ascofuranone and ascochlorin

Fungi-derived polyketide-terpenoid hybrids are important meroterpenoid natural products that possess diverse structure scaffolds with a broad spectrum of bioactivities. Herein, we focus on an ever-increasing group of meroterpenoids, orsellinic acid-sesquiterpene hybrids comprised of biosynthetic start unit orsellinic acid coupling to a farnesyl group or/and its modified cyclic products. The review entails the search of China National Knowledge Infrastructure (CNKI), Web of Science, Science Direct, Google Scholar, and PubMed databases up to June 2022. The key terms include "orsellinic acid", "sesquiterpene", "ascochlorin", "ascofuranone", and "

Topics: Ascomycota; Humans; Sesquiterpenes; Terpenes

Covering: up to July 2020Fungal meroterpenoid cyclases are a recently discovered emerging family of membrane-integrated, non-canonical terpene cyclases. They catalyze the conversion of hybrid isoprenic precursors towards complex scaffolds and are therefore of great importance in the structure diversification in meroterpenoid biosynthesis. The products of these pathways exhibit intriguing molecular scaffolds and highly potent bioactivities, making them privileged structures from Nature and attractive candidates for drug development or industrial applications. This review will provide a comprehensive and comparative view on fungal meroterpenoid cyclases, their intriguing chemistries and importance for the scaffold formation step towards polycyclic meroterpenoid natural products.

Topics: Alkenes; Biological Products; Carboxy-Lyases; Diterpenes; Fungal Proteins; Phenols; Phylogeny; Pyridines; Pyrones; Sesquiterpenes; Terpenes

Ascofuranone (AF) and ascochlorin (AC) are meroterpenoids produced by various filamentous fungi, including

Topics: Acremonium; Alkenes; Biosynthetic Pathways; Fungal Proteins; Genes, Fungal; Models, Molecular; Multigene Family; Phenols; Sesquiterpenes

Topics: Acremonium; Alkenes; Ascomycota; Fermentation; Phenols; Phylogeny; Sesquiterpenes

Trypanosoma brucei is a parasite that causes human African trypanosomiasis (HAT). The parasites depend on the cyanide-insensitive trypanosome alternative oxidase (TAO) for their vital aerobic respiration. Ascofuranone (AF), a potent and specific sub-nanomolar inhibitor of the TAO quinol oxidase, is a potential novel drug with selectivity for HAT, because mammalian hosts lack the enzyme. To elucidate not only the inhibition mechanism but also the inhibitor-enzyme interaction, AF derivatives were designed and synthesized, and the structure-activity relationship was evaluated. Here we identified the pharmacophore of AF that interacts with TAO. The detailed inhibitory profiles indicated that the 1-formyl and 6-hydroxyl groups, which might contribute to intramolecular hydrogen bonding and/or serve as hydrogen-bonding donors, were responsible for direct interaction with the enzyme.

Topics: Alkenes; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Molecular Structure; Oxidoreductases; Phenols; Protozoan Proteins; Recombinant Proteins; Sesquiterpenes; Structure-Activity Relationship; Trypanosoma brucei brucei; Trypanosomiasis, African

Living organisms have developed a wide variety of energy metabolism to survive within the specialized environments. There is a remarkable diversity in mitochondrial electron transport system, which might be potential targets for chemotherapy. Atovaquone, clinically used to treat malaria and pneumocystis pneumonia, is a specific inhibitor of Qo site in the cytochrome bc(1) complex of Plasmodium falciparum and Pneumocystis jirovecii. Phytopathogenic fungus, Ascochyta viciae produces two antibiotics, ascochlorin and ascofuranone. Ascochlorin specifically binds to inhibit the electron transport of both Qi and Qo sites in cytochrome bc(1) complex. Besides the unique respiratory inhibition, further investigation is in progress to elucidate the effects on cancer cells. On the other hand, ascofuranone specifically inhibits cyanide-insensitive trypanosome alternative oxidase, which is a sole terminal oxidase in the mitochondrion of Trypanosoma brucei, causative of African trypanosomiasis. In vivo study suggests that ascofuranone is a promising candidate for chemotherapeutic agents to treat African trypanosomiasis.

