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Journal ArticleDOI: 10.1039/D0OB02162H

The chemistry and biology of fungal meroterpenoids (2009-2019).

04 Mar 2021-Organic and Biomolecular Chemistry (The Royal Society of Chemistry)-Vol. 19, Iss: 8, pp 1644-1704
Abstract: Fungal meroterpenoids are secondary metabolites from mixed terpene-biosynthetic origins. Their intriguing chemical structural diversification and complexity, potential bioactivities, and pharmacological significance make them attractive targets in natural product chemistry, organic synthesis, and biosynthesis. This review provides a systematic overview of the isolation, chemical structural features, biological activities, and fungal biodiversity of 1585 novel meroterpenoids from 79 genera terrestrial and marine-derived fungi including macrofungi, Basidiomycetes, in 441 research papers in 2009-2019. Based on the nonterpenoid starting moiety in their biosynthesis pathway, meroterpenoids were classified into four categories (polyketide-terpenoid, indole-, shikimate-, and miscellaneous-) with polyketide-terpenoids (mainly tetraketide-) and shikimate-terpenoids as the primary source. Basidiomycota produced 37.5% of meroterpenoids, mostly shikimate-terpenoids. The genera of Ganoderma, Penicillium, Aspergillus, and Stachybotrys are the four dominant producers. Moreover, about 56% of meroterpenoids display various pronounced bioactivities, including cytotoxicity, enzyme inhibition, antibacterial, anti-inflammatory, antiviral, antifungal activities. It's exciting that several meroterpenoids including antroquinonol and 4-acetyl antroquinonol B were developed into phase II clinically used drugs. We assume that the chemical diversity and therapeutic potential of these fungal meroterpenoids will provide biologists and medicinal chemists with a large promising sustainable treasure-trove for drug discovery.

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16 results found


Journal ArticleDOI: 10.1002/ANIE.202106275
Yue-Lan Li1, Li Zhuo1, Xiaobin Li2, Yongqiang Zhu2  +5 moreInstitutions (2)
27 Sep 2021-Angewandte Chemie
Abstract: There is a continuous need for novel microbial natural products to fill the drying-up drug development pipeline. Herein, we report myxadazoles from Myxococcus sp. SDU36, a family of novel chimeric small molecules that consist of N-ribityl 5,6-dimethylbenzimidazole and a linear fatty acid chain endowed with an isoxazole ring. The experiments of genome sequencing, gene insertion mutation, isotope labelling, and precursor feeding demonstrated that the fatty acid chain was encoded by a non-canonical PKS/NRPS gene cluster, whereas the origin of N-ribityl 5,6-dimethylbenzimidazole was related to the vitamin B12 metabolism. The convergence of these two distinct biosynthetic pathways through a C-N coupling led to the unique chemical framework of myxadazoles, which is an unprecedented hybridization mode in the paradigm of natural products. Myxadazoles exhibited potent vasculogenesis promotion effect and moderate antithrombotic activity, underscoring their potential usage for the treatment of cardiovascular diseases.

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Topics: Gene cluster (52%), Isoxazole (52%)

3 Citations


Journal ArticleDOI: 10.1002/ANIE.202104182
Yan Zong1, Ze-Jun Xu1, Rongxiu Zhu1, Ai-Hong Su1  +6 moreInstitutions (1)
05 Jul 2021-Angewandte Chemie
Abstract: An enantioselective synthetic approach for preparing manginoids and guignardones, two types of biogenetically related meroterpenoids, is reported. This bioinspired and divergent synthesis employs an oxidative 1,3-dicarbonyl radical-initiated cyclization and cyclodehydration of the common precursor to forge the central ring of the manginoids and guignardones, respectively, at a late stage. Key synthetic steps include silica-gel-promoted semipinacol rearrangement to form the 6-oxabicyclo[3.2.1]octane skeleton and the Suzuki-Miyaura reaction of vinyl bromide to achieve fragment coupling. This synthesis protocol enables the asymmetric syntheses of four fungal meroterpenoids from commercially available materials.

