anisomycin and preussin

Triple-negative breast cancer (TNBC) represents an aggressive subtype of breast cancer (BC) with a typically poorer prognosis than other subtypes of BC and limited therapeutic options. Therefore, new drugs would be particularly welcome to help treat TNBC. Preussin, isolated from the marine sponge-associated fungus,

Topics: Anisomycin; Cell Line, Tumor; Cell Proliferation; Humans; MDA-MB-231 Cells; Triple Negative Breast Neoplasms

Topics: Animals; Anisomycin; Antineoplastic Agents; Aspergillus; Breast Neoplasms; Cell Culture Techniques; Cell Proliferation; Cell Survival; Drug Screening Assays, Antitumor; Female; Humans; MCF-7 Cells; Porifera

New pyrrolidine alkaloids, preussins C-I (1-7) and (11 R)/(11 S)-preussins J and K (8 and 9), were isolated from the sponge-derived fungus Aspergillus flocculosus 16D-1. The structures and configurations of these preussins were elucidated by detailed spectroscopic analysis, modified Mosher's method, and comparisons with literature data. These compounds showed strong to moderate inhibitory activity toward IL-6 production in lipopolysaccharide-induced THP-1 cells with IC

Topics: Animals; Anisomycin; Antibiotics, Antineoplastic; Antifungal Agents; Aspergillus; Cell Line; Humans; Interleukin-6; Lipopolysaccharides; Magnetic Resonance Spectroscopy; Porifera

Short syntheses of oxa-preussin, racemic preussin and (-)-preussin are reported. Starting from a racemic 3-nonyl-substituted methoxyallene derivative, its lithiation and addition to phenylethanal provided the corresponding allenyl alcohol that was converted into two diastereomeric dihydrofuran derivatives by silver nitrate-catalyzed 5-endo-trig cyclization. The acid hydrolysis of the enol ether moiety gave heterocyclic ketones and subsequent highly stereoselective reductions with l-selectride furnished 2-benzyl-5-nonylfuran-3-ol derivatives in good overall yield. The major all-cis-diastereomer has the skeleton and relative configuration of preussin and is hence called oxa-preussin. An analogous sequence with the same allene, but an N-sulfonyl imine as the electrophile, finally led to racemic preussin. The stereoselectivities of the individual steps are discussed in detail. With an enantiopure 2-benzyl-5-nonylpyrrolidin-3-one intermediate the preparation of (-)-preussin with an enantiomeric ratio of >95 : 5 could be accomplished in a few steps. The sign of the optical rotation of this product finally proved the absolute configurations of its precursors and demonstrated that our chiral auxiliary-based route led to the antipode of the natural product. The cytotoxicity of several of the prepared heterocycles against MCF-7 tumor cells was investigated and five compounds, including racemic and enantiopure (-)-preussin, were identified as highly cytotoxic with IC50 values in the range of 3-6 μM.

Topics: Alcohols; Alkadienes; Anisomycin; Catalysis; Cytotoxins; Humans; Hydrolysis; Inhibitory Concentration 50; Ketones; MCF-7 Cells; Stereoisomerism

A diastereoselective approach to trans-4-hydroxy-5-substituted 2-pyrrolidinones 1 (P

Topics: Amino Acids; Anisomycin; Depsipeptides; Lactams; Lactones; Molecular Conformation; Pyrrolidinones; Stereoisomerism

A new pyrrolidine alkaloid, preussin B (1), was isolated from the culture extract of the fungus Simplicillium lanosoniveum TAMA 173 along with the known congener preussin (2). The structure and absolute configuration of 1 were determined by spectroscopic analysis and spectral comparison with 2. Feeding experiments with 13C-labeled precursors revealed that the pyrrolidine ring of 1 was assembled from acetate and l-phenylalanine by a PKS-NRPS hybrid biosynthetic pathway.

