3-acyltetramic Acid Research Articles

Study of Amino Acid-Derived 3-Acyltetramic Acids as Herbicidal Agents.

The growing problem of herbicide resistance necessitates the development of novel herbicidal active ingredients, together with other integrated weed management approaches. Natural products are a major source of inspiration for novel actives. In previous research, we identified a 3-acyltetramic acid of microbial origin that inhibited algal growth in marine biofilms, at least in part through inhibition of photosystem II. In this work, we demonstrate the herbicidal effect of this lead compound and construct multiple libraries to test the impact of the different substituents of the central scaffold in order to study the structure-activity relationships. Among these analogues, the highest activities were found for medium- to long-chain acyl groups and apolar secondary amino acid residues. Finally, we provide first insights into the herbicidal mechanisms and present preliminary field-trial and ecotoxicological results for TA12-Pro, the most active analogue in our library. Together, this research shows the potential of 3-acyltetramic acids for herbicide development.

Biological production of epicoccamide-aglycone and its cytotoxicity

Epicoccamide (EPC) is an O-d-mannosylated acyltetramic acid of Epicoccum origin and is a bolaamphiphilic fungal polyketide. EPC displays weak toxicity against Staphylococcus aureus and HeLa cell lines. The EPC biosynthetic gene cluster was previously identified in Epicoccum nigrum and knockout of the glycosyltransferase gene (epcB) abolished EPC production. EPC-aglycone was expected in the epcB knockout but was not found. This study demonstrates that extractive culture using the hydrophobic resin Diaion HP-20 resulted in the production of EPC-aglycone, which was isolated using chromatographic separation techniques, and its structural identity was substantiated by chemical analyses. EPC-aglycone displayed strong antibacterial activity against Staphylococcus aureus, with the minimal inhibitory concentration of 1 μg/mL (64 μg/mL for EPC). EPC-aglycone displayed higher levels of growth inhibition against HeLa cell line (the half inhibitory concentration, 19 μM) and WI-38 (15 μM) cell line than EPC (76 μM and 38 μM vs. HeLa and WI-38, respectively). The dose–response curve fit of growth inhibition indicated that EPC-aglycone adopted a shallow curve (low slope factor), which was different from that of EPC, suggesting that their cellular targets are distinct from each other. This study substantiates that the d-mannose attachment is the final step in EPC biosynthesis, showcasing a glycosylation-mediated modulation of the biological activity of simple acyltetramic acid. This study also highlights the usefulness of extractive cultures in mining cryptic microbial natural products.

Efficient Total Synthesis and Herbicidal Activity of 3-Acyltetramic Acids: Endogenous Abscisic Acid Synthesis Regulators.

An efficient synthesis method will allow a large number of tetramic acid analogues to be synthesized for property and potency optimization. In this study, a facile and efficient method was described for the synthesis of 3-acyltetramic acids. The synthesis was accomplished mainly via (1) mild intramolecular cyclization and (2) the formation of β-ketoamides between nucleophiles and acyl Meldrum's acids. 3-Acyltetramic acid exhibited phytotoxicity against Echinochloa crusgalli and Portulaca oleracea. At a dosage of 750 g ha-1, 6k and 6a showed high herbicidal activity against E. crusgalli, Digitaria sanguinalis and P. oleracea, Amaranthus retroflexus, respectively. 6k inhibited the synthesis of endogenous abscisic acid, thus seedling germination and plant growth. The incorporation of various acyl Meldrum's acids and amino acid esters was applicable to the parallel synthesis of 3-acyltetramic acids. The mode of action and herbicidal activity indicate that 3-tetramic acid had good herbicidal performance and was a promising herbicide candidate. This study will provide a reference for novel herbicide development.

Synthetic Approach to the Natural N-Nitrosohydroxylamino Tetramic Acid JBIR-141.

