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Enzymatic Synthesis of Novel and Bioactive Compounds

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: closed (20 February 2023) | Viewed by 11650

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Prof. Dr. Te-Sheng Chang

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Guest Editor

Department of Biological Sciences and Technology, National University of Tainan, Tainan, Taiwan
Interests: biotransformation and bioactivity-guided purification of novel and bioactive molecules from plants, fungus, or herbs; biotransformation of flavonoids or triterpenoids; enzymatic synthesis of novel flavonoids or triterpenoids

Special Issue Information

Dear Colleagues,

Finding a new compound is an important step in the development of new drugs. In addition to synthetic and natural sources, enzymatic synthesis or biotransformation is an alternative way to obtain new compounds. Precursor compounds are biotransformed by enzymes to form new compounds. Furthermore, some biotransformation can modify the functional groups of precursors to improve the bioactivities of the precursor compounds. Accordingly, the special issue focuses on the researches reporting identifying new compounds from enzymatic synthesis or biotransformation. Researches about on the finding enzymes from microorganisms and the applications of the enzymes on productions of new compounds are welcome in this issue. Manuscripts describing productions of new bioactive flavonoids or terpenoids by known enzymatic biotransformation are also suitable for this issue.

Prof. Dr. Te-Sheng Chang
Guest Editor

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Keywords

biotransformation
enzyme
synthesis
flavonoids
terpenoids

Published Papers (6 papers)

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Research

16 pages, 1981 KiB

Open AccessArticle

Enhanced Bioactivity of Tailor-Made Glycolipid Enriched Manuka Honey

by André Delavault, Ahmed E. Zoheir, Delphine Muller, Rebecca Hollenbach, Kersten S. Rabe, Katrin Ochsenreither, Jens Rudat and Christoph Syldatk

Int. J. Mol. Sci. 2022, 23(19), 12031; https://doi.org/10.3390/ijms231912031 - 10 Oct 2022

Viewed by 1949

Abstract

Glycolipids can be synthetized in deep eutectic solvents (DESs) as they possess low water content allowing a reversed lipase activity and thus enables ester formation. Based on this principle, honey can also serve as a media for glycolipid synthesis. Indeed, this supersaturated sugar solution is comparable in terms of physicochemical properties to the sugar-based DESs. Honey-based products being commercially available for therapeutic applications, it appears interesting to enhance its bioactivity. In the current work, we investigate if enriching medical grade honey with in situ enzymatically-synthetized glycolipids can improve the antimicrobial property of the mixture. The tested mixtures are composed of Manuka honey that is enriched with octanoate, decanoate, laurate, and myristate sugar esters, respectively dubbed GOH, GDH, GLH, and GMH. To characterize the bioactivity of those mixtures, first a qualitative screening using an agar well diffusion assay has been performed with methicillin-resistant Staphylococcus aureus, Bacillus subtilis, Candida bombicola, Escherichia coli, and Pseudomonas putida which confirmed considerably enhanced susceptibility of these micro-organisms to the different glycolipid enriched honey mixtures. Then, a designed biosensor E. coli strain that displays a stress reporter system consisting of three stress-specific inducible, red, green, and blue fluorescent proteins which respectively translate to physiological stress, genotoxicity, and cytotoxicity was used. Bioactivity was, therefore, characterized, and a six-fold enhancement of the physiological stress that was caused by GOH compared to regular Manuka honey at a 1.6% (v/v) concentration was observed. An antibacterial agar well diffusion assay with E. coli was performed as well and demonstrated an improved inhibitory potential with GOH upon 20% (v/v) concentration. Full article

(This article belongs to the Special Issue Enzymatic Synthesis of Novel and Bioactive Compounds)

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29 pages, 5552 KiB

Open AccessArticle

Chemoenzymatic Synthesis of Optically Active Ethereal Analog of iso-Moramide—A Novel Potentially Powerful Analgesic †

by Paweł Borowiecki

Int. J. Mol. Sci. 2022, 23(19), 11803; https://doi.org/10.3390/ijms231911803 - 5 Oct 2022

