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Fourteen azaphilone-type polyketides (1-14), including nine new ones (1-6 and 8-10), were isolated from cultures of Vitex rotundifolia-associated Penicillium sp. JVF17, and their structures were determined by spectroscopic analysis together with computational methods and chemical reactions. Neuroprotective effects of the isolated compounds were evaluated against glutamate-induced neurotoxicity. Treatment with compounds 3, 6, 7, and 11-14 increased cell viabilities of hippocampal neuronal cells damaged by glutamate, with compound 12 being the most potent. Compound 12 markedly decreased intracellular Ca2+ and nuclear condensation levels. Mechanistically, molecular markers of apoptosis induced by treatment with glutamate, i.e., phosphorylation of MAPKs and elevated Bax/Bcl-2 expression ratio, were significantly lowered by compound 12. The azaphilones with an isoquinoline core structure were more active than those with pyranoquinones, but N-substitution decreased the activity. This study, including the structure-activity relationship, indicates that the azaphilone scaffold is a promising lead toward the development of novel neuroprotective agents.

Medicinal plants are one of the most important sources of antiviral agents and lead compounds. Lignans are a large class of natural compounds comprising two phenyl propane units. Many of them have demonstrated biological activities, and some of them have even been developed as therapeutic drugs. In this review, 630 lignans, including those obtained from medicinal plants and their chemical derivatives, were systematically reviewed for their antiviral activity and mechanism of action. The compounds discussed herein were published in articles between 1998 and 2020. The articles were identified using both database searches (e.g., Web of Science, Pub Med and Scifinder) using key words such as: antiviral activity, antiviral effects, lignans, HBV, HCV, HIV, HPV, HSV, JEV, SARS-CoV, RSV and influenza A virus, and directed searches of scholarly publisher's websites including ACS, Elsevier, Springer, Thieme, and Wiley. The compounds were classified on their structural characteristics as 1) arylnaphthalene lignans, 2) aryltetralin lignans, 3) dibenzylbutyrolactone lignans, 4) dibenzylbutane lignans, 5) tetrahydrofuranoid and tetrahydrofurofuranoid lignans, 6) benzofuran lignans, 7) neolignans, 8) dibenzocyclooctadiene lignans and homolignans, and 9) norlignans and other lignoids. Details on isolation and antiviral activities of the most active compounds within each class of lignan are discussed in detail, as are studies of synthetic lignans that provide structure-activity relationship information.

Traditional Chinese medicine (TCM) was the primary source of medical treatment for the people inhabiting East Asia for thousands of years. These ancient practices have incorporated a wide variety of materia medica including plants, animals and minerals. As modern sciences, including natural products chemistry, emerged, there became increasing efforts to explore the chemistry of this materia medica to find molecules responsible for their traditional use. Insects, including beetles have played an important role in TCM. In our survey of texts and review articles on TCM materia medica, we found 48 species of beetles from 34 genera in 14 different families that are used in TCM. This review covers the chemistry known from the beetles used in TCM, or in cases where a species used in these practices has not been chemically studied, we discuss the chemistry of closely related beetles. We also found several documented uses of beetles in Traditional Korean Medicine (TKM), and included them where appropriate. There are 129 chemical constituents of beetles discussed.

Endophytes are defined as microorganisms which live in plant tissues without causing any apparent negative effects to the host plant. Endophytes have been considered rich sources for natural products since they produce an array of chemically diverse bioactive secondary metabolites. Consistent with the hypothesis that endophytes help the survival and growth of host plants by producing secondary metabolites, many compounds derived from endophytes exhibit potent antimicrobial activity. Interestingly, some endophytes have been reported to produce the same metabolites as the host plants, probably due to horizontal gene transfer. In this review, metabolites produced by endophytes as well as their host plants are briefly introduced, with the emphasis on their value as pharmaceutical lead compounds. We have defined lead compounds as secondary metabolites with antimicrobial activities with Minimal Inhibitory Concentration values less than 20 μM (5 μg/mL). The endophytic metabolites with antimicrobial activities are classified into two groups according to the mode of inhibition: (1) antibiotic metabolites that kill or inhibit growth of microorganisms (2) endophyte-derived compounds with inhibitory activity against quorum sensing. Disruption of quorum sensing, which is a microbial communication system, has recently emerged as a novel target for antibiotic development since it affords a new modality to reduce microbial infection. Although currently there are no commercially-available antibiotics derived from endophytes, it is expected that new antibiotics based on several modes of action will be developed and marketed due to increasing research emphasis in this field.

