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Biotransformation of Hydroxychalcones As a Method of Obtaining Novel and Unpredictable Products Using Whole Cells of Bacteria

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Biotransformation of Hydroxychalcones As a Method of Obtaining Novel and Unpredictable Products Using Whole Cells of Bacteria catalysts Article Biotransformation of Hydroxychalcones as a Method of Obtaining Novel and Unpredictable Products Using Whole Cells of Bacteria Joanna Kozłowska 1,* , Bartłomiej Potaniec 1,2 and Mirosław Anioł 1 1 Department of Chemistry, Faculty of Biotechnology and Food Science, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland; [email protected] (B.P.); [email protected] (M.A.) 2 Łukasiewicz Research Network—PORT Polish Center for Technology Development, Stabłowicka 147, 54-066 Wrocław, Poland * Correspondence: [email protected] Received: 27 September 2020; Accepted: 8 October 2020; Published: 12 October 2020 Abstract: The aim of our study was the evaluation of the biotransformation capacity of hydroxychalcones—2-hydroxy-40-methylchalcone (1) and 4-hydroxy-40-methylchalcone (4) using two strains of aerobic bacteria. The microbial reduction of the α,β-unsaturated bond of 2-hydroxy-40- methylchalcone (1) in Gordonia sp. DSM 44456 and Rhodococcus sp. DSM 364 cultures resulted in isolation the 2-hydroxy-40-methyldihydrochalcone (2) as a main product with yields of up to 35%. Additionally, both bacterial strains transformed compound 1 to the second, unexpected product of reduction and simultaneous hydroxylation at C-4 position—2,4-dihydroxy-40-methyldihydrochalcone (3) (isolated yields 12.7–16.4%). During biotransformation of 4-hydroxy-40-methylchalcone (4) we observed the formation of three products: reduction of C=C bond—4-hydroxy-40-methyldihydrochalcone (5), reduction of C=C bond and carbonyl group—3-(4-hydroxyphenyl)-1-(4-methylphenyl)propan-1-ol (6) and also unpredictable 3-(4-hydroxyphenyl)-1,5-di-(4-methylphenyl)pentane-1,5-dione (7). As far as our knowledge is concerned, compounds 3, 6 and 7 have never been described in the scientific literature. Keywords: biotransformation; biologically active compounds; chalcone; dihydrochalcone 1. Introduction Chalcones are α,β-unsaturated ketones belonging to polyphenolic compounds called flavonoids. Their chemical structure is characterized by an open flavanone skeleton consisting of two aromatic rings joined with a three-carbon linker containing a C=C bond (Figure1). Chalcones are bioactive compounds occurring in nature as plant secondary metabolites, which are a protective barrier against damage caused by microorganisms, insects or animals. Diversity of their structure results in a broad spectrum of activities e.g., anticancer [1], antibacterial [2], antifungal, antioxidant, anti-inflammatory and antimalarial [3–5]. Hydroxychalcones have attracted an unflagging interest in the scientific community due to an increased tendency to hydrogen bond between the -OH group and amino acids present in active sites of enzymes. Furthermore, non-polar effects among the aromatic rings A or B in chalcone and benzyl groups, of e.g., Tyr or Trp, enhance binding of hydroxychalcones with a peripheral anionic site of human acetylcholinesterase. These results showed potential of 20-hydroxychalcone derivatives as inhibitors of Alzheimer’s disease [6]. Catalysts 2020, 10, 1167; doi:10.3390/catal10101167 www.mdpi.com/journal/catalysts CatalystsCatalysts2020 2020, 10,, 10 1167, x FOR PEER REVIEW 2 of2 11of 11 Catalysts 2020, 10, x FOR PEER REVIEW 2 of 11 3' 2' 3' 4' 3' 3 8 2' 4' 4' 3' 2' 2 3 4 7 8 O 5' 2 4' 2'1' α 2 4 7 O 6' 5' 5' 5 6 2 3 1' α 1 6' 5' 6' β 6 5 6 5 3 O 1 6' β 6 5 O O O Chalcone Flavanone Chalcone Flavanone FigureFigure 1. Structure1. Structure of of chalcone chalcone and and flavanone. flavanone. Figure 1. Structure of chalcone and flavanone. Moreover,Moreover, plant plant extracts extracts are are rich rich in chalcones in chalcones with with reduced reduced double double carbon–carbon carbon–carbon bond bond known known as Moreover, plant extracts are rich in chalcones with reduced double carbon–carbon bond known dihydrochalcones.as dihydrochalcones. One of the mostOne popular of examplesthe most is phloretin popular (20,40,6 0-trihydroxydihydrochalcone)examples is phloretin as dihydrochalcones. One of the most popular examples is phloretin and(2′,4 its′,6′‐trihydroxydihydrochalcone) glycosides forms, phlorizin and (phloretinits glycosides 20-β- Dforms,-glucopyranoside) phlorizin (phloretin and phloretin 2′‐β‐D‐ (2′,4′,6′‐trihydroxydihydrochalcone) and its glycosides forms, phlorizin (phloretin 2′‐β‐D‐ 30,5glucopyranoside)0-di-C-glucoside and (Figure phloretin2) occurring 3′,5′‐di‐ inC‐glucoside apples, apple-derived (Figure 2) occurring products in andapples, kumquats apple‐derived [ 7]. Hydrogenationglucopyranoside)products and ofkumquats the andα ,βphloretin-unsaturated [7]. Hydrogenation 