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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (15 August 2021) | Viewed by 35313

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Prof. Dr. Toyonobu Usuki

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Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, Tokyo, Japan
Interests: natural products; amino acids; extraction and isolation; total synthesis; palladium-catalyzed cross-coupling; ionic liquid; LC-MS/MS; structure–activity relationship; drug discovery

Prof. Dr. Akira Kawamura

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Department of Chemistry, Hunter College of CUNY, 695 Park Avenue, 1312N, New York, NY 10065, USA
Interests: natural products chemistry; immunology; plant-microbe interaction

Prof. Dr. Masaru Hashimoto

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Guest Editor

Faculty of Agriculture and Life Science, Hirosaki University, Aomori, Japan
Interests: Isolation and structural elucidation of natural products; DFT based sepactral discussions

Special Issue Information

Dear Colleagues,

Natural product research has mainly dealt with extraction/isolation/structure elucidation, total synthesis, and biosynthesis in the classical sense. Recently, natural product research has spread across many fields including chemical biology, medicinal chemistry, analytical chemistry, and material sciences. All researchers working in this borderless field are cordially invited to contribute original research papers or reviews to this Special Issue of Molecules, which will report on natural product-related research including total synthesis, methodology, extraction/isolation/structure elucidation, structure–activity relationship, medicinal chemistry, biosynthesis, material sciences, analytical chemistry, and chemical biology. Work in any field related to natural products is welcome.

Prof. Dr. Toyonobu Usuki
Dr. Akira Kawamura
Prof. Dr. Masaru Hashimoto
Guest Editors

Manuscript Submission Information

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Keywords

Natural products
Total synthesis
Methodology
Extraction/isolation/structure elucidation
Structure–activity relationship
Medicinal chemistry
Chemical biology
Material science

Published Papers (12 papers)

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12 pages, 2301 KiB

Open AccessCommunication

Unambiguous Stereochemical Assignment of Cyclo(Phe-Pro), Cyclo(Leu-Pro), and Cyclo(Val-Pro) by Electronic Circular Dichroic Spectroscopy

by Alison Domzalski, Liliana Margent, Valeria Vigo, Faizunnahar Dewan, Naga Vara Kishore Pilarsetty, Yujia Xu and Akira Kawamura

Molecules 2021, 26(19), 5981; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26195981 - 02 Oct 2021

Cited by 1 | Viewed by 2689

Abstract

2,5-diketopiperazines (DKPs) are cyclic dipeptides ubiquitously found in nature. In particular, cyclo(Phe-Pro), cyclo(Leu-Pro), and cyclo(Val-Pro) are frequently detected in many microbial cultures. Each of these DKPs has four possible stereoisomers due to the presence of two chirality centers. However, absolute configurations of natural DKPs are often ambiguous due to the lack of a simple, sensitive, and reproducible method for stereochemical assignment. This is an important problem because stereochemistry is a key determinant of biological activity. Here, we report a synthetic DKP library containing all stereoisomers of cyclo(Phe-Pro), cyclo(Leu-Pro), and cyclo(Val-Pro). The library was subjected to spectroscopic characterization using mass spectrometry, NMR, and electronic circular dichroism (ECD). It turned out that ECD can clearly differentiate DKP stereoisomers. Thus, our ECD dataset can serve as a reference for unambiguous stereochemical assignment of cyclo(Phe-Pro), cyclo(Leu-Pro), and cyclo(Val-Pro) samples from natural sources. The DKP library was also subjected to a biological screening using assays for E. coli growth and biofilm formation, which revealed distinct biological effects of cyclo(D-Phe-L-Pro). Full article

(This article belongs to the Special Issue Recent Advances on Natural Product Research)

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12 pages, 3907 KiB

Open AccessArticle

The Impact of Apple Variety and the Production Methods on the Antibacterial Activity of Vinegar Samples

by Mohammed Kara, Amine Assouguem, Omkulthom Mohamed Al kamaly, Safaâ Benmessaoud, Hamada Imtara, Hamza Mechchate, Christophe Hano, Abdou Rachid Zerhouni and Jamila Bahhou

Molecules 2021, 26(18), 5437; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26185437 - 07 Sep 2021

