Study of Phenoxy Radical Couplings Using the Enzymatic Secretome of

Overview

Journal Front Chem

Specialty Chemistry

Date 2024 Jun 12

PMID 38863677

Authors

Robin Huber

Laurence Marcourt

Fabien Felix

Sebastien Tardy

Emilie Michellod

Leonardo Scapozza

Jean-Luc Wolfender

Katia Gindro

Emerson Ferreira Queiroz

Affiliations

Soon will be listed here.

Abstract

Phenoxy radical coupling reactions are widely used in nature for the synthesis of complex molecules such as lignin. Their use in the laboratory has great potential for the production of high value compounds from the polyphenol family. While the enzymes responsible for the generation of the radicals are well known, the behavior of the latter is still enigmatic and difficult to control in a reaction flask. Previous work in our laboratory using the enzymatic secretome of containing laccases has shown that incubation of stilbenes leads to dimers, while incubation of phenylpropanoids leads to dimers as well as larger coupling products. Building on these previous studies, this paper investigates the role of different structural features in phenoxy radical couplings. We first demonstrate that the presence of an exocyclic conjugated double bond plays a role in the generation of efficient reactions. In addition, we show that the formation of phenylpropanoid trimers and tetramers can proceed via a decarboxylation reaction that regenerates this reactive moiety. Lastly, this study investigates the reactivity of other phenolic compounds: stilbene dimers, a dihydro-stilbene, a 4--methyl-stilbene and a simple phenol with the enzymatic secretome of . The observed efficient dimerization reactions consistently correlate with the presence of a para-phenol conjugated to an exocyclic double bond. The absence of this structural feature leads to variable results, with some compounds showing low conversion or no reaction at all. This research has allowed the development of a controlled method for the synthesis of specific dimers and tetramers of phenylpropanoid derivatives and novel stilbene derivatives, as well as an understanding of features that can promote efficient radical coupling reactions.

References

Nivelle L, Hubert J, Courot E, Borie N, Renault J, Nuzillard J . Cytotoxicity of Labruscol, a New Resveratrol Dimer Produced by Grapevine Cell Suspensions, on Human Skin Melanoma Cancer Cell Line HT-144. Molecules. 2017; 22(11). PMC: 6150286. DOI: 10.3390/molecules22111940. View

Righi D, Huber R, Koval A, Marcourt L, Schnee S, Le Floch A . Generation of Stilbene Antimicrobials against Multiresistant Strains of through Biotransformation by the Enzymatic Secretome of . J Nat Prod. 2020; 83(8):2347-2356. DOI: 10.1021/acs.jnatprod.0c00071. View

Huber R, Marcourt L, Koval A, Schnee S, Righi D, Michellod E . Chemoenzymatic Synthesis of Complex Phenylpropanoid Derivatives by the Secretome and Evaluation of Their Wnt Inhibition Activity. Front Plant Sci. 2022; 12:805610. PMC: 8792767. DOI: 10.3389/fpls.2021.805610. View

Sangha A, Davison B, Standaert R, Davis M, Smith J, Parks J . Chemical factors that control lignin polymerization. J Phys Chem B. 2013; 118(1):164-70. DOI: 10.1021/jp411998t. View

Davin L, Wang H, Crowell A, Bedgar D, Martin D, Sarkanen S . Stereoselective bimolecular phenoxy radical coupling by an auxiliary (dirigent) protein without an active center. Science. 1997; 275(5298):362-6. DOI: 10.1126/science.275.5298.362. View

Park S, Jeong Y, Park S, Kim S, Kim Y, Shin G . Highly Efficient Bioconversion of -Resveratrol to -Viniferin Using Conditioned Medium of Grapevine Callus Suspension Cultures. Int J Mol Sci. 2022; 23(8). PMC: 9026456. DOI: 10.3390/ijms23084403. View

