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Laccase-mediated synthesis of bioactive natural products and their analogues.

ABSTRACT: Laccases are a class of multicopper oxidases that catalyse the one-electron oxidation of four equivalents of a reducing substrate, with the concomitant four-electron reduction of dioxygen to water. Typically, they catalyse many anabolic reactions, in which mostly phenolic metabolites were subjected to oxidative coupling. Alternatively, laccases catalyse the degradation or modification of biopolymers like lignin in catabolic processes. In recent years, laccases have proved valuable and green biocatalysts for synthesising compounds with therapeutic value, including antitumor, antibiotic, antimicrobial, and antioxidant agents. Further up to date applications include oxidative depolymerisation of lignin to gain new biomaterials and bioremediation processes of industrial waste. This review summarizes selected examples from the last decade's literature about the laccase-mediated synthesis of biologically active natural products and their analogues; these will include lignans and neolignans, dimeric stilbenoids, biflavonoids, biaryls and other compounds of potential interest for the pharmaceutical industry. In addition, a short section about applications of laccases in natural polymer modification has been included.

SUBMITTER: Cardullo N

PROVIDER: S-EPMC9175115 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Laccase-mediated synthesis of bioactive natural products and their analogues.

Cardullo Nunzio N Muccilli Vera V Tringali Corrado C

RSC chemical biology 20220418 6

Laccases are a class of multicopper oxidases that catalyse the one-electron oxidation of four equivalents of a reducing substrate, with the concomitant four-electron reduction of dioxygen to water. Typically, they catalyse many anabolic reactions, in which mostly phenolic metabolites were subjected to oxidative coupling. Alternatively, laccases catalyse the degradation or modification of biopolymers like lignin in catabolic processes. In recent years, laccases have proved valuable and green bioc ...[more]

PMID: 35755186

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Project description:Full details of the development of a direct coupling of catharanthine with vindoline to provide vinblastine are described along with key mechanistic and labeling studies. Following an Fe(III)-promoted coupling reaction initiated by generation of a presumed catharanthine radical cation that undergoes a subsequent oxidative fragmentation and diastereoselective coupling with vindoline, addition of the resulting reaction mixture to an Fe(III)-NaBH(4)/air solution leads to oxidation of the C15'-C20' double bond and reduction of the intermediate iminium ion directly providing vinblastine (40-43%) and leurosidine (20-23%), its naturally occurring C20' alcohol isomer. The yield of coupled products, which exclusively possess the natural C16' stereochemistry, approaches or exceeds 80% and the combined yield of the isomeric C20' alcohols is >60%. Preliminary studies of Fe(III)-NaBH(4)/air oxidation reaction illustrate a generalizable trisubstituted olefin scope, identify alternatives to O(2) trap at the oxidized carbon, provide a unique entry into C20' functionalized vinblastines, and afford initial insights into the observed C20' diastereoselectivity. The first disclosure of the use of exo-catharanthine proceeding through Delta(19',20')-anhydrovinblastine in such coupling reactions is also detailed with identical stereochemical consequences. Incorporating either a catharanthine N-methyl group or a vindoline N-formyl group precludes Fe(III)-promoted coupling, whereas the removal of the potentially key C16 methoxy group of vindoline does not adversely impact the coupling efficiency. Extension of these studies provided a total synthesis of vincristine (2) via N-desmethylvinblastine (36, also a natural product), 16-desmethoxyvinblastine (44) and 4-desacetoxy-16-desmethoxyvinblastine (47) both of which we can now suggest are likely natural products produced by C. roseus, desacetylvinblastine (62) and 4-desacetoxyvinblastine (59), as well as a series of key analogues bearing systematic modifications in the vindoline subunit. Their biological evaluation provided additional insights into the key functionality within the vindoline subunit contributing to the activity and sets the foundation on which further, more deep-seated changes in the structures of 1 and 2 will be explored in future studies.

Project description:Covering: 2000 to up to 2023α,β-Dehydroamino acids (dhAAs) are unsaturated nonproteinogenic amino acids found in a wide array of naturally occurring peptidyl metabolites, predominantly those from bacteria. Other organisms, such as fungi, higher plants and marine invertebrates, have also been found to produce dhAA-containing peptides. The α,β-unsaturation in dhAAs has profound effects on the properties of these molecules. They display significant synthetic flexibility, readily undergoing reactions such as Michael additions, transition-metal-catalysed cross-couplings, and cycloadditions. These residues in peptides/proteins also exhibit great potential in bioorthogonal applications using click chemistry. Peptides containing contiguous dhAA residues have been extensively investigated in the field of foldamers, self-assembling supermolecules that mimic biomacromolecules such as proteins to fold into well-defined conformations. dhAA residues in these peptidyl materials tend to form a 2.05-helix. As a result, stretches of dhAA residues arrange in an extended conformation. In particular, peptidyl foldamers containing β-enamino acid units display interesting conformational, electronic, and supramolecular aggregation properties that can be modulated by light-dependent E-Z isomerization. Among approximately 40 dhAAs found in the natural product inventory, dehydroalanine (Dha) and dehydrobutyrine (Dhb) are the most abundant. Dha is the simplest dehydro-α-amino acid, or α-dhAA, without any geometrical isomers, while its re-arranged isomer, 3-aminoacrylic acid (Aaa or ΔβAla), is the simplest dehydro-β-amino acid, or β-enamino acid, and displays E/Z isomerism. Dhb is the simplest α-dhAA that exhibits E/Z isomerism. The Z-isomer of Dhb (Z-Dhb) is sterically favourable and is present in the majority of naturally occurring peptides containing Dhb residues. Dha and Z-Dhb motifs are commonly found in ribosomally synthesized and post-translationally modified peptides (RiPPs). In the last decade, the formation of Dha and Dhb motifs in RiPPs has been extensively investigated, which will be briefly discussed in this review. The formation of other dhAA residues in natural products (NPs) is, however, less understood. In this review, we will discuss recent advances in the biosynthesis of peptidyl NPs containing unusual dhAA residues and cryptic dhAA residues. The proposed biosynthetic pathways of these natural products will also be discussed.

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Laccase-mediated synthesis of bioactive natural products and their analogues.

Publications

Laccase-mediated synthesis of bioactive natural products and their analogues.

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