Topics: Alkaloids; Anisomycin; Hypocreales; Molecular Structure; Multienzyme Complexes; Peptide Synthases; Phenylalanine; Stereoisomerism; Streptomyces

A straightforward and stereoselective synthesis of the alkaloid preussin is described starting from decanal and diethyl 3-diazo-2-oxopropylphosphonate. The key steps are an aza-Michael reaction from an α,β-unsaturated diazoketone followed by a highly stereoselective Cu-catalyzed ylide formation and then a [1,2]-Stevens rearrangement. This strategy is feasible for extension to preussin analogues, demonstrating its utility for the rapid construction of all-cis-substituted pyrrolidines.

Topics: Aldehydes; Anisomycin; Molecular Structure; Stereoisomerism

A convergent and stereoselective synthesis of 2,5-disubstituted 3-hydroxypyrrolidines has been developed that involves reductive annulation of β-iminochlorohydrins, which are readily available from β-ketochlorohydrins, and provides rapid access to a variety of 2,5-syn-pyrrolidines. Application of this process to the concise (three-step) synthesis of the fungal metabolite (+)-preussin and analogues of this substance is reported.

Topics: Anisomycin; Molecular Structure; Stereoisomerism; Time Factors

Topics: Alkaloids; Alkylation; Amides; Anisomycin; Combinatorial Chemistry Techniques; Ketones; Lactams; Molecular Structure; Oxidation-Reduction; Piperidines; Pyrrolidines; Stereoisomerism

(S)-N-(2-pyrrolidinylmethyl)pyrrolidine/trifluoroacetic acid (3:1) combination catalyzed the direct addition of alkyl methyl ketones to beta-dimethyl(phenyl)silylmethylene malonate at the methyl terminal with high yield and excellent regio- and enantioselectivity. The silyl group played crucial roles in regioselection and substrate reactivity.

Topics: Acetone; Anisomycin; Catalysis; Ketones; Malonates; Oxazolidinones; Pyrrolidines

Pyrrolidine enones, derived from 3-oxo pyrrolidine 2-phosphonates and a HWE reaction with aldehydes, on Luche reduction give pyrrolidine allylic alcohols. The alcohols on hydrogenation (Pd/H2) give cis-2,5-disubstituted pyrrolidines and on treatment with TFA-NaBH3CN undergo a hydroxy directed reduction to trans-2,5-disubstituted pyrrolidines.

Topics: Anisomycin; Catalysis; Organophosphonates; Pyrrolidines; Stereoisomerism

[reaction: see text] A new stereoselective synthesis of the antifungal and antitumor agents Preussin and 3-epi-Preussin via a Pd-catalyzed carboamination of a protected amino alcohol is described. The key transformation leads to simultaneous formation of the N-C2 bond and the C1'-aryl bond, and allows installation of the aryl group one step from the end of the sequence. This strategy permits the facile construction of a variety of preussin analogues bearing different aromatic groups.

Topics: Anisomycin; Antifungal Agents; Antineoplastic Agents; Aspergillus; Combinatorial Chemistry Techniques; Molecular Structure; Palladium; Stereoisomerism

Many viruses use programmed -1 ribosomal frameshifting to ensure the correct ratio of viral structural to enzymatic proteins. Alteration of frameshift efficiencies changes these ratios, in turn inhibiting viral particle assembly and virus propagation. Previous studies determined that anisomycin, a peptidyl transferase inhibitor, specifically inhibited -1 frameshifting and the ability of yeast cells to propagate the L-A and M(1) dsRNA viruses (J. D. Dinman, M. J. Ruiz-Echevarria, K. Czaplinski, and S. W. Peltz, 1997, Proc. Natl. Acad. Sci. USA 94, 6606-6611). Here we show that preussin, a pyrollidine that is structurally similar to anisomycin (R. E. Schwartz, J. Liesch, O. Hensens, L. Zitano, S. Honeycutt, G. Garrity, R. A. Fromtling, J. Onishi, and R. Monaghan, 1988. J. Antibiot. (Tokyo) 41, 1774--1779), also inhibits -1 programmed ribosomal frameshifting and virus propagation by acting at the same site or through the same mechanism as anisomycin. Since anisomycin is known to assert its effect at the ribosomal A-site, we undertook a pharmacogenetic analysis of mutants of trans-acting eukaryotic elongation factors (eEFs) that function at this region of the ribosome. Among mutants of eEF1A, a correlation is observed between resistance/susceptibility profiles to preussin and anisomycin, and these in turn correlate with programmed -1 ribosomal frameshifting efficiencies and killer virus phenotypes. Among mutants of eEF2, the extent of resistance to preussin correlates with resistance to sordarin, an eEF2 inhibitor. These results suggest that structural features associated with the ribosomal A-site and with the trans-acting factors that interact with it may present a new set of molecular targets for the rational design of antiviral compounds.