Paniagua C, Bilkova A, Jackson P, Dabravolski S, Riber W, Didi V . Dirigent proteins in plants: modulating cell wall metabolism during abiotic and biotic stress exposure. J Exp Bot. 2017; 68(13):3287-3301. DOI: 10.1093/jxb/erx141. View

Queiroz E, Alfattani A, Afzan A, Marcourt L, Guillarme D, Wolfender J . Utility of dry load injection for an efficient natural products isolation at the semi-preparative chromatographic scale. J Chromatogr A. 2019; 1598:85-91. DOI: 10.1016/j.chroma.2019.03.042. View

Xie C, Yuan H, Qu J, Xing J, Lu B, Wang X . Biocatalytic production of acyclic bis[bibenzyls] from dihydroresveratrol by crude Momordica charantia peroxidase. Chem Biodivers. 2009; 6(8):1193-201. DOI: 10.1002/cbdv.200800229. View

10.

Wilkens A, Paulsen J, Wray V, Winterhalter P . Structures of two novel trimeric stilbenes obtained by horseradish peroxidase catalyzed biotransformation of trans-resveratrol and (-)-epsilon-viniferin. J Agric Food Chem. 2010; 58(11):6754-61. DOI: 10.1021/jf100606p. View

11.

Liu S, Li X, Chen B, Ouyang X, Xie Y, Chen D . Phytophenol Dimerization Reaction: From Basic Rules to Diastereoselectivity and Beyond. Molecules. 2022; 27(15). PMC: 9369853. DOI: 10.3390/molecules27154842. View

12.

Shen T, Wang X, Lou H . Natural stilbenes: an overview. Nat Prod Rep. 2009; 26(7):916-35. DOI: 10.1039/b905960a. View

13.

Fuloria S, Sekar M, Khattulanuar F, Gan S, Mat Rani N, Ravi S . Chemistry, Biosynthesis and Pharmacology of Viniferin: Potential Resveratrol-Derived Molecules for New Drug Discovery, Development and Therapy. Molecules. 2022; 27(16). PMC: 9414909. DOI: 10.3390/molecules27165072. View

14.

Carson M, Kozlowski M . Recent advances in oxidative phenol coupling for the total synthesis of natural products. Nat Prod Rep. 2023; 41(2):208-227. PMC: 10709532. DOI: 10.1039/d3np00009e. View

15.

Tobimatsu Y, Schuetz M . Lignin polymerization: how do plants manage the chemistry so well?. Curr Opin Biotechnol. 2018; 56:75-81. DOI: 10.1016/j.copbio.2018.10.001. View

16.

Thach D, Maimone T . Making light work of lignan synthesis. Nat Chem. 2020; 13(1):7-9. DOI: 10.1038/s41557-020-00604-y. View

17.

Huber R, Koval A, Marcourt L, Heritier M, Schnee S, Michellod E . Chemoenzymatic Synthesis of Original Stilbene Dimers Possessing Wnt Inhibition Activity in Triple-Negative Breast Cancer Cells Using the Enzymatic Secretome of Pers. Front Chem. 2022; 10:881298. PMC: 9062038. DOI: 10.3389/fchem.2022.881298. View

18.

Zwygart A, Medaglia C, Huber R, Poli R, Marcourt L, Schnee S . Antiviral properties of trans-δ-viniferin derivatives against enveloped viruses. Biomed Pharmacother. 2023; 163:114825. PMC: 10158552. DOI: 10.1016/j.biopha.2023.114825. View

19.

Huber R, Marcourt L, Heritier M, Luscher A, Guebey L, Schnee S . Generation of potent antibacterial compounds through enzymatic and chemical modifications of the trans-δ-viniferin scaffold. Sci Rep. 2023; 13(1):15986. PMC: 10520035. DOI: 10.1038/s41598-023-43000-5. View

20.

Mazzaferro L, Huttel W, Fries A, Muller M . Cytochrome P450-catalyzed regio- and stereoselective phenol coupling of fungal natural products. J Am Chem Soc. 2015; 137(38):12289-95. DOI: 10.1021/jacs.5b06776. View