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From Wood to Tetrahydro-2-benzazepines in Three Waste-Free Steps: Modular Synthesis of Biologically Active Lignin-Derived Scaffolds.

ABSTRACT: Inherently complex, lignin-derived aromatic monomers comprising valuable structural moieties present in many pharmaceuticals would serve as ideal substrates for the construction of biologically active molecules. Here, we describe a strategy that incorporates all intrinsic functional groups present in platform chemicals obtained by lignin depolymerization into value-added amines, using sustainable catalytic methods and benign solvents. Our strikingly efficient protocol provides access to libraries of aminoalkyl-phenol derivatives and seven-membered N-heterocycles directly from wood in two, respectively three, waste-free steps. Several molecules in these libraries have shown promising antibacterial or anticancer activities, emphasizing the advantage of this modular synthetic strategy and the potential for drug discovery. The sustainable catalytic pathways presented here can lead to significant benefits for the pharmaceutical industry where reduction of hazardous waste is a prime concern, and the described strategies that lead to high-value products from non-edible biomass waste streams also markedly increase the economic feasibility of lignocellulosic biorefineries.

SUBMITTER: Elangovan S

PROVIDER: S-EPMC6813559 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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From Wood to Tetrahydro-2-benzazepines in Three Waste-Free Steps: Modular Synthesis of Biologically Active Lignin-Derived Scaffolds.

Elangovan Saravanakumar S Afanasenko Anastasiia A Haupenthal Jörg J Sun Zhuohua Z Liu Yongzhuang Y Hirsch Anna K H AKH Barta Katalin K

ACS central science 20191011 10

Inherently complex, lignin-derived aromatic monomers comprising valuable structural moieties present in many pharmaceuticals would serve as ideal substrates for the construction of biologically active molecules. Here, we describe a strategy that incorporates all intrinsic functional groups present in platform chemicals obtained by lignin depolymerization into value-added amines, using sustainable catalytic methods and benign solvents. Our strikingly efficient protocol provides access to librarie ...[more]

PMID: 31660439

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Project description:Plant lignin is regarded as an important source for soil humic substances (HSs). Nonetheless, it remains unclear whether microbial metabolism on lignin is related to the genesis of unique HS biological activities (e.g., direct plant stimulation). Here, selected white-rot fungi (i.e., Ganoderma lucidum and Irpex lacteus) and plant litter- or mountain soil-derived microbial consortia were exploited to structurally modify lignin, followed by assessing the plant-stimulatory activity of the lignin-derived products. Parts solubilized by microbial metabolism on lignin were proven to exhibit organic moieties of phenol, carboxylic acid, and aliphatic groups and the enhancement of chromogenic features (i.e., absorbance at 450 nm), total phenolic contents, and radical-scavenging capacities with the cultivation times. In addition, high-resolution mass spectrometry revealed the shift of lignin-like molecules toward those showing either more molar oxygen-to-carbon or more hydrogen-to-carbon ratios. These results support the findings that the microbes involved, solubilize lignin by fragmentation, oxygenation, and/or benzene ring opening. This notion was also substantiated by the detection of related exoenzymes (i.e., peroxidases, copper radical oxidases, and hydrolases) in the selected fungal cultures, while the consortia treated with antibacterial agents showed that the fungal community is a sufficient condition to induce the lignin biotransformation. Major families of fungi (e.g., Nectriaceae, Hypocreaceae, and Saccharomycodaceae) and bacteria (e.g., Burkholderiaceae) were identified in the lignin-enriched cultures. All the microbially solubilized lignin products were likely to stimulate plant root elongation in the order selected white-rot fungi > microbial consortia > antibacterial agent-treated microbial consortia. Overall, this study supports the idea that microbial transformation of lignin can contribute to the formation of biologically active organic matter. IMPORTANCE Structurally stable humic substances (HSs) in soils are tightly associated with soil fertility, and it is thus important to understand how soil HSs are naturally formed. It is believed that microbial metabolism on plant matter contributes to natural humification, but detailed microbial species and their metabolisms inducing humic functionality (e.g., direct plant stimulation) need to be further investigated. Our findings clearly support that microbial metabolites of lignin could contribute to the formation of biologically active humus. This research direction appears to be meaningful not only for figuring out the natural processes, but also for confirming natural microbial resources useful for artificial humification that can be linked to the development of high-quality soil amendments.

Project description:Four previously undescribed drimane sesquiterpenoids were isolated from submerged cultures of the wood-inhabiting basidiomycete Dentipellis fragilis along with two compounds that were previously reported as synthetic or biotransformation compounds but not as natural products. The constitution and relative configuration of these compounds was determined based on high-resolution electrospray ionization mass spectrometry as well as by 1D and 2D nuclear magnetic resonance spectroscopy. The absolute configurations were established based on exemplary calculation of circular dichroism spectra and comparison with measured data as well as on biogenetic considerations. The biological activities of the isolated compounds were assessed in antimicrobial, cytotoxicity and neurotrophic assays. 10-Methoxycarbonyl-10-norisodrimenin (3) exhibited weak activity against the Gram-positive bacterium Staphylococcus aureus and the zygomycete Mucor hiemalis with minimal inhibitory concentrations of 66.7 μg mL-1. In addition, compound 3 showed weak inhibition of the mammalian cell line KB3.1 (human endocervical adenocarcinoma) with a half maximal inhibitory concentration of 21.2 μM. The neurotrophic activities of 15-hydroxyisodrimenin (1) and 10-carboxy-10-norisodrimenin (5) were assed in neurite outgrowth and real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) assays. When supplemented with 5 ng mL-1 nerve growth factor (NGF), the drimanes 1 and 5 induced neurite outgrowth in PC-12 (rat pheochromocytoma) cells compared to cells solely treated with NGF. As evaluated by RT-qPCR, compounds 1 and 5 also increased NGF and brain-derived neurotrophic factor expression levels in 1321N1 astrocytoma cells. Interestingly, the current study only represents the second report on neurotrophic activities of this widespread class of terpenoids. The only other available study deals with Cyathus africanus, another basidiomycete that can produce drimanes and cyathanes, but is only distantly related to Dentipellis and the Hericiaceae.

Dataset Information

From Wood to Tetrahydro-2-benzazepines in Three Waste-Free Steps: Modular Synthesis of Biologically Active Lignin-Derived Scaffolds.

Publications

From Wood to Tetrahydro-2-benzazepines in Three Waste-Free Steps: Modular Synthesis of Biologically Active Lignin-Derived Scaffolds.

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