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Chemical Reviews Dec 2016Fostriecin and related natural products present a significant challenge for synthetic chemists due to their structural complexity and chemical sensitivity. This review... (Review)
Review
Fostriecin and related natural products present a significant challenge for synthetic chemists due to their structural complexity and chemical sensitivity. This review will chronicle the successful efforts of synthetic chemists in the construction of these biologically active molecules. Key carbon-carbon bond forming reactions will be highlighted, as well as the methods used to install the numerous stereocenters present in this class of compounds.
Topics: Alkenes; Biological Products; Cyclization; Cycloaddition Reaction; Hydroxylation; Lactones; Polyenes; Pyrones; Stereoisomerism
PubMed: 28027648
DOI: 10.1021/acs.chemrev.6b00488 -
Angewandte Chemie (International Ed. in... Nov 2019A biomimetic route to farnesyl pyrophosphate and dimethyl orsellinic acid (DMOA)-derived meroterpenoid scaffolds has yet to be reported despite great interest from the...
A biomimetic route to farnesyl pyrophosphate and dimethyl orsellinic acid (DMOA)-derived meroterpenoid scaffolds has yet to be reported despite great interest from the chemistry and biomedical research communities. A concise synthetic route with the potential to access DMOA-derived meroterpenoids is highly desirable to create a library of related compounds. Herein, we report novel dearomatization methodology followed by polyene cyclization to access DMOA-derived meroterpenoid frameworks in six steps from commercially available starting materials. Furthermore, several farnesyl alkene substrates were used to generate structurally novel, DMOA-derived meroterpenoid derivatives. DFT calculations combined with experimentation provided a rationale for the observed thermodynamic distribution of polycyclization products.
Topics: Biomimetics; Cyclization; Polyenes; Polyisoprenyl Phosphates; Sesquiterpenes; Terpenes
PubMed: 31515901
DOI: 10.1002/anie.201910710 -
Applied and Environmental Microbiology Oct 2013Recent work has uncovered genes for two glycosyltransferases that are thought to catalyze mannosylation of mycosaminyl sugars of polyene macrolides. These two genes are...
Recent work has uncovered genes for two glycosyltransferases that are thought to catalyze mannosylation of mycosaminyl sugars of polyene macrolides. These two genes are nypY from Pseudonocardia sp. strain P1 and pegA from Actinoplanes caeruleus. Here we analyze these genes by heterologous expression in various strains of Streptomyces nodosus, producer of amphotericins, and in Streptomyces albidoflavus, which produces candicidins. The NypY glycosyltransferase converted amphotericins A and B and 7-oxo-amphotericin B to disaccharide-modified forms in vivo. The enzyme did not act on amphotericin analogs lacking exocyclic carboxyl or mycosamine amino groups. Both NypY and PegA acted on candicidins. This work confirms the functions of these glycosyltransferases and provides insights into their acceptor substrate tolerance. Disaccharide-modified polyenes may have potential as less toxic antibiotics.
Topics: Actinomycetales; Anti-Bacterial Agents; Biosynthetic Pathways; Disaccharides; Glycosyltransferases; Macrolides; Metabolic Engineering; Polyenes; Recombinant Proteins; Streptomyces
PubMed: 23913424
DOI: 10.1128/AEM.02197-13 -
Chemphyschem : a European Journal of... Dec 2022A detailed computational study of the intramolecular Alder-ene reaction of different 1,6-dienes at M06-2X(PCM)/TZ2P level of theory has been performed. We want to...
A detailed computational study of the intramolecular Alder-ene reaction of different 1,6-dienes at M06-2X(PCM)/TZ2P level of theory has been performed. We want to understand the influence of enophile-geminal substitution pattern in the cis : trans selectivity of the cyclization process. Our analysis of the reaction coordinate by means of activation strain model of chemical reactivity (ASM-distortion interaction model) reveals that the cis-selectivity observed for unactivated reagents is related with high stabilizing orbital interaction and lower strain energy, consequence of an early transition structure. On the other hand, the presence of activating groups increases the asynchronicity of the transition structures and reduces the activation barrier due to more stabilizing orbital and electrostatic interactions, favoring trans-selectivity.