Cited by 2 | Viewed by 2152

Abstract

To develop potent and safer analgesics, we designed and synthesized a novel enantiomerically enriched ethereal analog of (R)-iso-moramide, namely 2-[(2R)-2-(morpholin-4-yl)propoxy]-2,2-diphenyl-1-(pyrrolidin-1-yl)ethan-1-one. The titled active agent can potentially serve as a powerful synthetic opiate with an improved affinity and selectivity toward opioid receptors (ORs). This hypothesis was postulated based on docking studies regarding the respective complexes between the designed ligand and µ-OR, δ-OR, and κ-OR. The key step of the elaborated asymmetric synthesis of novel analog involves lipase-catalyzed kinetic resolution of racemic 1-(morpholin-4-yl)propan-2-ol, which was accomplished on a 10 g scale via an enantioselective transesterification employing vinyl acetate as an irreversible acyl donor in tert-butyl methyl ether (MTBE) as the co-solvent. Next, the obtained homochiral (S)-(+)-morpholino-alcohol (>99% ee) was functionalized into corresponding chloro-derivative using thionyl chloride (SOCl₂) or the Appel reaction conditions. Further transformation with N-diphenylacetyl-1-pyrrolidine under phase-transfer catalysis (PTC) conditions using O₂-saturated DMSO/NaOH mixture as an oxidant furnished the desired levorotatory isomer of the title product isolated in 26% total yield after three steps, and with 89% ee. The absolute configuration of the key-intermediate of (R)-(–)-iso-moramide was determined using a modified form of Mosher’s methodology. The preparation of the optically active dextrorotatory isomer of the titled product (87% ee) was carried out essentially by the same route, utilizing (R)-(–)-1-(morpholin-4-yl)propan-2-ol (98% ee) as a key intermediate. The spectroscopic characterization of the ethereal analog of iso-moramide and the enantioselective retention relationship of its enantiomers using HPLC on the cellulose-based chiral stationary phase were performed. Moreover, as a proof-of-principle, single-crystal X-ray diffraction (XRD) analysis of the synthesized 2-[(2R)-2-(morpholin-4-yl)propoxy]-2,2-diphenyl-1-(pyrrolidin-1-yl)ethan-1-one is reported. Full article

(This article belongs to the Special Issue Enzymatic Synthesis of Novel and Bioactive Compounds)

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14 pages, 1771 KiB

Open AccessArticle

Hydroxylation of Progesterone and Its Derivatives by the Entomopathogenic Strain Isaria farinosa KCh KW1.1

by Ewa Kozłowska, Jordan Sycz and Tomasz Janeczko

Int. J. Mol. Sci. 2022, 23(13), 7015; https://doi.org/10.3390/ijms23137015 - 24 Jun 2022

Cited by 2 | Viewed by 1363

Abstract

Progesterone biotransformation is worth studying because of the high industrial value of its derivatives. This study investigated the catalytic ability of the entomopathogenic filamentous fungus strain Isaria farinosa KCh KW1.1 to transform progesterone derivatives: 11α-hydroxyprogesterone, 17α-hydroxyprogesterone, 16α,17α-epoxyprogesterone and pregnenolone. In the culture of Isaria farinosa KCh KW1.1, 11α-hydroxyprogesterone was effectively transformed into only one product: 6β,11α-dihydroxyprogesterone. Transformation of 17α-hydroxyprogesterone gave three hydroxy derivatives: 6β,17α-dihydroxyprogesterone, 12β,17α-dihydroxyprogesterone and 6β,12β,17α-trihydroxyprogesterone. Two products: 6β-hydroxy-16α,17α-epoxyprogesterone and 6β,11α-dihydroxy-16α,17α-epoxyprogesterone, were obtained from the 16α,17α-epoxyprogesterone transformation. We isolated two compounds from the biotransformation medium with pregnenolone: 11α-hydroxy-7-oxopregnenolone and 5α,6α-epoxy-3β,11α-dihydroxypregnan-7,20-dione. In this study, we observed only mono- and dihydroxy derivatives of the tested substrates, and the number of obtained products for each biotransformation did not exceed three. Full article

(This article belongs to the Special Issue Enzymatic Synthesis of Novel and Bioactive Compounds)

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23 pages, 3080 KiB

Open AccessArticle

Glycosylation of Methylflavonoids in the Cultures of Entomopathogenic Filamentous Fungi as a Tool for Obtaining New Biologically Active Compounds

by Agnieszka Krawczyk-Łebek, Monika Dymarska, Tomasz Janeczko and Edyta Kostrzewa-Susłow

Int. J. Mol. Sci. 2022, 23(10), 5558; https://doi.org/10.3390/ijms23105558 - 16 May 2022

Cited by 13 | Viewed by 1632

Abstract

Flavonoid compounds are secondary plant metabolites with numerous biological activities; they naturally occur mainly in the form of glycosides. The glucosyl moiety attached to the flavonoid core makes them more stable and water-soluble. The methyl derivatives of flavonoids also show increased stability and intestinal absorption. Our study showed that such flavonoids can be obtained by combined chemical and biotechnological methods with entomopathogenic filamentous fungi as glycosylation biocatalysts. In the current paper, two flavonoids, i.e., 2′-hydroxy-4-methylchalcone and 4′-methylflavone, have been synthesized and biotransformed in the cultures of two strains of entomopathogenic filamentous fungi Isaria fumosorosea KCH J2 and Beauveria bassiana KCH J1.5. Biotransformation of 2′-hydroxy-4-methylchalcone resulted in the formation of two dihydrochalcone glucopyranoside derivatives in the culture of I. fumosorosea KCH J2 and chalcone glucopyranoside derivative in the case of B. bassiana KCH J1.5. 4′-Methylflavone was transformed in the culture of I. fumosorosea KCH J2 into four products, i.e., 4′-hydroxymethylflavone, flavone 4′-methylene-O-β-d-(4″-O-methyl)-glucopyranoside, flavone 4′-carboxylic acid, and 4′-methylflavone 3-O-β-d-(4″-O-methyl)-glucopyranoside. 4′-Methylflavone was not efficiently biotransformed in the culture of B. bassiana KCH J1.5. The computer-aided simulations based on the chemical structures of the obtained compounds showed their improved physicochemical properties and antimicrobial, anticarcinogenic, hepatoprotective, and cardioprotective potential. Full article