Cited by 18 | Viewed by 4784

Abstract

Apple vinegar is a natural product widely used in food and traditional medicine as it contains many bioactive compounds. The apple variety and production methods are two factors that play a major role in determining the quality of vinegar. Therefore, this study aims to determine the quality of apple vinegar samples from different varieties (Red Delicious, Gala, Golden Delicious, and Starking Delicious) prepared by three methods using small apple pieces, apple juice, and crushed apple, through determining the physicochemical properties and antibacterial activity of these samples. The antibacterial activity was studied against five pathogenic bacteria: Staphylococcus aureus, Klebsiella pneumonia, Escherichia coli (ATB: 57), Escherichia coli (ATB: 97), and Pseudomonas aeruginosa, using two methods, disk diffusion and microdilution, for determining the minimum inhibitory concentrations and the minimum bactericidal concentrations. The results of this study showed that the lowest pH value was 3.6 for Stark Delicious, obtained by liquid fermentation, and the highest acetic acid values were 4.7 and 4% for the vinegar of Red Delicious and Golden Delicious, prepared by solid fermentation, respectively. The results of the antibacterial activity showed considerable activity of apple vinegar on the tested strains. Generally, the Staphylococcus aureus strain appears less sensitive and Pseudomonas aeruginosa seems to be very sensitive against all samples, while the other strains have distinct sensitivities depending on the variety studied and the method used. A higher antibacterial activity was found in vinegar obtained by the apple pieces method and the Red Delicious variety, with a low MIC and MBC recorded, at 1.95 and 3.90 µL/mL, respectively. This study has shown that the choice of both apple variety and production method is therefore an essential step in determining and aiming for the desired quality of apple vinegar. Full article

(This article belongs to the Special Issue Recent Advances on Natural Product Research)

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14 pages, 19384 KiB

Open AccessArticle

Enhanced Aryltetralin Lignans Production in Linum Adventi-Tious Root Cultures

by Michela Alfieri, Iride Mascheretti, Roméo A. Dougué Kentsop, Roberto Consonni, Franca Locatelli, Monica Mattana and Gianluca Ottolina

Molecules 2021, 26(17), 5189; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26175189 - 27 Aug 2021

Cited by 5 | Viewed by 1894

Abstract

Lignans are the main secondary metabolites synthetized by Linum species as plant defense molecules. They are also valuable for human health, in particular, for their potent antiviral and antineoplastic properties. In this study, the adventitious root cultures of three Linum species (L. flavum, L. mucronatum and L. dolomiticum) were developed to produce aryltetralin lignans. The effect of two elicitors, methyl jasmonate and coronatine, on aryltetralin lignans production was also evaluated. The adventitious root cultures from L. dolomiticum were obtained and analyzed for the first time and resulted as the best producer for all the aryltetralins highlighted in this system: Podophyllotoxin, 6-methoxypodophyllotoxin and 6-methoxypodophyllotoxin-7-O-β-glucoside, the last showing a productivity of 92.6 mg/g DW. The two elicitors differently affected the production of the 6-methoxypodophyllotoxin and 6-methoxypodophyllotoxin-7-O-β-glucoside. Full article

(This article belongs to the Special Issue Recent Advances on Natural Product Research)

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19 pages, 2478 KiB

Open AccessArticle

Cyclohumulanoid Sesquiterpenes from the Culture Broth of the Basidiomycetous Fungus Daedaleopsis tricolor

by Ryuhi Kanehara, Akio Tonouchi, Katsuhiro Konno and Masaru Hashimoto

Molecules 2021, 26(14), 4364; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26144364 - 19 Jul 2021

Cited by 5 | Viewed by 2608

Abstract

A series of cyclohumulanoids, i.e., tricocerapicanols A–C (1a–1c), tricoprotoilludenes A (2a) and B (3), tricosterpurol (4), and tricoilludins A–C (5–7) were isolated along with known violascensol (2b) and omphadiol (8) from the culture broth of Daedaleopsis tricolor, an inedible but not toxic mushroom. The structures were fully elucidated on the basis of NMR spectroscopic analysis, and the suggested relative structures were confirmed via density functional theory (DFT)-based chemical shift calculations involving a DP4 probability analysis. In the present study, the ¹H chemical shifts were more informative than the ¹³C chemical shifts to distinguish the diastereomers at C-11. The absolute configurations of 1–5 were determined by comparing the experimental and calculated electronic circular dichroism (ECD) spectra. For 6 and 7, the same chirality was assigned according to their biosynthetic similarities with the other compounds. The successful assignment of some Cotton effects was achieved by utilizing DFT calculations using simple model compounds. The plausible biosynthesis of 1–7 was also discussed on the basis of the structural commonality and general cyclohumulanoid biosynthesis. Compounds 2a and 5 were found to simultaneously induce hyphal swelling and branching at 5.0 μg/mL against a test fungus Cochliobolus miyabeanus. Full article