Topics: Alkenes; Animals; Anti-Infective Agents; Antimalarials; Atovaquone; Humans; Mitochondria; Phenols; Sesquiterpenes

Ascochlorin, a prenylphenol antitumor antibiotic, profoundly increases the expression of endogenous p53 by increasing protein stability in the human osteosarcoma cells and human colon cancer cells. Ascochlorin also increases DNA binding activity to the p53 consensus sequence in nuclear extract and enhances transcription of p53 downstream targets. Ascochlorin specifically induces p53 phosphorylation at ser 392 without affecting ser 15 or 20, whereas DNA damaging agents typically phosphorylate these serines. Moreover, ascochlorin does not induce phosphorylation of ATM and CHK1, an established substrate of ATR that is activated by genotoxins, nor does it increase DNA strand break, as confirmed by comet assay. The structure-activity relationship suggests that p53 activation by ascochlorin is related to inhibition of mitochondrial respiration, which is further supported by the observation that respiratory inhibitors activate p53 in a manner similar to ascochlorin. These results suggest that ascochlorin, through the inhibition of mitochondrial respiration, activates p53 through a mechanism distinct from genotoxins.

Topics: Adenosine Triphosphate; Alkenes; Antibiotics, Antineoplastic; Ataxia Telangiectasia Mutated Proteins; Blotting, Western; Bone Neoplasms; Cell Cycle Proteins; Cell Line, Tumor; Cell Respiration; Checkpoint Kinase 1; Comet Assay; DNA Breaks, Double-Stranded; DNA-Binding Proteins; Electrophoretic Mobility Shift Assay; Fluorescent Antibody Technique; Humans; Mitochondria; Osteosarcoma; Phenols; Phosphorylation; Protein Kinases; Protein Serine-Threonine Kinases; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Serine; Sesquiterpenes; Structure-Activity Relationship; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

Dihydroorotate Dehydrogenase (DHODH) catalyzes the rate-limiting step in pyrimidine biosynthesis, and its inhibitors have been developed as drugs for treatment of immune diseases. We studied new DHODH inhibitors from microbial metabolites.. We established a rapid and effective high throughput screening method for screening DHODH inhibitors from microbial metabolites. The active compounds were isolated from the candidate strain by column chromatography and preparative HPLC.. We picked out F01WB-1315 strain as candidate from 4560 fungal strains. We isolated two active compounds F01WB-1315A and B, with IC50 of 0.07 microg/mL and 0.51 microg/mL, respectively. F01WB-1315B could completely inhibit the spleen lymphocytes proliferation stimulated by ConA in vitro, but F01WB-1315A only had 31.62% inhibitory activity. F01WB-1315A, B were identified to be Ascofuranone and Ascochlorin by their physicochemical properties, MS, 13C-NMR and 1H-NMR analysis.. F01WB-1315A and B are two strong specific DHODH inhibitors and show moderate inhibitory activity against spleen lymphocytes proliferation.

Topics: Alkenes; Animals; Cell Proliferation; Cells, Cultured; Dihydroorotate Dehydrogenase; Enzyme Inhibitors; Fungi; Lymphocytes; Magnetic Resonance Spectroscopy; Mice; Oxidoreductases Acting on CH-CH Group Donors; Phenols; Sesquiterpenes; Spectrometry, Mass, Electrospray Ionization

Nuclear receptor family proteins are structurally related transcription factors activated by specific lipophilic compounds. Because they are activated by a variety of hormonal molecules, including retinoic acid, vitamin D, and steroid hormones, they are assumed to be promising targets for clinical drugs. We previously found that one ascochlorin (1) derivative, 4-O-carboxymethyl-ascochlorin (2), is a potent agonist of peroxisome proliferator activated receptor gamma (PPARgamma). Here, we synthesized derivatives of 1, designated as a lead compound, to create new modulators of nuclear hormone receptors. Two derivatives, 4-O-carboxymethyl-2-O-methylascochlorin (9) and 4-O-isonicotinoyl-2-O-methylascochlorin (10), showed improved agonistic activity for PPARgamma and induced differentiation of a progenitor cell line, C3H10T1/2. We also found that 1, dehydroascofuranon (29), and a 2,4-O-diacetyl-1-carboxylic acid derivative of 1 (5) specifically activated estrogen receptors, PPARalpha, and an androgen receptor. All of the derivatives (1-29) activated the pregnane X receptor. These results suggest that the chemical structure of 1 is useful in designing novel modulators of nuclear receptors.

Topics: Alkenes; Animals; Cell Differentiation; Cells, Cultured; Fibroblasts; Furans; Genes, Reporter; Genetic Vectors; Glycolates; Humans; Inhibitory Concentration 50; Ligands; Mice; Models, Molecular; Osteosarcoma; Phenols; Plasmids; Receptors, Cytoplasmic and Nuclear; Recombinant Proteins; Rosiglitazone; Thiazoles; Thiazolidinediones; Transcription Factors; Transfection