(This article belongs to the Special Issue Enzymatic Synthesis of Novel and Bioactive Compounds)

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16 pages, 2448 KiB

Open AccessArticle

4′-Methylflavanone Glycosides Obtained Using Biotransformation in the Entomopathogenic Filamentous Fungi Cultures as Potential Anticarcinogenic, Antimicrobial, and Hepatoprotective Agents

by Agnieszka Krawczyk-Łebek, Monika Dymarska, Tomasz Janeczko and Edyta Kostrzewa-Susłow

Int. J. Mol. Sci. 2022, 23(10), 5373; https://doi.org/10.3390/ijms23105373 - 11 May 2022

Cited by 6 | Viewed by 1341

Abstract

Flavonoid compounds exhibit numerous biological activities and significantly impact human health. The presence of methyl or glucosyl moieties attached to the flavonoid core remarkably modifies their physicochemical properties and improves intestinal absorption. Combined chemical and biotechnological methods can be applied to obtain such derivatives. In the presented study, 4′-methylflavanone was synthesized and biotransformed in the cultures of three strains of entomopathogenic filamentous fungi, i.e., Isaria fumosorosea KCH J2, Beauveria bassiana KCH J1.5, and Isaria farinosa KCH J2.1. The microbial transformation products in the culture of I. fumosorosea KCH J2, flavanone 4′-methylene-O-β-D-(4″-O-methyl)-glucopyranoside, 2-phenyl-(4′-hydroxymethyl)-4-hydroxychromane, and flavanone 4′-carboxylic acid were obtained. Biotransformation of 4′-methylflavanone in the culture of B. bassiana KCH J1.5 resulted in the formation of one main product, i.e., flavanone 4′-methylene-O-β-D-(4″-O-methyl)-glucopyranoside. In the case of I. farinosa KCH J2.6 as a biocatalyst, three products, i.e., flavanone 4′-methylene-O-β-D-(4″-O-methyl)-glucopyranoside, flavanone 4′-carboxylic acid, and 4′-hydroxymethylflavanone 4-O-β-D-(4″-O-methyl)-glucopyranoside were obtained. The Swiss-ADME online simulations confirmed the increase in water solubility of 4′-methylflavanone glycosides and analyses performed using the Way2Drug Pass Online prediction tool indicated that flavanone 4′-methylene-O-β-D-(4″-O-methyl)-glucopyranoside and 4′-hydroxymethylflavanone 4-O-β-D-(4″-O-methyl)-glucopyranoside, which had not been previously reported in the literature, are promising anticarcinogenic, antimicrobial, and hepatoprotective agents. Full article

(This article belongs to the Special Issue Enzymatic Synthesis of Novel and Bioactive Compounds)

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13 pages, 2520 KiB

Open AccessArticle

Microbial Transformation of Yakuchinone A and Cytotoxicity Evaluation of Its Metabolites

by Chen Huo, Fubo Han, Yina Xiao, Hyun Jung Kim and Ik-Soo Lee

Int. J. Mol. Sci. 2022, 23(7), 3992; https://doi.org/10.3390/ijms23073992 - 3 Apr 2022

Cited by 2 | Viewed by 2192

Abstract

Yakuchinone A (1) is a bioactive diarylheptanoid isolated from the dried fruits of Alpinia oxyphylla. Microbial transformation has been recognized as an efficient method to produce new biologically active derivatives from natural products. In the present study, microbial transformation of yakuchinone A was performed with the fungus Mucor hiemalis KCTC 26779, which led to the isolation of nine new metabolites (2, 3a, 3b, and 4–9). Their structures were elucidated as (3S)-oxyphyllacinol (2), (3S,7R)- and (3S,7S)-7-hydroxyoxyphyllacinol (3a and 3b), (3S)-oxyphyllacinol-4′-O-β-d-glucopyranoside (4), (3S)-4″-hydroxyoxyphyllacinol (5), (3S)-3″-hydroxyoxyphyllacinol (6), (3S)-2″-hydroxyoxyphyllacinol (7), (3S)-2″-hydroxyoxyphyllacinol-2″-O-β-d-glucopyranoside (8), and (3S)-oxyphyllacinol-3-O-β-d-glucopyranoside (9) based on the comprehensive spectroscopic analyses and the application of modified Mosher’s method. All compounds were evaluated for their cytotoxic activities against melanoma, as well as breast, lung, and colorectal cancer cell lines. Compound 9, which was O-glucosylated on the diarylheptanoid alkyl chain, exhibited the most selective cytotoxic activities against melanoma cell lines with the IC₅₀ values ranging from 6.09 to 9.74 μM, indicating that it might be considered as a possible anti-cancer lead compound. Full article

(This article belongs to the Special Issue Enzymatic Synthesis of Novel and Bioactive Compounds)

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