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Topics: Semipinacol rearrangement (57%), Divergent synthesis (55%), Total synthesis (52%) ... show more

2 Citations


Open accessJournal Article
Abstract: A new grifolin derivative, named grifolene (1), together with grifolin (2), neogrifolin (3) and grifolic acid (4) was isolated from the fruiting bodies of the fungus Albatrellus yasuda. The structure of 1 was elucidated on the basis of extensive spectroscopic analysis.

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Topics: Albatrellus (56%), Polyporaceae (50%)

2 Citations


Journal ArticleDOI: 10.1016/J.BIOORG.2021.104950
Xiao-Hui Meng1, Fu-Ying Qin2, Xiao-Ting Jiang2, Yu Li1  +1 moreInstitutions (2)
Abstract: Five pairs of meroterpenoid enantiomers, (±)-gancochlearols J − N (1–5), were isolated from the fruiting bodies of Ganoderma cochlear. Their structures were elucidated on the basis of 1D and 2D NMR and HRESIMS data. The absolute configurations of gancochlearols J − M (1–4) were assigned by electronic circular dichroism (ECD) calculations. Biological evaluation showed that (–)-1 and (–)-2 could inhibit renal fibrosis in TGF-β1-induced rat kidney proximal tubular cells (NRK-52e).

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1 Citations


Journal ArticleDOI: 10.1021/ACS.ORGLETT.1C00951
Dexiu Yan1, Yudai Matsuda1Institutions (1)
16 Apr 2021-Organic Letters
Abstract: Heterologous expression of a cryptic gene cluster in the fungus Aspergillus funiculosus CBS 11656 led to the discovery of four new meroterpenoids, funiculolides A-D (1-4), derived from the aromatic polyketide 5-methylorsellinic acid (5-MOA) Intriguingly, funiculolide D (4), the apparent end product of the pathway, harbors an unusual spirocyclopentanone moiety, which is synthesized by the oxidative rearrangement catalyzed by the ferrous iron and α-ketoglutarate-dependent dioxygenase FncG

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Topics: Polyketide (52%), Heterologous expression (50%)

1 Citations


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475 results found


Open accessJournal ArticleDOI: 10.1038/NRD4510
Abstract: Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades, in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review strategies for natural product screening that harness the recent technical advances that have reduced these barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein-protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery.

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1,465 Citations


Journal ArticleDOI: 10.1016/S0162-3109(00)00188-0
Anthony C. Allison, Elsie M. Eugui1Institutions (1)
01 May 2000-Immunopharmacology
Abstract: Mycophenolate mofetil (MMF, CellCept(R)) is a prodrug of mycophenolic acid (MPA), an inhibitor of inosine monophosphate dehydrogenase (IMPDH). This is the rate-limiting enzyme in de novo synthesis of guanosine nucleotides. T- and B-lymphocytes are more dependent on this pathway than other cell types are. Moreover, MPA is a fivefold more potent inhibitor of the type II isoform of IMPDH, which is expressed in activated lymphocytes, than of the type I isoform of IMPDH, which is expressed in most cell types. MPA has therefore a more potent cytostatic effect on lymphocytes than on other cell types. This is the principal mechanism by which MPA exerts immunosuppressive effects. Three other mechanisms may also contribute to the efficacy of MPA in preventing allograft rejection and other applications. First, MPA can induce apoptosis of activated T-lymphocytes, which may eliminate clones of cells responding to antigenic stimulation. Second, by depleting guanosine nucleotides, MPA suppresses glycosylation and the expression of some adhesion molecules, thereby decreasing the recruitment of lymphocytes and monocytes into sites of inflammation and graft rejection. Third, by depleting guanosine nucleotides MPA also depletes tetrahydrobiopterin, a co-factor for the inducible form of nitric oxide synthase (iNOS). MPA therefore suppresses the production by iNOS of NO, and consequent tissue damage mediated by peroxynitrite. CellCept(R) suppresses T-lymphocytic responses to allogeneic cells and other antigens. The drug also suppresses primary, but not secondary, antibody responses. The efficacy of regimes including CellCept(R) in preventing allograft rejection, and in the treatment of rejection, is now firmly established. CellCept(R) is also efficacious in several experimental animal models of chronic rejection, and it is hoped that the drug will have the same effect in humans.

