whole‐cell microbial processes. The highly competitive nature of enzymatic processes compared to whole‐cell (fermentation) and chemical approaches is demonstrated with the example of the manufacture of optically active ethyl ( R )‐3‐hydroxybutyrate.

show abstract

Immobilization of Cholesterol Esterase for Use in Multiple Batch Biotransformations to Prepare (−)- FTC (Emtricitabine)

Cited by 14 publications

References 4 publications

Immobilization and Characterization of a Recombinant Thermostable Lipase (Pf2001) from Pyrococcus furiosus on Supports with Different Degrees of Hydrophobicity

Immobilization and Characterization of a Recombinant Thermostable Lipase (Pf2001) from Pyrococcus furiosus on Supports with Different Degrees of Hydrophobicity

Next generation organofluorine containing blockbuster drugs

Chiral Alcohols by Enzymatic Preparation

Contact Info

Product

Resources

About