Two new unique angucyclinones (1 and 2) with unprecedented ether bridges connecting carbons 5 and 7 were isolated from the cultures of Streptomyces bulli GJA1, an endophyte of Gardenia jasminoides, together with two known ones (3 and 4). The MS2-based molecular networking system facilitated the isolation of compounds with target functionalities. The stereochemistry of 1 was completely established by ROESY and ECD experiments. Compound 3 showed antivirulence activities by inhibiting the peptide toxin (PSMs) production and the biofilm formation of MRSA. Compounds 3 and 4 showed very potent anti-proliferative effects against OV1 and ES2 ovarian cancer cells.

Fourteen azaphilone-type polyketides (

Background: The ergosterol pathway is a prime antifungal target as it is required for fungal survival, yet is not involved in human homeostasis. Methods to study the ergosterol pathway, however, are often time-consuming. The minimum inhibitory concentration (MIC) assay is a simple research tool that determines the lowest concentration at which a novel antimicrobial is active in vitro with limited scope to determine the mechanism of action for a drug. Methods: In this study, we show that by adding hydrogen peroxide, an oxidative stressor, or glutathione (GSH), an antioxidant, to modify a commonly performed MIC assay allowed us to screen selectively for new antifungal drugs that target ergosterol biosynthesis in fungi. A human pathogen and dermatophyte,Microsporum gypseum, was used as a test organism. When exposed to ergosterol targeting drugs, the hydrogen peroxide treatment significantly decreased fungal survival by reducing ergosterol in the cell wall, whereas GSH increased survival of M. gypseum. Further, by performing a series of experiments with M. gypseum and Trichophyton rubrum, it was determined that the oxidative stress from hydrogen peroxide causes cell death at different developmental stages based on fungal species. Findings: These findings allow us to describe a simple, high-throughput method for simultaneously screening new antifungal drugs for activity and effects on the ergosterol pathway. Interpretation: By using this tool, two isoquinoline alkaloids were discovered to be potent inhibitors of ergosterol biosynthesis in vitro by reducing the amount of ergosterol without affecting the expression of 1,3-β-glucan. Both compounds also significantly reduced the severity of acanthosis, hyperkeratosis, spongiosis and dermal edema in vivo. Funding Statement: This work was supported by Faculty Research Grant, Hong Kong Baptist University (FRG 2/17-18/103), the Hong Kong Baptist University (HKBU) Interdisciplinary Research Matching Scheme (RC-IRMS/15-16/02),NSFC funding 31670360, 81973293, U1702286 and Natural Science Foundation of SZU 860-000002110131. Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: Female guinea pigs were used for the in vivo antifungal study, which was approved by the laboratory animal ethics committee of Shenzhen University, China [Approval number: SYXK (Yue) 2014-0140].

Glutamate neurotoxicity has been implicated in neuronal death in both acute CNS injury and in chronic neurodegenerative diseases. Five unique cyclic depsipeptides with neuroprotective activity, colletotrichamides A-E (1-5), were isolated from cultures of a halophyte Suaeda japonica-associated fungus, Colletotrichum gloeosporioides JS419. Spectroscopic analysis revealed that they were glycosylated cyclic lipodepsipeptides. Their relative configurations were determined by ROESY and J-based configuration analysis, and absolute configurations were established by chemical reactions including modified Mosher's method, advanced Marfey's method, and sugar derivatization. This is the first report of a glycosylated dimethyl-trioxygenated dodecanoyl moiety, and the relative as well as absolute stereochemistry was elucidated herein for the first time. Colletotrichamide C exhibited strong neuroprotective activity against glutamate in hippocampal HT22 cells.