(This article belongs to the Special Issue Recent Advances on Natural Product Research)

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7 pages, 826 KiB

Open AccessArticle

Effective Extraction of Limonene and Hibaene from Hinoki (Chamaecyparis obtusa) Using Ionic Liquid and Deep Eutectic Solvent

by Rina Yasutomi, Riki Anzawa, Masamitsu Urakawa and Toyonobu Usuki

Molecules 2021, 26(14), 4271; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26144271 - 14 Jul 2021

Cited by 2 | Viewed by 2864

Abstract

The essential oils of hinoki (Chamaecyparis obtusa) leaves have anti-bacterial, anti-fungal, and relaxation properties that are likely associated with the major components such as sabinene, α-terpinyl acetate, limonene, elemol, myrcene, and hibaene. The present study describes the use of a cellulose-dissolving ionic liquid (IL) [C₂mim][(MeO)(H)PO₂] and low-toxicity solvents called betaine-based deep eutectic solvents (DESs) for the efficient extraction of hinoki essential oils. As a control method, organic solvent extraction was performed using either hexane, ethyl acetate (EtOAc), or acetone at 30 °C for 1 h. Both the experimental and control methods were conducted under the same conditions, which relied on partial dissolution of the leaves using the IL and DESs before partitioning the hinoki oils into the organic solvent for analysis. Quantitative analysis was performed using gas chromatography–mass spectrometry (GC-MS) in selected ion monitoring (SIM) mode. The results indicated that extraction using the [C₂mim][(MeO)(H)PO₂]/acetone bilayer system improved the yields of limonene and hibaene, 1.5- and 1.9-fold, respectively, when compared with the control method. In addition, extraction using betaine/l-lactic acid (molar ratio 1:1) gave the greatest yields for both limonene and hibaene, 1.3-fold and 1.5-fold greater, respectively, than when using an organic solvent. These results demonstrate the effective extraction of essential oils from plant leaves under conditions milder than those needed for the conventional method. The less toxic and environmentally begin DESs for the extraction are also applicable to the food and cosmetic industries. Full article

(This article belongs to the Special Issue Recent Advances on Natural Product Research)

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14 pages, 1934 KiB

Open AccessArticle

Chemical Hemisynthesis of Sulfated Cyanidin-3-O-Glucoside and Cyanidin Metabolites

by Sarah Straßmann, Maike Passon and Andreas Schieber

Molecules 2021, 26(8), 2146; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26082146 - 08 Apr 2021

Cited by 6 | Viewed by 2030

Abstract

The metabolism of anthocyanins in humans is still not fully understood, which is partly due to the lack of reference compounds. It is known that sulfation is one way of the complex phase II biotransformation mechanism. Therefore, cyanidin-3-O-glucoside and the cyanidin aglycone were chemically converted to their sulfates by reaction with sulfur trioxide-N-triethylamine complex in dimethylformamide. The reaction products were characterized by UHPLC coupled to linear ion trap and IMS-QTOF mass spectrometry. Based on MS data, retention times, and UV-Vis spectra, the compounds could tentatively be assigned to A-, C-, or B-ring sulfates. Analysis of urine samples from two volunteers after ingestion of commercial blackberry nectar demonstrated the presence of two sulfated derivatives of the cyanidin aglycone and one sulfated derivative of the cyanidin-3-O-glucoside. It was found that both the A ring and the B ring are sulfated by human enzymes. This study marks an important step toward a better understanding of anthocyanin metabolism. Full article

(This article belongs to the Special Issue Recent Advances on Natural Product Research)

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12 pages, 1453 KiB

Open AccessArticle

Effects of a High-Molecular-Weight Polysaccharides Isolated from Korean Persimmon on the Antioxidant, Anti-Inflammatory, and Antiwrinkle Activity

by Ki Cheol Hwang, Hyun Young Shin, Woo Jung Kim, Mi Suk Seo and Hoon Kim

Molecules 2021, 26(6), 1600; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26061600 - 13 Mar 2021