Topics: Models, Molecular; Alnus; Polyenes
PubMed: 35942565
DOI: 10.1002/cphc.202200377 -
Microbial Biotechnology May 2014Bacteria from the Bacteroidetes phylum are known producers of the chemotaxonomic relevant flexirubins. These orange pigments comprise a non-isoprenoid aryl-polyene...
Bacteria from the Bacteroidetes phylum are known producers of the chemotaxonomic relevant flexirubins. These orange pigments comprise a non-isoprenoid aryl-polyene carboxylic acid esterified with a dialkylresorcinol. Herein, we report a gene cluster from Chitinophaga pinensis encoding the biosynthesis of the polyene moiety and the biochemical characterization of a tyrosine ammonia-lyase and a 4-coumarate-CoA ligase responsible for the initiation of the polyene biosynthesis. Additionally, the flexirubin of C. pinensis was characterized by a combination of feeding experiments, high-performance liquid chromatography tandem mass spectrometry and matrix-assisted laser desorption/ionization mass spectrometry.
Topics: Ammonia-Lyases; Bacteroidetes; Biosynthetic Pathways; Chromatography, High Pressure Liquid; Coenzyme A Ligases; Multigene Family; Polyenes; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tandem Mass Spectrometry
PubMed: 24467333
DOI: 10.1111/1751-7915.12110 -
Comparative Biochemistry and... Mar 2019The activities of two effectors, brevetoxin (PbTx) and manumycin-A (Man-A), of thioredoxin reductase (TrxR) have been evaluated against a series of fourteen TrxR...
The activities of two effectors, brevetoxin (PbTx) and manumycin-A (Man-A), of thioredoxin reductase (TrxR) have been evaluated against a series of fourteen TrxR orthologs originating from mammals, insects and protists and several mutants. Man-A, a molecule with numerous electrophilic sites, forms a covalent adduct with most selenocystine (Sec)-containing TrxR enzymes. The evidence also demonstrates that Man-A can form covalent adducts with some non-Sec-containing enzymes. The activities of TrxR enzymes towards various substrates are moderated by Man-A either positively or negatively depending on the enzyme. In general, the reduction of substrates by Sec-containing TrxR is inhibited and NADPH oxidase activity is activated. For non-Sec-containing TrxR the effect of Man-A on the reduction of substrates is variable, but NADPH oxidase activity can be activated even in the absence of covalent modification of TrxR. The effect of PbTx is less pronounced. A smaller subset of enzymes is affected by PbTx. With a single exception, the activities of most of this subset are activated. Although both PbTx variants can react with selenocysteine, a stable covalent adduct is not formed with any of the TrxR enzymes. The key findings from this work are (i) the identification of an alternate mechanism of toxicity for the algal toxin brevetoxin (ii) the demonstration that covalent modification of TrxR is not a prerequisite for the activation of NADPH oxidase activity of TrxR and (iii) the identification of an inhibitor which can discriminate between cytosolic and mitochondrial TrxR.
Topics: Animals; Gene Expression Regulation, Enzymologic; Humans; Insecta; Mammals; Marine Toxins; NADPH Oxidases; Oxocins; Polyenes; Polyunsaturated Alkamides; Species Specificity; Thioredoxin-Disulfide Reductase; Thioredoxins
PubMed: 30476593
DOI: 10.1016/j.cbpc.2018.11.015 -
Journal of the American Chemical Society Apr 2022We report the development of ureas as sterically undemanding pro-ligands for Pd catalysis. -Arylureas outperform phosphine ligands for the Pd-catalyzed heteroannulation...
We report the development of ureas as sterically undemanding pro-ligands for Pd catalysis. -Arylureas outperform phosphine ligands for the Pd-catalyzed heteroannulation of -tosyl--bromoanilines and 1,3-dienes, engaging diverse coupling partners for the preparation of 2-subsituted indolines, including sterically demanding substrates that have not previously been tolerated. Experimental and computational studies on model Pd-urea and Pd-ureate complexes are consistent with monodentate binding through the nonsubstituted nitrogen, which is uncommon for metal-ureate complexes.
