Mevinic Acids Research Articles

Biosynthesis of (S)-1-(1-naphthyl) ethanol by microbial ketoreductase.

(S)-1-(1-naphthyl) ethanol (SNE) is a chiral drug intermediate for the production of mevinic acid analog, a potent cholesterol agent. It acts as an HMG-CoA reductase inhibitor and is hence used in the synthesis of statins. Statins are lipid-lowering drugs used to lower cholesterol in the body. In our present study, we carried out whole-cell bioreduction of 1-Acetonaphthone to enantiopure SNE using selected microorganisms acquired by soil acclimation technique. The microorganism which exhibited higher bioreduction activity was determined using high-performance liquid chromatography (HPLC), and it was identified as Pichia kudriavzevii by ITS primer sequencing. After optimizing the parameters, Pichia sp. produced SNE with good conversion (75%), yield (67%), and excellent enantiomeric excess (100%). The microbial enzyme showed higher activity at 24-h-old supernatant. The crude and partially purified enzyme exhibited a specific activity of 51.13 U/mL and 62.72 U/mL, respectively, with a 1.22 purification fold.

Resolution of enantiopure (S)-1-(1-napthyl) ethanol from racemic mixture by a novel Bacillus cereus isolate.

Chiral intermediates have wide application and high demand in pharmaceutical, agricultural, and other biotechnological industries for the preparation of bulk drug substances or fine chemicals. (S)-1-(1-napthyl) ethanol is an important synthetic intermediate of mevinic acid analog and a potential inhibitor of 3-hydroxy methyl glutaryl coenzyme A reductase enzymes which is rate limiting for cholesterol synthesis. The present study focuses on the resolution of (RS)-1-(1-napthyl) ethanol using whole cell biotransformation approach. The screening of microbial strains for the specific conversion were performed by the enrichment techniques using (RS)-1-(1-napthyl) ethanol. Evaluation of resolution, i.e., the enantioselective conversion of (R)-1-(1-napthyl) ethanol into 1-acetonapthone and production of (S)-1-(1-napthyl) ethanol with high purity were carried out. Among the isolates, a novel strain Bacillus cereus WG3 was found to be potent for the resolution and conversion of (S)-1-(1-napthyl) ethanol. This strain showed 86% conversion of (R)-1-(1-napthyl) ethanol and 95% yield of S-1-(1-napthyl) ethanol with 80% ee after 24 h. Further, the optimization of biotransformation reactions was carried out and the optimal parameters were found to be pH 7.0 and temperature 30 °C.

Preparation of Enantiomerically Pure (S)-(-)-1-(1'-naphthyl)-ethanol by the Fungus Alternaria alternata.

(S)-(-)-1-(1'-napthyl)-ethanol (S-NE) is an important intermediate for the preparation of mevinic acid analogs, which is used for the treatment of hyperlipidemia. The objectives of the study were to isolate a microorganism that could effectively reduce 1-acetonaphthone (1-ACN) to S-NE, to determine the influence that the physicochemical parameters would have on the reduction by the isolated microorganism, and to attempt large-scale studies with the microorganism. Over the years fungi have been considered a promising biocatalyst and it has been presumed that many fungal species have not been isolated and therefore the current study focused on possible isolation of these microorganisms. A total of 72 fungal isolates were screened for their ability to reduce 1-ACN to its corresponding alcohol. The isolate, EBK-62, identified as Alternaria alternata, was found to be the most successful at reducing the ketone to the corresponding alcohol in the submerged culture. The reaction conditions were systematically optimized for the reducing agent A. alternata EBK-62, which showed high stereospecificity and good conversion for the reduction. The preparative scale study was carried out in a 2L bioreactor and a total of 4.9g of S-NE in optically pure form (>99% enantiomeric excess) was produced in 48h. Chirality 28:669-673, 2016. © 2016 Wiley Periodicals, Inc.