The winter firefly (Ellychnia corrusca) is common throughout the eastern United States and Canada. It is notable among fireflies (Coleoptera: Lampyridae) for its adult activity during the winter and early spring months, and for its lack of a light-producing organ. Multiple lines of evidence suggest that E. corrusca is chemically protected, specifically its unusual phenology which results in prolonged exposure to predators, its aposematic coloration, its reflex bleeding upon disturbance, and its relatedness to toxic firefly genera. Chemical investigation of this species revealed the presence of large quantities (>500 μg/beetle) of steroidal pyrones known as lucibufagins. The structures of these lucibufagins were determined using 1D and 2D NMR spectroscopy along with UHPLC-HRMS. Four of these compounds were previously detected in fireflies of the genus Photinus, while the remaining four, which contain a highly modified D-ring of the steroid core, are previously unknown. Analysis of reflex bleeding showed that the hemolymph contained the lucibufagins and that it was primarily released via a band of cuticular pores along the costal margin of the elytra. In addition, our analysis of the eggs, larva, and pupa established that all immature stages possess lucibufagins, thus representing the first instance of a firefly species for which all life stages have been investigated chemically.

Ellychnia corrusca (Winter Firefly) is one of few winter-active insects. Exposed throughout the season, this beetle appears vulnerable to insectivorous predators, but was recently shown to possess lucibufagins (LBGs), potent chemical defenses. The Winter Firefly is closely related to summer-active fireflies. To provide an adaptive explanation for this apparent phenological shift, we hypothesized that winter activity may protect the Winter Firefly from summer-active fireflies in the genus Photuris, predators that specialize on LBG-containing prey. To test this hypothesis, we studied the Winter Firefly and Photuris that occur sympatrically, but asynchronously as adults, at our Connecticut field sites. Through 2 experiments, we demonstrated that Photuris selectively consumes the Winter Firefly and sequesters its LBGs. Our findings are consistent with a hypothesis that winter activity by the Winter Firefly, by enabling early spring reproduction, provides phenological escape from a specialist predator.

Glutamate neurotoxicity has been implicated in neuronal death in both acute CNS injury and in chronic neurodegenerative diseases. Five unique cyclic depsipeptides with neuroprotective activity, colletotrichamides A-E (

In the course of our ongoing studies to discover bioactive chemical constituents from plants in the genus Isodon, two new diterpenes, kunminolide A (1) and rabdokunmin F (2) were isolated from the leaves of the medicinal plant Isodon interruptus. Kunminolide A (1) is a novel abietane-like diterpene with a novel skeleton, herein designated as 9, 10-seco-neoabietane. Rabdokunmin F (2) is an ent-kaurene diterpene with C-18 oxidized to a carboxylic acid group. The structures were determined by spectroscopic means including analysis of 1D- and 2D-NMR spectral data. Crystals of 1 obtained from methanol were suitable for X-ray analysis, which confirmed the chemical structure. Kunminolide A (1) demonstrated chemopreventive potential by inducing QR1 activity with a CD value of 14.3 µM, and rabdokunmin F (2) was found to have cytotoxic activities with IC50 values in the range of 1.1–3.0 µM.

Small molecules of biological origin continue to yield the most promising leads for drug design, but systematic approaches for exploring nature’s cache of structural diversity are lacking. Here, we demonstrate the use of 2D NMR spectroscopy to screen a library of biorationally selected insect metabolite samples for partial structures indicating the presence of new chemical entities. This NMR-spectroscopic survey enabled detection of novel compounds in complex metabolite mixtures without prior fractionation or isolation. Our screen led to discovery and subsequent isolation of two families of tricyclic pyrones in Delphastus catalinae , a tiny ladybird beetle that is employed commercially as a biological pest control agent. The D. catalinae pyrones are based on 23-carbon polyketide chains forming 1,11-dioxo-2,6,10-trioxaanthracene and 4,8-dioxo-1,9,13-trioxaanthracene derivatives, representing ring systems not previously found in nature. This study highlights the utility of 2D NMR-spectroscopic screening for exploring nature’s structure space and suggests that insect metabolomes remain vastly underexplored.

