Ascosalipyrrolidinone A, an antimicrobial alkaloid, from the obligate marine fungus Ascochyta salicorniae

From the green alga Ulva sp., the endophytic and obligate marine fungus Ascochyta salicorniae was isolated. A. salicorniae was mass cultivated and found to produce the unprecedented and structurally unusual tetramic acid containing metabolites ascosalipyrrolidinones A (1) and B (2). Additionally, the new natural product ascosalipyrone (3) and the known metabolites 4 and 5 were obtained. Ascosalipyrrolidinone A (1) has antiplasmodial activity toward Plasmodium falciparum strains K1 and NF 54, as well as showing antimicrobial activity and inhibiting tyrosine kinase p56lck.     

Epicoccarines A, B and epipyridone: tetramic acids and pyridone alkaloids from an Epicoccum sp. associated with the tree fungus Pholiota squarrosa

Investigation of the metabolic profile of a fungus (Epicoccum sp.) isolated from the fruiting body of the tree fungus Pholiota squarrosa led to the discovery of two novel tetramic acid derivatives, epicoccarine A (2) and B (3), as well as a new pyridone alkaloid, epipyridone (1), with an unusually cyclized side chain. It appears that 1 is biogenetically derived from the ring expansion of 2 followed by a proposed hetero-Diels-Alder reaction. 2 shows selective antibacterial activity against Gram positive bacteria, in particular Mycobacterium vaccae.     

Equisetin biosynthesis in Fusarium heterosporum

An iterative polyketide synthase-peptide synthetase hybrid assembles the HIV-1 integrase inhibitory tetramic acid, equisetin, in the filamentous fungus Fusarium heterosporum.     

Melophlins P, Q, R, and S: four new tetramic acid derivatives, from two Palauan marine sponges of the genus Melophlus

Four new tetramic acid derivatives, named melophlins P, Q, R, and S (1-4), were isolated from two marine sponges of the genus Melophlus collected at Palau, together with seven known melophlins A, D, E, G, H, I, and O. The structures of the new compounds were elucidated on the basis of their spectral data. The absolute stereochemistries at the tetramic acid moieties of the new compounds were determined as 1 : 1 mixtures (racemic) by ESI-LC/MS analysis of derivatives obtained by oxidation and hydrolysis of the respective parent compounds. Melophlins P-S (1-4) showed cytotoxicity against the murine leukemia cell line L1210 with IC(50) values of 20.0, 10.5, 0.85, and 5.13 muM, respectively.     

Penicillenols from Penicillium sp. GQ-7, an endophytic fungus associated with Aegiceras corniculatum

Six new tetramic acids derivatives, penicillenols A(1), A(2), B(1), B(2), C(1), and C(2) (1-6), together with citrinin, phenol A acid, phenol A, and dihydrocitrinin, were identified from Penicillium sp. GQ-7, an endophytic fungus associated with Aegiceras corniculatum. Their structures were elucidated on the basis of comprehensive spectral analysis. All the new compounds were evaluated for their cytotoxic effects on four cell lines by the MTT method. Penicillenols A(1) and B(1) showed cytotoxicities against HL-60 cell line with IC(50) values of 0.76 microM and 3.20 microM, respectively.     

Synthesis of spirotetramates via a Diels-Alder approach

A study toward the unusual spirotetramate core of the pyrroindomycin antibiotics employing an intermolecular Diels-Alder reaction of an exo-methylene tetramic acid dienophile is described. The exo-methylene tetramate is readily synthesized from S-methylcysteine, and its reactivity as a dienophile is compared with that of related dehydroalanine derivatives. An alternative approach to spirotetramates using a nitroalkene dienophile is also reported.     

A New Glycine Derivative and a New Indole Alkaloid from the Fermentation Broth of the Plant Endophytic Fungus Pestalotiopsis podocarpi Isolated from the Chinese Podocarpaceae Plant Podocarpus macrophyllus

A new glycine derivative, podocarpiamide ( 1 ), a new indole alkaloid, 1‐methoxy‐1H‐indol‐3‐ethanol ( 2 ), together with two known compounds, 1‐methoxy‐1H‐indole‐3‐acetic acid ( 3 ) and methyl 1‐methoxy‐1H‐indole‐3‐acetate ( 4 ), were isolated from the fermentation broth of the plant endophytic fungus Pestalotiopsis podocarpi. Their structures were elucidated by extensive spectroscopic analysis including 1D‐ and 2D‐NMR (HSQC, HMBC, and COSY) and MS experiments. Compound 1 has an interesting unusual carbamic acid structure.     

Synthesis and spectroscopic studies of 5‐arylidene‐3‐substituted tetramic acids as possible substrates for catalytic asymmetric hydrogenation

A new series of 5‐arylidene‐3‐substituted tetramic acids 6–19 have been synthesized by a condensation reaction of 3‐butanoyl tetramic acid 3 , 3‐ethoxycarbonyl tetramic acid 4 and 3 ‐acetyl tetramic acid 5 with a variety of substituted benzaldehydes. The structures of the isolated compounds 6–19 have been elucidated using FT‐IR, ¹H and ¹³C‐NMR spectroscopy, FAB‐MS spectroscopy as well as elemental analyses.     