Secondary Metabolites Isolated from the Strain Aspergillus terreus

Fungi produce a wide variety of secondary metabolites that are of human interest, among them antibiotics, cyclosporines, mevinic acids, alkaloids, and antifungal compounds [1]. In this research we isolated three natural compounds from a strain of Aspergillus terreus collected from “paramo de Guasca (Cundinamarca, Colombia).” The A. terreus was fermented in PGS and Saboraud media at room temperature for 12 days. The biomass obtained (36.5 g) was extracted by the Soxhlet method (hexane, CH2Cl2, EtOAc, and MeOH). The MeOH extract was chromatographed on silica gel 60 G and eluted in a mixture of EtOAc–MeOH 1:1. The mannitol (1) (180 mg) was isolated. The Sabouraud broth fermentation medium (20 L) was treated with hexane, CH2Cl2, and EtOAc. The CH2Cl2 extract was chromatographed on silica gel CC, and from the hexane– EtOAc 1:1 fraction, butyrolactone I (2) (40 mg) and R(–)-6-hydroxymellein (3) (8 mg) were isolated. Mannitol (1) is a white solid crystal with needle-shaped form (MeOH, H2O), mp 167.5 C. The spectral data of 1 agreed with those published earlier in the literature for mannitol [2]. According to the literature, mannitol has been isolated from the mycelium of Aspergillus species and other fungus. These compounds are believed to contribute to osmotic stabilization of cell hyphae and to form endogenous reserves that are metabolized continuously [3]. Butyrolactone I (2). White solid crystal with needle-shaped form (EtOAc, MeOH, and H2O), mp 92 C. UV spectrum (MeOH, max, nm): 203 and 307. PMR spectrum (400 MHz, DMSO-d6, , ppm, J/Hz): 7.52 (2H, d, J = 8.8, H-3, 5), 6.87 (2H, d, J = 8.8, H-2, 6), 6.53 (1H, d, J = 8.0, H-16), 6.48 (1H, dd, J = 8.0, 2.0, H-15), 6.40 (1H, d, J = 2.0, H-19), 5.02 (1H, t, J = 6.4, H-21), 3.74 (3H, s, H-12), 3.37 (2H, s, H-13), 3.00 (2H, d, J = 6.4, H-20), 1.63 (3H, s, H-23), 1.54 (3H, s, H-24). 13C NMR spectrum (100 MHz, D2O, , ppm): 169.59 (C-11), 168.70 (C-9), 156.79 (C-1), 153.09 (C-17), 136.88 (C-8), 133.96 (C-22), 131.59 (C-19), 129.26 (C-5), 129.26 (C-3), 128.97 (C-15), 127.51 (C-7), 124.36 (C-14), 126.25 (C-18), 121.74 (C-21), 121.38 (C-4), 115.75 (C-2), 115.75 (C-6), 114.84 (C-16), 85.63 (C-10), 53.21 (C-12), 38.32 (C-13), 28.85 (C-20), 25.43 (C-23), 17.48 (C-24).

Total Synthesis of a Mevinic Acid Analog

AbstractTotal synthesis of mevinic acid analog 1 has been achieved efficiently starting from chiral 2,3‐O‐isopropylidene‐D‐glyceraldehyde (2). The synthesis involves Mitsunobu reaction and Evans' intramolecular oxa‐Michael syn‐addition reactions as key steps.

ChemInform Abstract: Enantioselective Synthesis of the Lactone Moiety of the Mevinic Acids Using D-Xylose as a Chiral Precursor.

Homologation of the lactone 14 easily obtained from D-xylose afforded the pyranone 15, a key chiral synthon for the lactone portion of mevinic acids.

ChemInform Abstract: A Remarkable Short Synthesis of Optically Active Mevinic Acid Analogues by Biocatalytic Lactonization of syn-3,5-Dihydroxy Esters.

ChemInform Abstract: A Remarkable Short Synthesis of Optically Active Mevinic Acid Analogues by Biocatalytic Lactonization of syn-3,5-Dihydroxy Esters.

ChemInform Abstract: Asymmetric Synthesis of the Hydronaphthalene Moieties of Mevinic Acids.

Abstract The hydronaphthalene moieties of mevinic acids are synthesized enantioselectively by using the asymmetric intramolecular Diels-Alder reaction catalyzed by a chiral titanium reagent.

