High enantioselective resolution of racemic 2-arylpropionic acids in an enzyme membrane reactor

Ceynowa, Józef; Rauchfleisz, Marta

doi:10.1016/s1381-1177(03)00066-3

Cited by 32 publications

(24 citation statements)

References 29 publications

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“…Enantiopure carboxylic acid esters are important building blocks for the synthesis of many pharmaceuticals (for instance nonsteroidal anti-inflammatory drugs such as Ibuprofen), pesticides, and natural compounds such as pheromones. [2][3][4][5] 2-halogeno-carboxylic acid esters are important intermediates found in the synthetic pathways of a number of drugs such as prostaglandin, prostacyclin, semisynthetic penicillin, and thiazolium salts. [6][7][8][9] In particular, 2-bromo-o-tolylacetic acid ethyl ester is used as a precursor for the synthesis of analgesics and nonpeptide angiotensin II-receptor antagonists.…”

Section: Introductionmentioning

confidence: 99%

Improvement of Yarrowia lipolytica Lipase Enantioselectivity by Using Mutagenesis Targeted to the Substrate Binding Site

et al. 2009

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Lip2p lipase from Yarrowia lipolytica was shown to be an efficient catalyst for the resolution of 2-bromo-arylacetic acid esters, an important class of chemical intermediates in the pharmaceutical industry. Enantioselectivity of this lipase was improved by site-directed mutagenesis targeted to the substrate binding site. To guide mutagenesis experiments, the three-dimensional model of this lipase was built by homology modelling techniques by using the structures of lipases from Rhizomucor miehei and Thermomyces lanuginosa as templates. On the basis of this structural model, five amino acid residues (T88, V94, D97, V232, V285) that form the hydrophobic substrate binding site of the lipase were selected for site-directed mutagenesis. Position 232 was identified as crucial for the discrimination between enantiomers. Variant V232A displayed an enantioselectivity enhanced by one order of magnitude, whereas variant V232L exhibited a selectivity inversion. To further explore the diversity, position 232 was systematically replaced by the 19 possible amino acids. Screening of this library led to the identification of the V232S variant, which has a tremendously increased E value compared to the parental enzyme for the resolution of 2-bromo-phenylacetic acid ethyl ester (58-fold) and 2-bromo-o-tolylacetic acid ethyl ester (16-fold). In addition to the gain in enantioselectivity, a remarkable increase in velocity was observed (eightfold increase) for both substrates.

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Section: Introductionmentioning

confidence: 99%

Improvement of Yarrowia lipolytica Lipase Enantioselectivity by Using Mutagenesis Targeted to the Substrate Binding Site

et al. 2009

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“…In addition, two reference compounds, cyclohexyl ester of IBU (13) from compounds 1 and 2 upon reacting with cyclohexanol and acetic anhydride in good yields 37,38) (Chart 3). The processes of the above reactions were monitored by TLC.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Diosgenin-Ibuprofen Derivatives and Their Activities against Insulin-Dependent Diabetes Mellitus