Cytotoxic polyketides containing tetramic acid moieties isolated from the fungus Myceliophthora Thermophila: elucidation of the relationship between cytotoxicity and stereoconfiguration

Five new polyketides that contain tetramic acids, myceliothermophins A-E, were isolated from the thermophilic fungus Myceliophthora thermophila. Two sets of 5-alkyl-5-hydroxyl (or 5-methoxyl)-1H-pyrrol-2(5H)-one diastereomers, myceliothermophins A/B and C/D, were separated as pure compounds by using silica-gel column chromatography and recycling reverse-phase high-performance liquid chromatography (RP-HPLC). The relative configurations of the chiral centers in 5-alkyl-5-hydroxyl (or 5-methoxyl)-1H-pyrrol-2(5H)-one moieties were deduced from NOESY correlations. In the cytotoxic assay, the 5-(2-methylpropyldiene)-1H-pyrrol-2(5H)-one analogue (myceliothermophin E) exhibited inhibition against four cancer cell lines. In addition, the significant inhibitory effect of myceliothermophins A and C and the inactivity of myceliothermophins B and D revealed the importance of the relative configurations of 5-alkyl-5-hydroxyl (or 5-methoxyl)-1H-pyrrol-2(5H)-one moieties on their cytotoxicity potency against cancer cells.     

Tetramic acid and imidazolidinone syntheses via unexpected base induced cyclisations of alanine derived Weinreb amides

Reactions of N-protected derivatives of Weinreb amides of alanine with strong base unexpectedly gave tetramic acid derivatives or an imidazolidinone. The tetramic acid derivatives were obtained by unusual cyclisation of N-acyl N-methoxy derivatives of alanine Weinreb amide upon treatment with potassium hexamethyldisilazide and benzyl bromide. In contrast, treatment of a bromobenzylidine alanine Weinreb amide with potassium hexamethyldisilazide gave rise to cyclisation to form an imidazolidinone.     

Cryptocin, a potent tetramic acid antimycotic from the endophytic fungus Cryptosporiopsis cf. quercina

[formula: see text] The endophytic fungus Cryptosporiopsis cf. quercina produces cryptocin in culture. Among other fungi, this unique tetramic acid displays antimycotic activity against Pyricularia oryzae, the causal agent of rice blast disease. Cryptocin also possesses activity against a wide variety of plant pathogenic but not human pathogenic fungi. The fine rhomboid-like crystals of cryptocin allowed structural elucidation by X-ray crystallography. The importance of cryptocin to the symbiotic relationship of C. quercina to its hosts is briefly discussed.     

Synthesis of and tautomerism in 3-acyltetramic acids

The synthesis of 3-acyltetramic acids, the substructure of bioactive natural products, via O-acylation of tetramic acids with carboxylic acids followed by acyl migration, has been investigated. This acylation sequence is mediated by N,N'-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) and is very sensitive to the nature of the nitrogen substituent (R(1)), the nature of the carboxylic acid (R(2)CO(2)H), and the amount of DMAP. Acylation of N-acyl tetramic acids with an alkyl carboxylic acid using 1.3 equiv of DMAP (with 1.1 equiv of DCC) unexpectedly gave the 3-acyltetramic acid directly as a result of acyl migration induced by excess amounts of DMAP. On the other hand, N-unsubstituted, N-alkyl, and N-acyl tetramic acids with alkyl and aromatic carboxylic acids gave the O-acyl tetramic acids by using only 0.1 equiv of DMAP (with 1.1 equiv of DCC); these could be further rearranged to the acyl product by treatment with excess DMAP. The tautomeric equilibrium of these 3-acyltetramic acids in solution was found to strongly depend on the nitrogen substituent group (R(1)) rather than the 3-acyl group.     

Mild Construction of 3-Methyl Tetramic Acids Enabling a Formal Synthesis of Palau'imide

A general method to construct 3-methyl-4-O-methylated tetramic acids displaying a C-5 stereocenter is presented. The synthetic sequence employs a SmI(2)-mediated cyclization, whereby the chirality of the emerging tetramic acid core is retained from the starting chiral amino acid. Application to palau'imide is discussed.     

A concise,asymmetric synthesis of tetramic acid derivatives

[reaction: see text] A simple, asymmetric synthesis of tetramic acid derivatives is described in this paper. The key step is a carbonyl transfer from carbonyldiimidazole (CDI) to alpha-diimines (I) to form N-alkyl-4-alkylamino-5-methylenepyrrol-2-ones (II). In turn, these compounds can be easily transformed into tetramic acid derivatives (III) in two additional steps.     