3′,5′‐ bonddi‐C‐glucoside contributes of the α ,β‐(Figure tounsaturated changing 2) occurring the bond flavor contributes in valuesapples, of toapple compounds. changing‐derived the Forproductsflavor instance, values and the kumquats presenceof compounds. [7]. of neohesperidin Hydrogenation For instance, in of citrus the the α fruits ,β‐presenceunsaturated is characterized of neohesperidinbond contributes by a bitter in taste. tocitrus changing However, fruits the is neohesperidinflavorcharacterized values dihydrochalcone ofby compounds.a bitter taste. is For a non-cariogenic,However, instance, neohesperidinthe intensive presence and ofdihydrochalcone hypocaloric neohesperidin sweetener isin a citrusnon permitted‐ cariogenic,fruits by is thecharacterizedintensive EU and theand FDA byhypocaloric a as bitter a food sweetenertaste. additive However, [permitted8,9]. neohesperidin by the EU and dihydrochalcone the FDA as a food is additivea non‐cariogenic, [8,9]. intensive and hypocaloric sweetener permitted by the EU and the FDA as a food additive [8,9]. HOHOHO HOHOHO HOHOHO OHHOHOHO OH HO O OH O HO HO O O O OH O HO OH O O OH Phloretin Phlorizin Phloretin Phlorizin HO HOHO OH OH OH OH O OH OH O OH O O OH HO O O O O OH HOHOHO HO HO O O O OH HO HOHOHO HO O OH HO HO O O O H3C HO OH H C O OH O H3O OH O OH HO OH O HO HO OH O HO Phloretin 3,5‐di‐C‐glucoside HO Neohesperidin Phloretin 3,5‐di‐C‐glucoside Neohesperidin HO O HO O HO O HO O O OH O O OH OH O OH OH OH Daidzein Genistein Daidzein Genistein OH HOHO OH HO OH OH OH HOHO OH HO OH OH O O O O Isoliquiritigenin Butein Isoliquiritigenin Butein Figure 2. Structures of flavonoids occurring in different plants. Figure 2. Structures of flavonoids occurring in different plants. Chemical hydrogenationFigure 2. of Structures a double of bond flavonoids usually occurring requires in reagents different containing plants. transition metals, e.g., rutheniumChemical or hydrogenation iridium complex of [a10 double,11], which bond are usually relatively requires expensive. reagents Biotransformation containing transition is an alternativemetals,Chemical e.g., method ruthenium hydrogenation to obtain or iridium chalcone of a complex double derivatives [10,11],bond without usually which harmful are requires relatively compounds. reagents expensive. containing Biocatalysis Biotransformation transition is often describedmetals,is an alternative e.g., as a ruthenium part ofmethod green or iridium chemistryto obtain complex chalcone because [10,11], it derivatives is generally which withoutare conducted relatively harmful under expensive. compounds. mild and Biotransformation safe Biocatalysis conditions is isoften an alternative described method as a part to of obtain green chalcone chemistry derivatives because it without is generally harmful conducted compounds. under Biocatalysis mild and safe is often described as a part of green chemistry because it is generally conducted under mild and safe Catalysts 2020, 10, 1167 3 of 11 (room temperature and ambient pressure), avoids the use of toxic reagents and is usually performed in a water environment [12]. Furthermore, using whole cells of bacteria, yeast or fungi, has led to obtaining products in which classical synthesis would be troublesome or difficult to carry out. Current knowledge about flavonoid biotransformation presents various possibilities of an enzymatic apparatus of microorganisms, which are able to catalyze different reactions e.g., hydroxylation, dehydroxylation, O-methylation, O-demethylation, glycosylation, deglycosylation, hydrogenation, dehydrogenation, C ring cleavage, cyclization and reduction [13]. Microbial transformation leading to hydrogenation of the α,β-unsaturated bond in chalcones is popular among bacteria, filamentous fungi and yeast whole cell cultures. So far, the best-known enzymes responsible for the reduction of the C=C bond belongs to the Old Yellow Enzyme (OYE) family. Ene-reductases are flavin-dependent oxidoreductases that require NAD(P)H as a cofactor to their activity [14–16]. The OYE substrates include activated alkenes with an electron withdrawing groups (EWGs) such as aldehyde, ketone, nitro, carboxylic acid and other functional moieties [17]. The example of high bioconversion of 20-hydroxychalcone is a microbial transformation in Yarrowia lipolytica and Saccharomyces cerevisiae cultures, which led to receiving the corresponding dihydrochalcone as a product [18]. It is worth mentioning that the same biocatalysis conducted by cyanobacteria Anabaena laxa lasted about five times longer with relatively low efficiency [19]. Interestingly, for the Gram-negative bacterium Stenotrophomonas maltophilia, 12-day biotransformation of 20-hydroxy-3-methoxychalcone led to 20-hydroxy-3-methoxydihydrochalcone with yield of 36.1% [20]. The capacity of microorganisms for hydroxylation is based on the activity of cytochrome P450 monooxygenases.
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