Cited by 16 | Viewed by 3016

Abstract

Persimmon (Diospyros kaki), a familiar and widespread fruit worldwide, is known to exhibit several physiological effects because of the presence of pharmacologically active compounds called phytochemicals. However, its high-molecular-weight compounds, particularly polysaccharides, have not been extensively studied. In this study, D. kaki extract (DK) was fractionated into low- and high-molecular-weight fractions (DK-L and DK-H, respectively) through ethanol fractionation, and their effects on antioxidant, anti-inflammatory, and antiwrinkle activities were investigated by an in vitro system. DK-H contained significantly higher contents of neutral sugar, uronic acid, and polyphenols compared to DK and DK-L. Furthermore, DK-H exhibited significantly improved pharmacological activities, such as antioxidant, anti-inflammatory, and antiwrinkle properties, compared to those of DK and DK-L, demonstrating that DK-H may play an important role in mediating the beneficial effects of persimmon. Sugar composition analysis and molecular characterization indicated that DK-H consisted of a galacturonic acid (GalA)-rich polysaccharide with a molecular weight of >345 kDa that mainly comprised GalA and small amounts of neutral sugar and polyphenol residues. These results suggest that the bioactive fraction DK-H is likely to be a GalA-rich pectic polysaccharide containing a small number of polyphenol residues, which may be a novel candidate in the pharmaceutical and cosmeceutical industries. Full article

(This article belongs to the Special Issue Recent Advances on Natural Product Research)

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14 pages, 2370 KiB

Open AccessArticle

Methylation of Cyanidin-3-O-Glucoside with Dimethyl Carbonate

by Sarah Straßmann, Tillman Brehmer, Maike Passon and Andreas Schieber

Molecules 2021, 26(5), 1342; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26051342 - 03 Mar 2021

Cited by 4 | Viewed by 2529

Abstract

The approach presented in this study is the first for the hemisynthesis of methylated anthocyanins. It was possible to obtain cyanidin-3-O-glucoside derivatives with different degrees of methylation. Cautious identification of 4′-, 5-, and 7-OH monomethylated derivatives was also accomplished. The methylation agent used was the “green chemical” dimethyl carbonate (DMC), which is characterized by low human and ecological toxicity. The influence of the temperature, reaction time, and amount of the required diazabicyclo[5.4.0]undec-7-en (DBU) catalyst on the formation of the products was examined. Compared to conventional synthesis methods for methylated flavonoids using DMC and DBU, the conditions identified in this study result in a reduction of reaction time, and an important side reaction, so-called carboxymethylation, was minimized by using higher amounts of catalyst. Full article

(This article belongs to the Special Issue Recent Advances on Natural Product Research)

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12 pages, 9585 KiB

Open AccessArticle

Assignment of Absolute Configuration of Bromoallenes by Vacuum-Ultraviolet Circular Dichroism (VUVCD)

by Taiki Umezawa, Nakaba Mizutani, Koichi Matsuo, Yuugo Tokunaga, Fuyuhiko Matsuda and Tatsuo Nehira

Molecules 2021, 26(5), 1296; https://doi.org/10.3390/molecules26051296 - 27 Feb 2021

Cited by 3 | Viewed by 2403

Abstract

A new application of vacuum-ultraviolet circular dichroism (VUVCD), which enables the measurement of CD spectra in the vacuum-ultraviolet region (140–200 nm), for the assignment of the absolute configurations of bromoallenes is described. Bromoallene moieties are found in natural products obtained from many marine organisms. To date, the absolute configuration of bromoallenes has been assigned almost exclusively with Lowe’s rule, which is based on specific rotation. However, exceptions to Lowe’s rule have been reported arising from the presence of other substituents with large specific rotations. For the unambiguous assignment of the absolute configuration of the bromoallene moiety with its characteristic absorption wavelength at 180–190 nm due to the π–π* transition, VUVCD was applied to four pairs of bromoallene diastereomers prepared by modifying the synthetic scheme of omaezallene. The VUVCD spectra clearly showed positive or negative Cotton effects around 180–190 nm according to the configuration of the bromoallene employed, revealing the potential of VUVCD for determining absolute stereochemistry. Full article

(This article belongs to the Special Issue Recent Advances on Natural Product Research)

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24 pages, 4406 KiB

Open AccessArticle

Molecular and Cellular Effects of Chemical Chaperone—TUDCA on ER-Stressed NHAC-kn Human Articular Chondrocytes Cultured in Normoxic and Hypoxic Conditions

by Magdalena Kusaczuk, Monika Naumowicz, Rafał Krętowski, Bartosz Cukierman and Marzanna Cechowska-Pasko

Molecules 2021, 26(4), 878; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26040878 - 07 Feb 2021