ChemInform Abstract: An Expeditious Enantiospecific Synthesis of a Precursor of the Lactonic Portion of Mevinic Acids.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

QSAR & Complex Network Study of the HMGR Inhibitors Structural Diversity

Efficient drugs such as statins or mevinic acids are inhibitors of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGR), an enzyme responsible for the double reduction of 3-hydroxy-3-methyl-glutaryl coenzyme A. These compounds promoted the synthesis and evaluation of new inhibitors for HMGR, named HMGRIs. The high number of possible candidates creates the necessity of Quantitative Structure-Activity Relationship models in order to guide the HMGRI (3-hydroxy-3-methyl-glutaryl coenzyme A inhibitor) synthesis. In this work, we revised different computational studies for a very large and heterogeneous series of HMGRIs. First, we revised QSAR studies with conceptual parameters such as flexibility of rotation, probability of availability, etc; we then used the method of regression analysis; and QSAR studies in order to understand the essential structural requirement for binding with receptor. Next, we reviewed 3D QSAR, CoMFA and CoMSIA with different compounds to find out the structural requirements for 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) inhibitory activity.

QSAR and complex network study of the chiral HMGR inhibitor structural diversity

Efficient drugs such as statins or mevinic acids are inhibitors of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGR), an enzyme responsible for the double reduction of 3-hydroxy-3-methyl-glutaryl coenzyme A into mevalonic acid. These compounds promoted the synthesis and evaluation of new inhibitors for HMGR, named HMGRIs. The high number of possible candidates creates the necessity of Quantitative Structure–Activity Relationship models in order to guide the HMGRI synthesis. There are two main problems of the reported QSAR models: the homogeneous series of the compounds and the chirality of many candidates. In this work, we propose for the first time a QSAR model for a very large and heterogeneous series of HMGRIs. The model is based on the Topological Indices (TIs) of molecular structures. Using the predictions of this model as input, we construct the first complex network that describes the drug–drug similarity relationships for more than 1600 experimentally non-explored chiral HMGRIs isomers. We also presented a reduced version of this network (Giant Component) that contains the most representative set of chiral HMGRI candidates. The work suggests a new mixed application in the QSAR study of relevant aspects of structural diversity by using chiral/non-chiral TIs, combined with complex networks.

Stereoselective Synthesis of a Mevinic Acid Analogue

An efficient and versatile synthetic method for the stereoselective synthesis of a mevinic acid analogue is described. This approach uses a combination of a Cosford protocol with a catecholborane-mediated stereoselective reduction of acyclic P-hydroxy ketones to syn-1,3-diols, as key steps.

Metabolites from Endophytes of the Medicinal Plant Erythrina crista-galli

Erythrina crista-galli (Fabaceae) is used in Argentinean ethnopharmacology as anti-inflammatory medication, narcotic, desinfectant, and for the treatment of wounds. The common name of the tree is "ceibo" or coral tree. The dominating endophytes in E. crista-galli all belong to the genus Phomopsis as identified by microscopic features and the analysis of their ITS sequences. To investigate a possible contribution of Phomopsis spp. to the metabolites found in the plant, twelve different isolates were cultivated in different media. Besides several new metabolites a number of known compounds were detected: mellein, nectriapyrone, 4-hydroxymellein, scytalone, tyrosol, clavatol, mevinic acid, and mevalonolactone.

Biocatalytic synthesis of S(−)-1-(1′-naphthyl) ethanol by a novel isolate of Candida viswanathii

A new yeast strain Candida viswanathii MTCC 5158, isolated from soil, is capable of carrying out the enantioselective reduction of 1-acetonaphthone to S(−)-1-(1′-naphthyl) ethanol which is an important synthetic intermediate of mevinic acid analogue, (potential inhibitor of 3-hydroxy methyl glutaryl coenzyme A reductase). Studies on the culture conditions and catalytic performance of this microorganism showed that the carbonyl reductase occurs constitutively in C. viswanathii and its production is enhanced by feeding acetonaphthone (2 mM) during the early period of cultivation. Mannitol (1%, w/v) was found to be beneficial both for growth and enzyme production. Supplementation of the media with yeast extract (0.5%) and Ca 2+ (2 mM) enhanced the enzyme production. The optimal temperature and pH for the growth and enzyme production were 25 °C and 10, respectively. The organism produced enantiopure (S)-alcohol with good conversion (>97%) and almost absolute enantioselectivity (ee >99%). Parameters of the bioreduction reaction were optimized and the optimal temperature and pH for the reduction were found to be 25 °C and 8, respectively. The optimized substrate as well as the resting cell concentration was 2 and 200 g/l, respectively. The preparative scale reaction using resting cells of C. viswanathii yielded (S)-alcohol with 97% conversion and >99% ee.