An analogue of the Streptomyces metabolite JBIR-141, featuring a delicate N-nitrosohydroxylamine, a 3-acyltetramic acid, and an oxazoline, was synthesized by a convergent strategy from l-alanine, l-threonine, and l-glutamic acid. Key steps were the cyclization of an Ala-Thr derivative to give the oxazoline, a Dieckmann condensation affording the 3-acyltetramic acid, and the N-nitrosation of a hydroxylamino derivative of glutamic acid. An adequate protecting group strategy was established for coupling the three building blocks.

New 3-Acyl Tetramic Acid Derivatives from the Deep-Sea-Derived Fungus Lecanicillium fusisporum.

Seven rare C3-C6 reduced 3-acyl tetramic acid derivatives, lecanicilliumins A–G (1–7), along with the known analogue cladosporiumin D (8), were obtained from the extract of the deep-sea-derived fungus Lecanicillium fusisporum GXIMD00542 within the family Clavipitacae. Their structures were elucidated by extensive spectroscopic data analysis, quantum chemistry calculations and chemical reaction. Compounds 1, 2, 5–7 exhibited moderate anti-inflammatory activity against NF-κB production using lipopolysaccharide (LPS) induced RAW264.7 cells with EC50 values range of 18.49–30.19 μM.

Trichoderma reesei Contains a Biosynthetic Gene Cluster That Encodes the Antifungal Agent Ilicicolin H.

The trili biosynthetic gene cluster (BGC) from the well-studied organism Trichoderma reesei was studied by heterologous expression in the fungal host Aspergillus oryzae. Coexpression of triliA and triliB produces two new acyl tetramic acids. Addition of the ring-expanding cytochrome P450 encoded by triliC then yields a known pyridone intermediate to ilicicolin H and a new chain-truncated shunt metabolite. Finally, addition of the intramolecular Diels-Alderase encoded by triliD affords a mixture of 8-epi ilicicolin H and ilicicolin H itself, showing that the T. reesei trili BGC encodes biosynthesis of this potent antifungal agent. Unexpected A. oryzae shunt pathways are responsible for the production of the new compounds, emphasising the role of fungal hosts in catalysing diversification reactions.

Synthesis and Bioactivity of a Macrocidin B Stereoisomer.

A stereoisomer of macrocidin B, a presumed metabolite of the fungus Phoma macrostoma, was synthesized in 18 steps and 2.7% yield from protected l-tyrosine that was N-β-ketoacylated with a fully functionalized octanoyl Meldrum's acid. Dieckmann condensation gave a 3-acyltetramic acid, which was macrocyclized via Williamson etherification between the phenol and epi-bromohydrin termini. This macrocidin B stereoisomer showed a weaker herbicidal effect than macrocidin A and no similar inhibitory effect on biofilms of Staphylococcus aureus.

Natural tetramic acids elicit multiple inhibitory actions against mitochondrial machineries presiding over oxidative phosphorylation.

The mitochondrial machineries presiding over ATP synthesis via oxidative phosphorylation are promising druggable targets. Fusaramin, a 3-acyl tetramic acid isolated from Fusarium concentricum FKI-7550, is an inhibitor of oxidative phosphorylation in Saccharomyces cerevisiae mitochondria, although its target has yet to be identified. Fusaramin significantly interfered with [3H]ADP uptake by yeast mitochondria at the concentration range inhibiting oxidative phosphorylation. A photoreactive fusaramin derivative (pFS-5) specifically labeled voltage-dependent anion channel 1 (VDAC1), which facilitates trafficking of ADP/ATP across the outer mitochondrial membrane. These results strongly suggest that the inhibition of oxidative phosphorylation by fusaramin is predominantly attributable to the impairment of VDAC1 functions. Fusaramin also inhibited FoF1-ATP synthase and ubiquinol-cytochrome c oxidoreductase (complex III) at concentrations higher than those required for the VDAC inhibition. Considering that other tetramic acid derivatives are reported to inhibit FoF1-ATP synthase and complex III, natural tetramic acids were found to elicit multiple inhibitory actions against mitochondrial machineries.

Aminotenuazonic Acid: Isolation, Structure Elucidation, Total Synthesis and Herbicidal Activity of a New Tetramic Acid from Fruiting Bodies of Laccaria Species.