Hymenopsin A (1), hymenopsin B (2), and a new macrophorin analogue, 2′,3′-epoxy-13-hydroxy-4′-oxomacrophorin A (3), have been isolated from a fungicolous isolate of Hymenopsis sp. (MYC-1703; NRRL 37638). The structures and relative configurations of these compounds were assigned on the basis of 2D NMR and MS data, and the identity of 1 was confirmed by X-ray crystallographic analysis. The absolute configuration of 2 was proposed on the basis of CD analysis using both empirical and computational methods. Compounds 2 and 3 showed antibacterial activity against Staphylococcus aureus and Bacillus subtilis. Compound 3 was also active against Aspergillus flavus and Fusarium verticillioides.

Four new triterpenoid glycosides, kolokosides A-D (1-4), along with the known compound 19,20-epoxycytochalasin N, were isolated from cultures of a Hawaiian wood-decay fungus (Xylaria sp.). The structures and relative configurations of 1-4 were determined primarily by analysis of NMR data, and the absolute configuration of 1 was assigned by application of the exciton chirality method. Compound 1 exhibited activity against Gram-positive bacteria.

Although it has been widely recognized that hydrogen bonds play a significant role in the photophysics of molecules, this phenomenon has rarely been applied to the solvatochromic method for determination of dipole moments. The difference in the dipole moment between the ground and excited state was determined in protic and aprotic solvents using both the Lippert-Mataga equation and the Bilot-Kawski equation for bromocresol purple, a molecule capable of hydrogen-bond donation and acceptance. The dipole change in protic environments was determined to be 15.2 ± 1.0 D for the Lippert-Mataga method and 9.2 ± 1.0 D for the Bilot-Kawski method, while the change in aprotic environments was 10.4 ± 1.0 D and 6.7 ± 1.0 D, respectively. Both methods highlighted the importance of hydrogen bonding in stabilizing increased charge-separation of the excited state, allowing for larger changes in dipole moments in protic environments. This study further validates a simple, rational modification to the commonly used methods that allows access to dipole-moment data on dyes with hydrogen-bonding capabilities through solvatochromic experiments.

The peanut plant (Arachis hypogaea) is known to produce stilbene phytoalexins as a defensive response to fungal invasion; however, the distribution of phytoalexins among different organs of the peanut plant at early stages of growth under axenic conditions has not been studied. Axenic plants produced a stilbenoid, resveratrol, as well as soluble bound and free phenolic acids, including 4-methoxycinnamic acid, which is reported in peanuts for the first time. Neither resveratrol nor phenolic acids were found in the root mucilage; the prenylated stilbenes were restricted to the mucilage and were not found in other organs of the peanut plant. These findings may lead to a better understanding of the defensive role of peanut stilbenes and phenolic acids.

Three new caryophyllene-type sesquiterpene alcohols, 6-hydroxypunctaporonin E (1), 6-hydroxypunctaporonin B (2), and 6-hydroxypunctaporonin A (3), have been isolated from cultures of the fungicolous fungus Pestalotiopsis disseminata. The structures of 1-3 were determined mainly by analysis of 1D and 2D NMR data. The structure and absolute configuration of 6-hydroxypunctaporonin E (1) was confirmed through X-ray crystallographic analysis of its mono-bromobenzoate derivative. Compounds 1 and 2 showed activity against Gram-positive bacteria.