Application of Sulfur Ylide Mediated Epoxidations in the Asymmetric Synthesis of β‐Hydroxy‐δ‐lactones. Synthesis of a Mevinic Acid Analogue (II) and (+)‐Prelactone B (I).

Application of Sulfur Ylide Mediated Epoxidations in the Asymmetric Synthesis of β‐Hydroxy‐δ‐lactones. Synthesis of a Mevinic Acid Analogue (II) and (+)‐Prelactone B (I).

Application of sulfur ylide mediated epoxidations in the asymmetric synthesis of β-hydroxy-δ-lactones. Synthesis of a mevinic acid analogue and (+)-prelactone B

Catalytic and stoichiometric asymmetric sulfur ylide reactions were employed to prepare alkyl–aryl epoxide intermediates in a convergent manner. These epoxides were utilized in efficient syntheses of the mevinic acid analogue 1 and prelactone B.

α-Heterosubstituted Aldehydes in Organic Synthesis. Enantioselective Approaches to New Analogues of Mevinic Acids.

Various aldol approaches towards the asymmetric synthesis of the lactone moiety of HMG-CoA-reductase inhibitors are described. Auxiliary controlled as well as catalytic aldol reactions resulted only in modest to low selectivities, whereas 1,2-additions to readily available highly enantiomerically enriched α-heterosubstituted aldehydes yielded δ-hydroxy-β-ketoesters with a high degree of diastereocontrol and in good chemical yields. The novel mevinic acid analogues could then be obtained by syn -reduction of the addition products.

α-Heterosubstituted Aldehydes in Organic Synthesis. Enantioselective Approaches to New Analogues of Mevinic Acids

Various aldol approaches towards the asymmetric synthesis of the lactone moiety of HMG-CoA-reductase inhibitors are described. Auxiliary controlled as well as catalytic aldol reactions resulted only in modest to low selectivities, whereas 1,2-additions to readily available highly enantiomerically enriched α-heterosubstituted aldehydes yielded δ-hydroxy-β-ketoesters with a high degree of diastereocontrol and in good chemical yields. The novel mevinic acid analogues could then be obtained bysyn-reduction of the addition products.

ChemInform Abstract: Enantiomerically Pure Decalinic Structures from Carbohydrates Using Intramolecular Diels-Alder and Ferrier Carbocyclization.

The synthesis of enantiomerically pure decalinic structures, advanced intermediates for the synthesis of the hexahydronaphtalen part of mevinic acids, is described. The key steps are the intramolec...

Enantiomerically pure decalinic structures from carbohydrates using intramolecular Diels-Alder and Ferrier carbocyclization

The synthesis of enantiomerically pure decalinic structures, advanced intermediates for the synthesis of the hexahydronaphtalen part of mevinic acids, is described. The key steps are the intramolecular Diels-Alder cycloaddition of a suitably substituted sugar enone obtained via the Ferrier rearrangement of tri-O-acetyl-D-glucal with the appropriate alcohol representing the diene part of the system. Chemical manipulation of the resulting, diastereomerically pure, cycloadduct led to a 5,6-unsaturated carbohydrate which was submitted to the Ferrier carbocylization. This reaction proved difficult likely because of the embedding of the aglycon in a cycle, the hydration product of the double bond being the main product. This compound was in turn transformed into the decalinic structures by treatment in basic medium. The inverse strategy, Ferrier carbocyclization followed by IMDA of an enone and a diene linked via an ester bond was unsuccessful.Key words: Intramolecular Diels-Alder reaction, enantiomerically pure decalin, Ferrier carbocyclization, carbohydrates.