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Topics: Mycophenolate (65%), Mycophenolic acid (57%), Inosine-5′-monophosphate dehydrogenase (54%) ... show more

1,121 Citations


Journal ArticleDOI: 10.1038/NRMICRO3496
Abstract: Microorganisms produce a wealth of structurally diverse specialized metabolites with a remarkable range of biological activities and a wide variety of applications in medicine and agriculture, such as the treatment of infectious diseases and cancer, and the prevention of crop damage. Genomics has revealed that many microorganisms have far greater potential to produce specialized metabolites than was thought from classic bioactivity screens; however, realizing this potential has been hampered by the fact that many specialized metabolite biosynthetic gene clusters (BGCs) are not expressed in laboratory cultures. In this Review, we discuss the strategies that have been developed in bacteria and fungi to identify and induce the expression of such silent BGCs, and we briefly summarize methods for the isolation and structural characterization of their metabolic products.

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Topics: Fungal genetics (51%)

550 Citations


Open accessJournal ArticleDOI: 10.1016/J.CELL.2020.01.021
Jonathan M. Stokes1, Kevin Yang1, Kyle Swanson1, Wengong Jin1  +18 moreInstitutions (5)
20 Feb 2020-Cell
Abstract: Due to the rapid emergence of antibiotic-resistant bacteria, there is a growing need to discover new antibiotics. To address this challenge, we trained a deep neural network capable of predicting molecules with antibacterial activity. We performed predictions on multiple chemical libraries and discovered a molecule from the Drug Repurposing Hub-halicin-that is structurally divergent from conventional antibiotics and displays bactericidal activity against a wide phylogenetic spectrum of pathogens including Mycobacterium tuberculosis and carbapenem-resistant Enterobacteriaceae. Halicin also effectively treated Clostridioides difficile and pan-resistant Acinetobacter baumannii infections in murine models. Additionally, from a discrete set of 23 empirically tested predictions from >107 million molecules curated from the ZINC15 database, our model identified eight antibacterial compounds that are structurally distant from known antibiotics. This work highlights the utility of deep learning approaches to expand our antibiotic arsenal through the discovery of structurally distinct antibacterial molecules.

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467 Citations


Journal ArticleDOI: 10.1126/SCIENCE.282.5392.1324
Shenping Liu1, Joanne Widom1, Christopher W. Kemp1, Craig M. Crews1  +1 moreInstitutions (1)
13 Nov 1998-Science
Abstract: The fungal metabolite fumagillin suppresses the formation of new blood vessels, and a fumagillin analog is currently in clinical trials as an anticancer agent. The molecular target of fumagillin is methionine aminopeptidase-2 (MetAP-2). A 1.8 A resolution crystal structure of free and inhibited human MetAP-2 shows a covalent bond formed between a reactive epoxide of fumagillin and histidine-231 in the active site of MetAP-2. Extensive hydrophobic and water-mediated polar interactions with other parts of fumagillin provide additional affinity. Fumagillin-based drugs inhibit MetAP-2 but not MetAP-1, and the three-dimensional structure also indicates the likely determinants of this specificity. The structural basis for fumagillin's potency and specificity forms the starting point for structure-based drug design.

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Topics: Fumagillin (75%), METAP2 (58%)

391 Citations


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No. of citations received by the Paper in previous years
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202114
20161
20091