Metabolic Investigation and Auxiliary Enzyme Modelization of the Pyrrocidine Pathway Allow Rationalization of Paracyclophane-Decahydrofluorene Formation.

Fungal paracyclophane-decahydrofluorene-containing natural products are complex polycyclic metabolites derived from similar hybrid PKS-NRPS pathways. Herein we studied the biosynthesis of pyrrocidines, one representative of this family, by gene inactivation in the producer coupled to thorough metabolic analysis and molecular modeling of key enzymes. We characterized nine pyrrocidines and analogues as well as in mutants a variety of accumulating metabolites with new structures including rare -decalin, cytochalasan, and fused 6/15/5 macrocycles.

Combinatory Library of Microorganisms in the Selection of Reductive Activity Applied to a Ketone Mixture: Unexpected Highlighting of an Enantioselective Oxidative Activity.

Biocatalytic processes are increasingly used in organic synthesis for the preparation of targeted molecules or the generation of molecular diversity. The search for the biocatalyst is often the bottleneck in the development of the process. We described a combinatorial approach for the selection of active strains from a library of microorganisms.

Bioconversion of antifungal viridin to phytotoxin viridiol by environmental non-viridin producing microorganisms.

Biotransformation of viridin, an antifungal produced by biocontrol agent, with non-viridin producing microorganisms is studied. The results show that some environmental non-targeted microorganisms are able to reduce it in the known phytotoxin viridiol, and its 3-epimer. Consequently, this reduction, which happens in some cases by detoxification mechanism, could be disastrous for the plant in a biocontrol of plant disease.

Biotransformation of guttiferones, metabolites, by , an endophytic fungus isolated from its leaves.

The search for active microorganisms for the biotransformation of guttiferone A (1) and C (6) has been successfully undertaken from a collection of endophytic fungi of Symphonia globulifera. Of the twenty-five isolates obtained from the leaves, three are active and have been identified as Bipolaris cactivora. The products obtained are the result of xanthone cyclisation with the formation of two regioisomers among four possible and corresponding to 1,16-oxy-guttiferone and 3,16-oxy-guttiferone.

Molecular crosstalk between the endophyte Paraconiothyrium variabile and the phytopathogen Fusarium oxysporum - Modulation of lipoxygenase activity and beauvericin production during the interaction.

Plants comprise many asymptomatic fungal endophytes with potential roles of plant protection against abiotic and biotic stresses. Endophytes communicate with their host plant, with other endophytes and with invading pathogens but their language remains largely unknown. This work aims at understanding the chemical communication and physiological interactions between the fungal endophyte Paraconiothyrium variabile and the phytopathogen Fusarium oxysporum.

Identification of Antimicrobial Compounds from -Associated Endophyte Using Molecular Network Approach.

The emergence of multidrug resistant bacterial pathogens and the increase of antimicrobial resistance constitutes a major health challenge, leading to intense research efforts being focused on the discovery of novel antimicrobial compounds. In this study, endophytes were isolated from different parts of plant (leaves, wood and latex) belonging to the Euphorbiaceae family and known to produce antimicrobial compounds, and chemically characterised using Molecular Network in order to discover novel antimicrobial molecules. One fungal endophyte extract obtained from latex showed significant antimicrobial activity with Minimal Inhibitory Concentration on methicillin-resistant at 16 µg/mL.

Inhibition of Phytophthora species, agents of cocoa black pod disease, by secondary metabolites of Trichoderma species.

Cocoa production is affected by the black pod disease caused by several Phytophthora species that bring, about each year, an estimated loss of 44% of world production. Chemical control remains expensive and poses an enormous risk of poisoning for the users and the environment. Biocontrol by using antagonistic microorganisms has become an alternative to the integrated control strategy against this disease.

Microbial biotransformation of furosemide for environmental risk assessment: identification of metabolites and toxicological evaluation.

Some widely prescribed drugs are sparsely metabolized and end up in the environment. They can thus be a focal point of ecotoxicity, either themselves or their environmental transformation products. In this context, we present a study concerning furosemide, a diuretic, which is mainly excreted unchanged.

A coupled Bio-EF process for mineralization of the pharmaceuticals furosemide and ranitidine: Feasibility assessment.

A coupled Bio-EF treatment has been applied as a reliable process for the degradation of the pharmaceuticals furosemide (FRSM) and ranitidine (RNTD) in aqueous medium, in order to reduce the high energy consumption related to electrochemical technology. In the first stage of this study, electrochemical degradation of the drugs was assessed by the electro-Fenton process (EF) using a BDD/carbon-felt cell. Biodegradability of the drugs solutions was enhanced reaching BOD5/COD ratios close to the biodegradability threshold of 0.

Bioelectro-Fenton: A sustainable integrated process for removal of organic pollutants from water: Application to mineralization of metoprolol.

The relevant environmental hazard related to the presence of pharmaceuticals in water sources requires the development of high effective and suitable wastewater treatment technologies. In the present work, a hybrid process coupling electro-Fenton (EF) process and aerobic biological treatment (Bio-EF process) was implemented for the efficient and cost-effective mineralization of beta-blocker metoprolol (MPTL) aqueous solutions. Firstly, operating factors influencing EF process were assessed.

Unexpected talaroenamine derivatives and an undescribed polyester from the fungus Talaromyces stipitatus ATCC10500.