(5S,6S)-Aminotenuazonic acid, a new 3-acyltetramic acid, related to the well-known mycotoxin tenuazonic acid has been isolated from fruiting bodies of Laccaria bicolor. Its structure was mostly established by analysis of its 2D NMR and HR-(+)-ESI-MS spectra. A total synthesis starting from N-Boc-l-isoleucine gave (5S,6S)-aminotenuazonic acid in 8 % yield over nine steps (67 % de). The key steps of the total synthesis are a light-initiated Hofmann-Löffler-Freytag radical chain reaction and a Dieckmann cyclisation. The relative and absolute configurations of the natural product were determined by comparison of its NMR and CD spectra with those of the corresponding enantiopure synthetic compounds. Metabolic profiling of crude extracts of different mushrooms showed that aminotenuazonic acid is present in all four of the investigated Laccaria species. Aminotenuazonic acid shows phytotoxic activities against the root and shoot growth of Lepidium sativum, Pinus sylvestris and Arabidopsis thaliana comparable to those of tenuazonic acid.

A Synthetic Route to the MT1-MMP Inhibitor Ancorinoside D

A methyl ester of ancorinoside D, a 3-acyltetramic acid metabolite of a sponge Penares sollasi, was synthesised in ten steps starting from a protected β-d-glucopyranosyl-(1→4)-d-galactopyranosyltrichloroacetimidate donor. Its attachment to the left half of the 3-acyl spacer by a Schmidt glycosylation, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-mediated oxidation to the uronic acid, introduction of the Z-alkene via Wittig reaction, and functionalisation of the spacer terminus with Meldrum’s acid gave a β-keto ester that reacted with dimethyl N-methyl-d-aspartate under neutral conditions to afford a fully protected ancorinoside D as the product of an unusual domino N-acylation–Dieckmann condensation. Global deprotection left a methyl ester of ancorinoside D, which resisted all saponification attempts.

Nematicidal Activity of 3-Acyltetramic Acid Analogues Against Pine Wood Nematode, Bursaphelenchus xylophilus.

Among 98 3-acyltetramic acid analogues, compounds 1c, 2c, 2f and 2g, showed >90% nematicidal activity against the pine wood nematode Bursaphelenchus xylophilus at a 10 μg/mL concentration. The nematicidal activities of compounds 1d, 1h, and 2k were a little lower at 88.0%, 85.8%, and 57.2% at a 10 μg/mL concentration, respectively. The nematicidal activity of emamection benzoate, widely used in Korea for the prevention of pine wilt disease, was 32.3% at a 10 μg/mL concentration. Other 3-acyltetramic acid analogues showed less than 30% nematicidal activity. A structure-activity relationship study indicated that the chain length of the C-acyl substituent was very important for high nematicidal activity. All active compounds had C13H27 or C11H23 acyl substituents, in two closely related groups with the common physicochemical properties of a polar surface area 57.6A2, PSA (polar surface area) 7.8–8.6% and ClogP (calculated partition coefficient) 5.1–5.9 and a polar surface area 75–84A2, PSA 11.1–11.6% and ClogP 4.7–5.1, respectively. Our study indicates that active 3-acyltetramic acid analogues could have potential as lead compounds for developing novel pine wood nematode control agents.

Synthesis of the fungus metabolite cladosin C

Cladosin C is one of the few known enaminotetramic acids, isolated from extracts of the deep sea fungus Cladosporium sphaerospermum. It was synthesised in ten steps and 14% overall yield by a late-stage amination of the corresponding 3-acyltetramic acid. This was obtained by a Dieckmann condensation of an N-β-ketoacylaminoester derived from dehydrovalinate and the thioester-terminated side chain containing the stereogenic centre which stemmed from poly-(R)-3-hydroxybutyrate.

Synthesis of an Isomer of the Decalinoyltetramic Acid Methiosetin by a Stereocontrolled IMDA Reaction of a Metal-Chelated 3-Trienoyltetramate.