The maize endophyte Acremonium zeae is antagonistic to kernel rotting and mycotoxin producing fungi Aspergillus flavus and Fusarium verticillioides in cultural tests for antagonism, and interferes with A. flavus infection and aflatoxin contamination of preharvest maize kernels. Chemical studies of an organic extract from maize kernel fermentations of Acremonium zeae (NRRL 13540), which displayed significant antifungal activity against Aspergillus flavus and F. verticillioides, revealed that the metabolites accounting for this activity were two newly reported antibiotics pyrrocidines A and B. Pyrrocidines were detected in fermentation extracts for 12 NRRL cultures of Acremonium zeae isolated from maize kernels harvested in Illinois (4/4 cultures), North Carolina (5/5), Georgia (1/2) and unrecorded locations within the USA (2/2). Pyrrocidine B was detected by LCMSMS in whole symptomatic maize kernels removed at harvest from ears of a commercial hybrid that were wound-inoculated in the milk stage with A. zeae (NRRL 13540) or (NRRL 13541). The pyrrocidines were first reported from the fermentation broth of an unidentified filamentous fungus LL-Cyan426, isolated from a mixed Douglas Fir hardwood forest on Crane Island Preserve, Washington, in 1993. Pyrrocidine A exhibited potent activity against most Gram-positive bacteria, including drug-resistant strains, and was also active against the yeast Candida albicans. In an evaluation of cultural antagonism between 13 isolates of A. zeae in pairings with A. flavus (NRRL 6541) and F. verticillioides (NRRL 25457), A. zeae (NRRL 6415) and (NRRL 34556) produced the strongest reaction, inhibiting both organisms at a distance while continuing to grow through the resulting clear zone at an unchanged rate. Maximum colony diameters for A. zeae (NRRL 6415) and (NRRL 13540), on potato dextrose agar after 14 d, were attained within the range of 25–30 °C, with less growth recorded at 15° and 37.5° and no growth at 5°. Potential interactions between A. zeae and other maize endophytes are considered and the significance of these interactions relative to the aflatoxin and fumonisin contamination of preharvest maize is presented. This is the first report of natural products from Acremonium zeae.

Angelonia angustifolia Benth. is a small herbaceous plant with documented use as an anti-inflammatory remedy by indigenous cultures in Latin America. It has subsequently been developed as an ornamental annual widely available in nurseries in the United States. Chemical investigation led to the discovery that lupeol is the major organic soluble constituent in the roots, and is present in large quantities in the aerial structures of the plant. Lupeol was identified by 1D and 2D NMR spectroscopic techniques and quantified by HPLC-MS. The concentration of lupeol (9.14 mg/g in roots) in A. angustifolia is approximately 3 times higher than any previously reported sources. Therefore, the amount of lupeol in the roots of a single individual of A. angustifolia greatly exceeds the previously determined topical threshold for significant reduction of inflammation. The presence of topically therapeutic levels of lupeol in A. angustifolia provides chemical rationale for its indigenous use. In addition, the established cultivation of A. angustifolia could allow this plant to be used as a source of the important bioactive molecule lupeol, or to be developed as a nutraceutical without damaging wild populations.

A new pigmented, optically active, low molecular weight metabolite has been isolated from peanut (Arachis hypogaea) kernels challenged by four species of Aspergillus. The structure of the new compound, termed SB-1, was elucidated by analysis of 1H NMR, 13C NMR, and mass spectrometric data. The SB-1 molecule bears prenylated benzenoid and but-2-enolide moieties and represents an unusual class of compounds. The closest known analogue to SB-1 was isolated from heartwood of Pericopsis elata. Both A. hypogaea and P. elata belong to the family Leguminosae. The new metabolite was accumulated in different peanut genotypes challenged by five Aspergillus species and may be an important representative of a new class of peanut phytoalexins. SB-1 production often exceeds production of major known stilbenes. Keywords: Peanuts; Arachis hypogaea; groundnuts; phytoalexin; but-2-enolide; stilbene; structure elucidation; NMR; HPLC-MS