Heliconols A-C: antimicrobial hemiketals from the freshwater aquatic fungus Helicodendron giganteum

[Structure: see text] Cultures of the freshwater aquatic fungus Helicodendron giganteum afforded three new compounds, heliconols A-C (1-3), that contain an unusual reduced furanocyclopentane unit. The structures of these metabolites were assigned by analysis of 1D and 2D NMR data. The absolute configuration of heliconol A (1) was assigned by single-crystal X-ray crystallographic analysis of its dibromobenzoate derivative. Heliconol A showed antifungal and antibacterial activities in disk diffusion assays.     

Cytotoxic tetramic acid derivative produced by a plant type-III polyketide synthase

The tetramic acid (2,4-pyrrolidinedione) scaffold has been recognized as an important structural feature because of its mycotoxic, antibacterial, antiviral, and antioxidant activities. This important class of natural products is reportedly produced by the type-I polyketide synthase/nonribosomal peptide synthetase (PKS/NRPS) hybrid megaenzyme systems. In contrast, the benzalacetone synthase (BAS) from Rheum palmatum is a structurally simple, plant-specific type-III PKS that catalyzes the one-step decarboxylative condensation of malonyl-CoA with 4-coumaroyl-CoA. The type-III PKS exhibits unusually broad substrate specificity and notable catalytic versatility. Here we report that R. palmatum BAS efficiently produces a series of unnatural, novel tetramic acid derivatives by the condensation of malonyl-CoA with aminoacyl-CoA thioesters chemically synthesized from L- and D-amino acids. Remarkably, the novel tetramic acid dimer D-5 formed from D-phenylalanoyl-CoA showed moderate antiproliferative activity against murine leukemia P388 cells.     

Fusaroside, a unique glycolipid from Fusarium sp., an endophytic fungus isolated from Melia azedarach

Fusaroside (1), a unique trehalose-containing glycolipid composed of the 4-hydroxyl group of a trehalose unit attached to the carboxylic carbon of a long-chain fatty acid, was isolated from the organic extract of fermentation broths of an endophytic fungus, Fusarium sp. LN-11 isolated from the leaves of Melia azedarach. Six known compounds, phalluside (2), (9R*,10R*,7E)-6, 9,10-trihydroxyoctadec-7-enoic acid (3), porrigenic acid (4), (9Z)-2,3-dihydroxypropyl octadeca-9-enoate (5), cerevisterol (6) and ergokonin B (7), were also isolated from this fungus. The glycolipid contains a rare branched long-chain fatty acid (C(20:4)) with a conjugated diene moiety and a conjugated ketone moiety. The structure of the new compound 1 was elucidated by spectroscopic methods (1D and 2D NMR experiments, MS) and chemical degradations. The metabolites 1-5 were shown to have moderate to weak active against the brine shrimp larvae. To our knowledge, this is the first report of isolation of the first representative of a new family of glycolipids from natural sources.     

Highly oxygenated lanostane triterpenoids from the fungus Ganoderma applanatum

Two new highly oxygenated lanostane triterpenoids, ganoderic acid AP2 (1) and ganoderic acid AP3 (2), were isolated from the fruiting bodies of the fungus Ganoderma applanatum (Ganodermataceae), along with four known analogues, ganoderenic acids A, B, D and G (3-6). The structures of the new compounds were elucidated on the basis of extensive spectroscopic analysis.     

Thioesterase-like role for fungal PKS-NRPS hybrid reductive domains

Fungal reduced polyketides possess diverse structures exploring a broad region of chemical space despite their synthesis by very similar enzymes. Many fungal polyketides are capped by diverse amino acid-derived five-membered rings, the tetramic acids and related pyrrolidine-2-ones. The known tetramic acid synthetase enzymes in fungi contain C-terminal reductive (R) domains that were proposed to release reduced pyrrolidine-2-one intermediates en route to the tetramic acids. To determine the enzymatic basis of pyrrolidine-2-one diversity, we overexpressed equisetin synthetase (EqiS) R domains and analyzed their reactivity with synthetic substrate analogs. We show that the EqiS R domain does not perform a reducing function and does not bind reducing cofactors. Instead, the EqiS R catalyzes a Dieckmann condensation, with an estimated kcat approximately 15 s(-1). This role differs from the redox reactions normally catalyzed by short chain dehydrogenase/reductase superfamily enzymes.     

Gastrolatathioneine,an unusual ergothioneine derivative from an aqueous extract of “tian ma”: A natural product co-produced by plant and symbiotic fungus

Gastrolatathioneine (1), an unusual natural product derived from ergothioneine, a fungal amino acid containing an imidazole-2-thione moiety, was isolated from an aqueous extract of "tian ma" (the Gastrodia elata rhizomes). The structure of 1 including the absolute configuration was determined by extensive spectroscopic data analysis, combined with comparison of an experimental circular dichroism spectrum and calculated electronic circular dichroism spectra of stereoisomers, and confirmed by X-ray crystallography. The natural origin of 1 was proved by HPLC-ESIMS analysis of the crude extract. A biogenetic pathway of 1 is proposed on the basis of metabolic post-modification of ergothioneine that is biosynthesized by a symbiotic fungus. The plant and symbiotic fungus are co-producers of 1.