Topics: Catalysis; Ligands; Palladium; Polyenes; Urea
PubMed: 35380831
DOI: 10.1021/jacs.2c01019 -
The Journal of Antibiotics Dec 1974
Topics: Animals; Binding Sites; Chickens; Cholesterol; Filipin; Intestinal Mucosa; Liposomes; Phosphatidylcholines; Polyenes; Protein Binding
PubMed: 4478771
DOI: 10.7164/antibiotics.27.943 -
Annals of Clinical Microbiology and... May 2014There is a pressing need to identify novel antifungal drug targets to aid in the therapy of life-threatening mycoses and overcome increasing drug resistance. Identifying... (Comparative Study)
Comparative Study
BACKGROUND
There is a pressing need to identify novel antifungal drug targets to aid in the therapy of life-threatening mycoses and overcome increasing drug resistance. Identifying specific mechanisms of action of membrane-interacting antimicrobial drugs on the model fungus Saccharomyces cerevisiae is one avenue towards addressing this issue. The S. cerevisiae deletion mutants Δizh2, Δizh3, Δaif1 and Δstm1 were demonstrated to be resistant to amphibian-derived antimicrobial peptides (AMPs). The purpose of this study was to examine whether AMPs and polyene antifungals have a similar mode of action; this was done by comparing the relative tolerance of the mutants listed above to both classes of antifungal.
FINDINGS
In support of previous findings on solid media it was shown that Δizh2 and Δizh3 mutants had increased resistance to both amphotericin B (1-2 μg ml-1) and nystatin (2.5 - 5 μg ml-1) in liquid culture, after acute exposure. However, Δaif1 and Δstm1 had wild-type levels of susceptibility to these polyenes. The generation of reactive oxygen species (ROS) after exposure to amphotericin B was also reduced in Δizh2 and Δizh3. These data indicated that polyene antifungal and AMPs may act via distinct mechanisms of inducing cell death in S. cerevisiae.
CONCLUSIONS
Further understanding of the mechanism(s) involved in causing cell death and the roles of IZH2 and IZH3 in drug susceptibility may help to inform improved drug design and treatment of fungal pathogens.
Topics: Amphotericin B; Antifungal Agents; Antimicrobial Cationic Peptides; Gene Deletion; Microbial Sensitivity Tests; Microbial Viability; Nystatin; Polyenes; Saccharomyces cerevisiae
PubMed: 24884795
DOI: 10.1186/1476-0711-13-18 -
Journal of Pharmacy & Pharmaceutical... 2003The purpose of this review article is to review the development of a number of liposomal polyene antibiotics. (Review)
Review
PURPOSE
The purpose of this review article is to review the development of a number of liposomal polyene antibiotics.
BACKGROUND
In the past thirty years, the increase in life-threatening pre-systemic and systemic fungal infections within cancer, diabetic and AIDS patients have reached alarming proportions. A number of antifungal agents have been developed to combat this problem. In particular, polyene antibiotics such as Amphotericin B (AmB) and Nystatin (Nys) have remained the most effective and widely used agents in the treatment of these infections. However, their administration is limited by dose-dependent toxicities. One such dose-limiting toxicity is renal toxicity. Polyene antibiotic-induced renal toxicity is believed to be mediated by the drug anchoring to cholesterol within the mammalian cell membrane, resulting in pore formation, abnormal electrolyte flux, decrease in adenosine triphosphate (ATP), and eventually a loss of cell viability.
CONCLUSION
In the 1980s and 90s a number of promising lipid-based AmB and Nys formulations were developed to overcome these toxicities. This article will review the development of these liposomal polyene antibiotics.
Topics: Adenosine Triphosphate; Amphotericin B; Animals; Antifungal Agents; Chemistry, Pharmaceutical; Cholesterol; Drug Carriers; Drug Delivery Systems; History, 20th Century; History, 21st Century; Humans; Liposomes; Nystatin; Polyenes
PubMed: 12753730
DOI: No ID Found