tetronic-acid and tetramic-acid

Covering: up to 20153-Acylated tetramic and tetronic acids are characterized by a low pKa and are likely to be deprotonated under physiological conditions. In addition, their structure makes them excellent chelators of metallic cations. We will discuss the significance of these chemical properties with regard to the biological properties and mechanisms of action of these compounds, highlighting the importance of considering them as salts or chelates for biological purposes, rather than acids.

Topics: Acylation; Biological Products; Furans; Molecular Structure; Pyrrolidinones

Significant developments in the isolation of tetramic acids and tetronic acids, in the elucidation of their biosyntheses and their biological activities and in laboratory syntheses are reviewed with a focus on those derivatives with medicinal and pharmacological relevance. Important new members of the title compound families isolated since the year 2000 are covered as well as new biological aspects of some earlier congeners.

Topics: Animals; Biology; Furans; Humans; Peptides; Pyrrolidinones; Structure-Activity Relationship

Natural products containing tetronic acid or tetramic acid moieties continue to attract the interest of chemists, biologists, and physicians due to their challenging structures and to the wide range of biological activities they display. This review portrays the structural varieties of tetronic and tetramic acids and the spectrum of possible therapeutically relevant effects in man for exemplary derivatives. Their biosynthetic origin from alpha-amino and alpha-hydroxy acids is briefly discussed as is the relationship between their structures and their modes of interaction with biochemical effectors such as metal cations or enzymes. A short overview of laboratory syntheses of the heterocyclic core structures of tetramic and tetronic acids is provided with an emphasis on those emulating the biosynthesis. A synthesis from the alpha-amino or alpha-hydroxy esters and the cumulated phosphorus ylide Ph(3)PCCO based upon a domino addition-intra-Wittig alkenation sequence is presented with applications to the preparation of the antibiotics reutericyclin and tenuazonic acid, the cytotoxic melophlin B, and the enzyme inhibitor RK-682. Procedural advantages of immobilizing either starting component by attaching it to a resin and its exploitation in the parallel synthesis of libraries of potential drug candidates are described. The basic domino reaction can even be extended by further C-C bond forming steps when starting from suitable alpha-hydroxy or alpha-amino allyl esters. Depending on the chosen reaction conditions, bioactive intermediates of formally three to seven step long cascades can be obtained. Among them, herbicidal 3-alkyltetronic acids and lactone endoperoxides with antiplasmodial activity exceeding that of the natural antimalarial lead artemisinin. Hence, this domino reaction gives access to diversely functionalized derivatives of tetronic and tetramic acids. As it can also be ported to solid phase, it is ideally suited for parallel and combinatorial processing. Future developments might include running such domino sequences in continuous mode in arrays of "labs on microchips".

Topics: Biological Products; Furans; Polyketide Synthases; Pyrrolidinones

A series of 3-oxo-C12-HSL, tetramic acid, and tetronic acid analogues were synthesized to gain insights into the structural requirements for quorum sensing inhibition in Staphylococcus aureus. Compounds active against agr were noncompetitive inhibitors of the autoinducing peptide (AIP) activated AgrC receptor, by altering the activation efficacy of the cognate AIP-1. They appeared to act as negative allosteric modulators and are exemplified by 3-tetradecanoyltetronic acid 17, which reduced nasal cell colonization and arthritis in a murine infection model.

Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; Cell Line; Furans; Indicators and Reagents; Iron Chelating Agents; Mice; Microbial Sensitivity Tests; Nasal Cavity; Peptides, Cyclic; Protein Kinases; Pyrrolidinones; Quorum Sensing; Signal Transduction; Small Molecule Libraries; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship

Nodulisporacid A (1) was isolated from a marine-derived fungus Nodulisporium sp. CRIF1, while vermelhotin (5) was obtained from an unidentified fungus CRI247-01 (a member of the Order Pleosporales). Both 1 and 5 occurred as equilibrium E/Z mixtures. Ester derivatives (2 and 3) and vermelhotin (5) showed cytotoxic activity against eleven cancer cell lines. Nodulisporacid A (1) and vermelhotin (5) exhibited moderate antiplasmodial activity.

Topics: 4-Butyrolactone; Animals; Antimalarials; Antineoplastic Agents, Phytogenic; Biological Products; Cell Line, Tumor; Drug Screening Assays, Antitumor; Furans; Humans; Molecular Structure; Plasmodium falciparum; Pyrrolidines; Pyrrolidinones; Xylariales

Based on a pharmacophore hypothesis substituted tetramic and tetronic acid 3-carboxamides as well as dihydropyridin-2-one-3-carboxamides were investigated as inhibitors of undecaprenyl pyrophosphate synthase (UPPS) for use as novel antimicrobial agents. Synthesis and structure-activity relationship patterns for this class of compounds are discussed. Selectivity data and antibacterial activities for selected compounds are provided.

Topics: Alkyl and Aryl Transferases; Amides; Cyclization; Drug Design; Enzyme Inhibitors; Escherichia coli; Furans; Microbial Sensitivity Tests; Molecular Structure; Polyisoprenyl Phosphates; Protein Conformation; Pyrrolidinones; Sesquiterpenes; Streptococcus pneumoniae; Structure-Activity Relationship