Cited by 5 | Viewed by 2470

Abstract

Osteoarthritis (OA) is considered one of the most common arthritic diseases characterized by progressive degradation and abnormal remodeling of articular cartilage. Potential therapeutics for OA aim at restoring proper chondrocyte functioning and inhibiting apoptosis. Previous studies have demonstrated that tauroursodeoxycholic acid (TUDCA) showed anti-inflammatory and anti-apoptotic activity in many models of various diseases, acting mainly via alleviation of endoplasmic reticulum (ER) stress. However, little is known about cytoprotective effects of TUDCA on chondrocyte cells. The present study was designed to evaluate potential effects of TUDCA on interleukin-1β (IL-1β) and tunicamycin (TNC)-stimulated NHAC-kn chondrocytes cultured in normoxic and hypoxic conditions. Our results showed that TUDCA alleviated ER stress in TNC-treated chondrocytes, as demonstrated by reduced CHOP expression; however, it was not effective enough to prevent apoptosis of NHAC-kn cells in either normoxia nor hypoxia. However, co-treatment with TUDCA alleviated inflammatory response induced by IL-1β, as shown by down regulation of Il-1β, Il-6, Il-8 and Cox2, and increased the expression of antioxidant enzyme Sod2. Additionally, TUDCA enhanced Col IIα expression in IL-1β- and TNC-stimulated cells, but only in normoxic conditions. Altogether, these results suggest that although TUDCA may display chondoprotective potential in ER-stressed cells, further analyses are still necessary to fully confirm its possible recommendation as potential candidate in OA therapy. Full article

(This article belongs to the Special Issue Recent Advances on Natural Product Research)

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20 pages, 2850 KiB

Open AccessArticle

The Effect of Cultivation Method of Strawberry (Fragaria x ananassa Duch.) cv. Honeoye on Structure and Degradation Dynamics of Pectin during Cold Storage

by Magdalena Drobek, Magdalena Frąc, Artur Zdunek and Justyna Cybulska

Molecules 2020, 25(18), 4325; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25184325 - 21 Sep 2020

Cited by 17 | Viewed by 3566

Abstract

The high quality and long shelf life of strawberry fruit are largely dependent on the cultivation method. The goal of this experiment was to study the effect of different cultivation methods on molecular structure and rheological properties of pectin extracted from strawberry quality parameters during cold storage. Three methods of cultivation of strawberry cv. Honeoye were tested: organic cultivation on raised beds, organic cultivation with the flat-planted method and conventional cultivation with the flat-planted method. The nanostructure of pectin (AFM), its chemical structure (FT-IR) and rheological properties were studied. The fruits were also tested by size, dry matter, firmness, acidity and the content of soluble solids, anthocyanin, phenolics, vitamin C and galacturonic acid. Pectin isolated from organic strawberries was more rapidly degraded than conventional strawberry pectin, which limits the possibilities for their processing and use as gelling or stabilizing agents at 20 °C. The differences in fruit quality were particularly noticeable with respect to the anthocyanin content, which was significantly higher for organic strawberry. The organic fruit also had better sensory properties because of its lower acidity and higher soluble solid content (SSC). These and other results from this experiment showed that strawberries produced by organic farming methods had better biochemical properties compared to conventional fruit; however, pectin transformation undergone faster limits their further technological applications. Full article

(This article belongs to the Special Issue Recent Advances on Natural Product Research)

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Review

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17 pages, 3667 KiB

Open AccessReview

Lipid A-Mediated Bacterial–Host Chemical Ecology: Synthetic Research of Bacterial Lipid As and Their Development as Adjuvants

by Atsushi Shimoyama and Koichi Fukase

Molecules 2021, 26(20), 6294; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26206294 - 18 Oct 2021

Cited by 7 | Viewed by 2308

Abstract

Gram-negative bacterial cell surface component lipopolysaccharide (LPS) and its active principle, lipid A, exhibit immunostimulatory effects and have the potential to act as adjuvants. However, canonical LPS acts as an endotoxin by hyperstimulating the immune response. Therefore, LPS and lipid A must be structurally modified to minimize their toxic effects while maintaining their adjuvant effect for application as vaccine adjuvants. In the field of chemical ecology research, various biological phenomena occurring among organisms are considered molecular interactions. Recently, the hypothesis has been proposed that LPS and lipid A mediate bacterial–host chemical ecology to regulate various host biological phenomena, mainly immunity. Parasitic and symbiotic bacteria inhabiting the host are predicted to possess low-toxicity immunomodulators due to the chemical structural changes of their LPS caused by co-evolution with the host. Studies on the chemical synthesis and functional evaluation of their lipid As have been developed to test this hypothesis and to apply them to low-toxicity and safe adjuvants. Full article

(This article belongs to the Special Issue Recent Advances on Natural Product Research)

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