Chemical investigation of the fungus Talaromyces stipitatus ATCC 10500, whose genome has been sequenced, led to the isolation of four undescribed talaroenamines B-E along with the known talaroenamine A. Their structures were elucidated on the basis of spectroscopic studies including mass spectrometry, extensive 2D NMR and electronic circular dichroism (ECD). Interestingly, talaroenamine A had previously been isolated from the strain of T.

Direct biosynthetic cyclization of a distorted paracyclophane highlighted by double isotopic labelling of L-tyrosine.

The biosynthesis of pyrrocidines, fungal PK-NRP compounds featuring a strained [9]paracyclophane, was investigated in Acremonium zeae. We used a synthetic L-tyrosine probe, labelled with oxygen 18 as a reporter of phenol reactivity and carbon 13 as a tracer of incorporation of this exogenous precursor. The ((18)O)phenolic oxygen was incorporated, suggesting that phenol behaves as a nucleophile during the formation of the bent aryl ether.

The fungal leaf endophyte Paraconiothyrium variabile specifically metabolizes the host-plant metabolome for its own benefit.

Fungal endophytes live inside plant tissues and some have been found to provide benefits to their host. Nevertheless, their ecological impact is not adequately understood. Considering the fact that endophytes are continuously interacting with their hosts, it is conceivable that both partners have substantial influence on each other's metabolic processes.

Anticipating the fate and impact of organic environmental contaminants: a new approach applied to the pharmaceutical furosemide.

The presence of trace levels of organic contaminants in the environment is currently an environmental concern. When these contaminants are subjected to environmental transformations, environmental transformation products (ETPs) are obtained, whose structures often remain unknown. The absence of information concerning these new compounds makes them unavailable and consequently makes their environmental detection as well as their (eco)toxicological study impossible.

Synthesis of novel guttiferone A derivatives: in-vitro evaluation toward Plasmodium falciparum, Trypanosoma brucei and Leishmania donovani.

The catechol pharmacomodulation of the natural product guttiferone A, isolated from the Symphonia globulifera tree, led to the semisynthesis of a collection of twenty derivatives. The ester and ether derivatives of guttiferone A were evaluated for their anti-plasmodial, trypanocidal and anti-leishmanial activities. Some compounds described below have shown potent antiparasitic activity against Plasmodium falciparum, Trypanosoma brucei and Leishmania donovani in a range from 1 to 5 μM.

Yeast-mediated xanthone synthesis through oxidative intramolecular cyclization.

Benzoylphloroglucinol derivatives are natural products showing diverse biological activities that could be modulated by structural modifications. For this purpose, we studied the biotransformation of guttiferone A and of maclurin using a combinatorial approach for screening active microorganism strains. We found a novel and unexpected yeast-catalyzed oxidation that has selectively given a new oxy-guttiferone A and norathyriol.

A new cytochrome P450 belonging to the 107L subfamily is responsible for the efficient hydroxylation of the drug terfenadine by Streptomyces platensis.

Fexofenadine, an antihistamine drug used in allergic rhinitis treatment, can be produced by oxidative biotransformation of terfenadine by Streptomyces platensis, which involves three consecutive oxidation reactions. We report here the purification and identification of the enzyme responsible for the first step, a cytochrome P450 (P450)-dependent monooxygenase. The corresponding P450, designated P450(terf), was found to catalyze the hydroxylation of the t-butyl group of terfenadine and exhibited UV-Vis characteristics of a P450.

Semisynthesis and antiproliferative evaluation of a series of 3'-aminoflavones.

A series of 3'-aminoflavones 5,6,7,8-tetra- or 5,7-dioxygenated on the A-ring was synthesized from tangeretin or naringin, two natural Citrus flavonoids. These flavones were evaluated for antiproliferative activity, activation of apoptosis, and inhibition of tubulin assembly. The most antiproliferative flavones exhibit a common 5-hydroxy-6,7,8-trimethoxy substitution pattern on the A-ring.

Biotransformation of polymethoxylated flavonoids: access to their 4'-O-demethylated metabolites.

Regioselective O-demethylation of the flavones tangeretin (1) and 3-hydroxytangeretin (6) into their 4'-O-demethylated metabolites was performed by using an Aspergillus niger strain. This method serves as a straightforward alternative to multistep synthesis or semisynthesis. The microbial approach is complementary to the chemical procedure, which furnishes a 5-O-demethylated product.

Design and synthesis of selective, high-affinity inhibitors of human cytochrome P450 2J2.

The active site topology, substrate specificity, and biological roles of the human cytochrome P450 CYP2J2, which is mainly expressed in the cardiovascular system, are poorly known even though recent data suggest that it could be a novel biomarker and potential target for therapy of human cancer. This paper reports a first series of high-affinity, selective CYP2J2 inhibitors that are related to terfenadine, with K(i) values as low as 160nM, that should be useful tools to determine the biological roles of CYP2J2.

Microbial oxidation of terfenadine and ebastine into fexofenadine and carebastine.

The oxidation of tert-butyl-phenyl group of title compounds by some microorganisms was studied. We have optimized the conditions of culture to increase the formation of acid metabolites and to avoid the formation of side products. We showed that an oxidative activity is induced by soybean peptones in Streptomyces platensis.