Xin

Wang

Guo

et al. 2013

CHEMICAL & PHARMACEUTICAL BULLETIN

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The synthesis and anti-diabetes activities of diosgenin-ibuprofen derivatives were investigated. Ibuprofen (IBU) was chemically coupled with diosgenin either directly or through amino acid esters linkers. The effects of these compounds on lipopolysaccharide (LPS)-induced nitric oxide (NO) generation were assessed. The results showed spirost-5-en-3β-yl (2-(4-isobutyl-phenyl)-propionate) (4) was of better activity to suppress the production of NO in the supernatant of LPS-stimulated RAW264.7 cells. In vivo investigation on nonobese diabetic (NOD) mice indicated that compound 4 decreased the incidence of insulin-dependent diabetes mellitus (IDDM; type 1 diabetes) of NOD mice which suggested a potential activity of compound 4 against type 1 diabetes.Key words diosgenin-ibuprofen; nitric oxide generation; type 1 diabetes Diabetes mellitus (DM) is a common but complicated metabolic disease characterized by hyperglycemia. Insulin-dependent diabetes mellitus (IDDM; type 1 diabetes) results from the damage of the insulin-secreting β-cells in the pancreas through an autoimmune process, leading to permanent deficiency of endogenous insulin. [1][2][3] Although patients with this form of diabetes could depend on exogenous insulin to sustain life, serious complications such as cardiovascular diseases, blindness, kidney failure and stroke caused by hyperglycemia will lead to a high fatality rate.4-6) Therefore, applying processes or compounds that can strictly control the level of blood glucose or protect islet β-cells against destruction may be an alternative way to treat type 1 diabetes.Proinflammatory cytokines are cytotoxic to β-cells and have been implicated in the pathogenesis of type 1 diabetes. [7][8][9] Insulin which is the primary medication used to treat the diabetes and prevent complications in all DM patients suppresses the inflammatory process of type 1 diabetes through preventing hyperglycemia and modulating key inflammatory molecules.10) On one hand, there were studies suggesting that some non-steroidal anti-inflammatory drugs (NSAIDs) are effective in the treatment of type 1 diabetes, such as lisofylline (LSF), 11) pentoxifylline (PTX) 12) and aspirin. [13][14][15][16][17] Ibuprofen (IBU), also a NSAID, was reported to have the capacity of controlling blood glucose concentration and promoting glucose tolerance.13) It becomes toxic only at very high doses and has a wide therapeutic window.18) The anti-inflammatory activities of IBU were connected with the inhibition of cyclooxygenase enzymes, which reduce the synthesis of prostaglandins. It has also an inhibitory effect on the inducible nitric oxide synthase (iNOS) protein which diminishes the synthesis of the proinflammatory cytokines.19-21) On the other hand, steroidal anti-inflammatory drugs (SAIDS) could induce apoptosis or cell death of inflammatory cells and inhibit the production of inflammatory cytokines which are involved in the regulation of glucose metabolism and β-cell secretion.22) Diosgenin, an aglycone of steroidal saponins, possesses a variety o...

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“…52,115 Higher free enzyme loading was required for the esterification process to achieve performance comparable with the TSP-EMR, 75 but in chiral hydrolysis the free enzyme processes use lower enzyme quantity to achieve 100% product enantiomeric excess. 24,51 One of the focuses of TSP-EMR operations is distribution of materials. All the existing reactions take place at the organic interfaces, thus the substrates are frequently circulated in the organic phase.…”

Section: Further Needsmentioning

confidence: 99%

“…Conversion and separation of the enantiomers can take place in a single operation, 21,22 thus selective removal of products from reaction sites increases conversion of productinhibited or thermodynamically unfavourable reactions. 23,24 The EMR overcomes disadvantages of batch stirred tank reactors, 25 -27 consumes low energy and is easy to scale-up. 28,29 Compared with other technologies, the EMR has high productivity and stability, better control of single enantiomers production, enriched and concentrated products and decreased reaction times.…”

Section: Introductionmentioning

confidence: 99%

Enzymatic membrane reactors: the determining factors in two separate phase operations

Agustian¹,

Kamaruddin²,

Bhatia³

2011

J of Chemical Tech & Biotech

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A two separate phase-enzymatic membrane reactor is an attractive process since it has a large interfacial area and exchange surfaces, simultaneous reaction and separation and other benefits. Many factors influence its successful operation, and these include characteristics of the enzyme, membrane, circulating fluids and reactor operations. Although the operating conditions are the main factor, other factors must be considered before, during or after its application. At the initial stage of reactor development, the solubility of substrates and products, type of operation, membrane material and size, enzyme preparation and loading procedure, and cleanliness of the recirculated fluids should be specified. The immobilization site, reactor arrangement, dissolved or no-solvent operation, classic or emulsion operation and immobilized or suspended enzyme(s) are determined later. Some factors still need further studies. Utilization of the technology is described for use from multigram-to plant-scale capacity to process racemic and achiral compounds. The racemates were resolved primarily by kinetic resolution, but dynamic kinetic resolution has been exploited. The technology focused on hydrolytic reactions, but esterification processes were also exploited.

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High enantioselective resolution of racemic 2-arylpropionic acids in an enzyme membrane reactor

Cited by 32 publications

References 29 publications

Improvement of Yarrowia lipolytica Lipase Enantioselectivity by Using Mutagenesis Targeted to the Substrate Binding Site

Improvement of Yarrowia lipolytica Lipase Enantioselectivity by Using Mutagenesis Targeted to the Substrate Binding Site

Synthesis of Diosgenin-Ibuprofen Derivatives and Their Activities against Insulin-Dependent Diabetes Mellitus

Enzymatic membrane reactors: the determining factors in two separate phase operations

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