equisetin and tetramic-acid

A late stage Diels-Alder reaction is used to prepare a mixture of JBIR-22, a natural product from the Equisetin family of tetramic acids, and one of its diastereomers. This is achieved in just 8 steps from pyruvate. The success of the late stage DA approach is discussed in the context of the biosynthesis of JBIR-22 (and perhaps related natural products).

Topics: Cyclization; Molecular Structure; Naphthalenes; Pyrrolidinones; Stereoisomerism; Tetrahydronaphthalenes

Coculture of the fungus Fusarium pallidoroseum with the bacterium Saccharopolyspora erythraea was found to produce three new decalin-type tetramic acid analogues related to equisetin. The structures were determined by spectroscopic methods. The absolute configurations were established by circular dichroism spectroscopy and comparing the data with those of equisetin.

Topics: Coculture Techniques; Fusarium; Molecular Structure; Pyrrolidinones; Saccharopolyspora; Tetrahydronaphthalenes

Three new decalin-type tetramic acid analogues, pyrrolocins A (1), B (2), and C (3), were defined as products of a metabolic pathway from a fern endophyte, NRRL 50135, from Papua New Guinea. NRRL 50135 initially produced 1 but ceased its production before chemical or biological evaluation could be completed. Upon transfer of the biosynthetic pathway to a model host, 1-3 were produced. All three compounds are structurally related to equisetin-type compounds, with 1 and 3 having a trans-decalin ring system, while 2 has a cis-fused decalin. All were active against Mycobacterium tuberculosis, with the trans-decalin analogues 1 and 3 exhibiting lower MICs than the cis-decalin analogue 2. Here we report the isolation, structure elucidation, and antimycobacterial activities of 1-3 from the recombinant expression as well as the isolation of 1 from the wild-type fungus NRRL 50135.

Topics: Anti-Bacterial Agents; Bacillus subtilis; Endophytes; Ferns; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Mycobacterium tuberculosis; Naphthalenes; Nuclear Magnetic Resonance, Biomolecular; Papua New Guinea; Pyrrolidinones; Staphylococcus aureus; Stereoisomerism; Streptococcus pneumoniae; Tetrahydronaphthalenes

Tetramic acids constitute a large class of natural products isolated from a variety of different fungal and bacterial species. While the presence of the distinctive 2,4-pyrrolidinedione ring system defines this class of compounds, these compounds are widely diverse both structurally and in the biological activities that they display. Equisetin-like compounds are tetramic acids that have been shown to be growth inhibitory towards bacteria, fungi, yeasts and mammalian cell lines; however, the mechanisms inhibiting prokaryotic and eukaryotic cell growth have not been fully explained. Here we report the isolation and biological characterisation of a novel equisetin-like tetramic acid named tetramic acid-289 (TA-289) produced by a Fusarium sp. fungus. This compound displayed pH- and carbon source-dependent cytotoxic effects in Saccharomyces cerevisiae and caused an irreversible cell cycle block via a microtubule independent mechanism. To fully elucidate a mechanism, we used an unbiased approach employing chemogenomic profiling of the yeast deletion library and demonstrated that TA-289 hypersensitive deletion strains are also sensitive to oxidants, respiratory inhibitors and have abnormal mitochondrial morphology. In support of the hypothesis that TA-289 perturbs mitochondrial function, we demonstrated the ability of this compound to generate reactive oxygen species only during fermentative growth, an effect reliant on an intact electron transport chain. In addition, mitochondrial morphological defects were detected upon exposure to TA-289 independent of the increase in oxidative stress. The generation of reactive oxygen species was not the sole cause of cell death by TA-289, as only partial amelioration of cell death was achieved by the deletion of genes encoding components of the electron transport chain, despite these deletions causing attenuation of the magnitude of oxidative stress. We propose that TA-289 induces cell death via the direct inhibition of a mitochondrially localised target or targets, and that the mitochondrial morphology defect and ROS production observed in this study is a direct consequence of the induction of cell death. This study highlights the complex interplay between mitochondrial function, cell death and the generation of reactive oxygen species when elucidating the mode-of-action of compounds that cause oxidative stress and cell death, and further deepens the mystery surrounding the molecular basis of the activity of equisetin-like

Topics: Antifungal Agents; Cell Cycle; Gene Expression Regulation, Fungal; Hydrogen-Ion Concentration; Membrane Potential, Mitochondrial; Microbial Viability; Mitochondria; Oxidative Stress; Pyrrolidinones; Reactive Oxygen Species; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Signal Transduction; Tetrahydronaphthalenes

(+)-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.

Topics: Antineoplastic Agents, Phytogenic; Biomimetics; Cyclization; Cycloaddition Reaction; Heterocyclic Compounds, 4 or More Rings; Oxidation-Reduction; Pyrrolidinones; Stereoisomerism; Tetrahydronaphthalenes