An isomer of the 3-decalinoyltetramic acid methiosetin was synthesized for the first time. The decalin moiety was established by a late-stage intramolecular Diels-Alder cyclization catalyzed by Me2AlCl or La(OTf)3. Its high diastereoselectivity arose from stereoinduction by a well-defined metal O,O-chelate complex of the 3-acyltetramic acid moiety. The nature of the metal and the bulkiness of the residues at the tetramic acid chelator are decisive for the stereochemical outcome.

Total Synthesis of Aurantoside G, an N-β-Glycosylated 3-Oligoenoyltetramic Acid from Theonella swinhoei.

The first synthesis of a natural N-glycosylated 3-acyltetramic acid is reported. Aurantoside G (1 g), a deep-red metabolite of the marine sponge Theonella swinhoei, is highly delicate in the pure state. It features a chlorinated dodecapentaenoyl side chain at an l-asparagine-derived tetramic acid, the ring nitrogen atom of which is linked to a β-configured d-xylose. The side chain was built through consecutive Wittig and HWE reactions and used to N-acylate the amino group of an asparaginate that had already been N-xylosylated through a Fukuyama-Mitsunobu reaction. This N-acylation step fixes the β-configuration of the xylose, which is essential for the antifungal activity, but only if the sugar carries bulky, electron-rich protecting groups such as PMB. In the final step, the heterocycle was closed quantitatively through a basic Lacey-Dieckmann condensation of an entirely unprotected precursor.

A simple and efficient method for the preparation of 5-hydroxy-3-acyltetramic acids.

Oxidation of the bisenolates of 3-acyltetramic acid to the corresponding 5-hydroxylated compounds using molecular oxygen is reported. The deprotection of the resulting compounds was also achieved.

ChemInform Abstract: Total Synthesis of (+)‐Fusarisetin A: A Biomimetic Approach.

This article outlines our recent efforts to synthesize (+)-fusarisetin A, a naturally occurring 3-acyltetramic acid, by a route based on a hypothetical biosynthesis. Our research suggests that the biosynthesis of (+)-fusarisetin A might involve the aerobic oxidation of equisetin, possibly mediated by metal oxidants or by photochemically produced reactive oxygen species.

ChemInform Abstract: New Routes Towards Reutericyclin Analogues.

AbstractA range of N‐acylpyrrolo[3,4‐c]isoxazoles [cf.

New routes towards reutericyclin analogues

A range of N-acylpyrrolo[3,4-c]isoxazoles and derived N-acyltetramides has been prepared via a nitrile oxide dipolar cycloaddition approach, as analogues of the acyltetramic acid metabolite reutericyclin, of interest for its antibiotic potential against Gram-positive bacteria including hospital-acquired infections of resistant Clostridium difficile.

Total Synthesis of (+)-Fusarisetin A: A Biomimetic Approach

This article outlines our recent efforts to synthesize (+)-fusarisetin A, a naturally occurring 3-acyltetramic acid, by a route based on a hypothetical biosynthesis. Our research suggests that the biosynthesis of (+)-fusarisetin A might involve the aerobic oxidation of equisetin, possibly mediated by metal oxidants or by photochemically produced reactive oxygen species.

Biomimetic Synthesis of Equisetin and (+)‐Fusarisetin A

(+)-Fusarisetin A belongs to a group of acyl tetramic acid natural products that show potential anticancer activity. Equisetin, a biogenetically related acyl tetramic acid, contains the basic skeleton of (+)-fusarisetin A. We proposed that equisetin and (+)-fusarisetin A share a biosynthetic pathway that starts with naturally occurring (S)-serine and an unsaturated fatty acid. In support of this hypothesis, we have demonstrated that a cyclization sequence involving an intramolecular Diels-Alder reaction followed by a Dieckmann cyclization of polyenoylamino acid yielded equisetin. The aerobic oxidation of equisetin, promoted by either Mn(III)/O2 or a reactive oxygen species (ROS) produced by visible-light chemistry, gave peroxyfusarisetin, which could be easily reduced to (+)-fusarisetin A. We report herein detailed information on the biogenetic synthesis of equisetin and (+)-fusarisetin A.