Topics: Anisomycin; Antiviral Agents; Drug Design; Frameshift Mutation; Genotype; Kinetics; Models, Molecular; Peptide Elongation Factor G; Protein Structure, Secondary; Ribosomal Proteins; Ribosomes; Saccharomyces cerevisiae; Structure-Activity Relationship; Time Factors

All the eight stereoisomers of (+)-preussin (1b), an antifungal agent inhibiting the growth of fission yeast and human cancer cells, were synthesized in two steps by non-stereoselective reactions and chromatographic separation, starting from L- and D-N-protected-phenylalaninal (2). Their bioassay revealed all of the stereoisomers to be almost equally bioactive.

Topics: Anisomycin; Antifungal Agents; Magnetic Resonance Spectroscopy; Schizosaccharomyces; Stereoisomerism

In this paper, we report that (+)-preussin, a pyrrolidinol alkaloid originally identified as an antifungal agent, has growth-inhibitory and cytotoxic effects on human cancer cells. Preussin was found to be a potent inhibitor of cyclin E kinase (CDK2-cyclin E) in vitro (50% inhibitory concentration; approximately 500 nM) and to inhibit cell cycle progression into S phase. In agreement with these findings, the level of the cyclin-dependent kinase inhibitor p27(KIP-1) is increased in response to preussin treatment while the expression of both cyclin A and the transcription factor E2F-1 is down-regulated. Preussin also induces programmed cell death (apoptosis), which requires caspase activation and involves the release of cytochrome c from mitochondria. This induction of apoptosis is not blocked by high levels of Bcl-2, which usually confers resistance to chemotherapeutic agents. Taken together, our data indicate that preussin could be a promising lead compound for the development of a new class of potent antitumor drugs.

Topics: Anisomycin; Antineoplastic Agents; Apoptosis; Caspases; Cyclin-Dependent Kinases; Cytochrome c Group; Cytosol; DNA; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Enzyme Activation; Enzyme Inhibitors; Flow Cytometry; Genes, bcl-2; Humans; Immunoblotting; Methionine; Tumor Cells, Cultured

The N-alkoxycarbonyl substituted 2,3-dihydropyrroles 3 and 8 are converted to 2-benzyl-3-pyrrolidinols by the Paternò - Büchi reaction followed by hydrogenolysis. Since the addition of the photoexcited benzaldehyde at the unsaturated heterocycle proceeds in a syn fashion, the benzyl group at C-2 and the hydroxy group at C-3 of the product are cis oriented. The simple and facial diastereoselectivities of the Paternò-Büchi reaction were studied more closely and the relative configuration of the products was elucidated. The thermodynamically less stable endo product is formed as a result of simple diastereoselection. The face differentiation in 2-substituted 2,3-dihydropyrroles is presumably due to the nonplanarity of these heterocycles, which forces attack of the carbonyl group on the face with the existing substituent. All-cis-pyrrolidinols are consequently formed after hydrogenolysis. Following this route, a total synthesis of the pyrrolidinol alkaloid (+)-preussin (1) was conducted, which yielded the target compound in a total yield of 11% over nine steps starting from L-pyroglutaminol (11).

Topics: Anisomycin; Antifungal Agents; Aspergillus ochraceus; Hydrogen; Immunosuppressive Agents; Magnetic Resonance Spectroscopy; Models, Molecular; Organophosphorus Compounds; Pyrroles; Pyrrolidines; Stereoisomerism

[structure] The enantioselective total synthesis of (+)-preussin, a potent antifungal agent, has been achieved. The key steps are a Pd(0)-catalyzed oxazoline-forming reaction from L-phenylalanine, hydrogenolysis, and subsequent diastereoselective reductive cyclization of the intermediate aminoketone to pyrrolidine using Pearlman's catalyst.

Topics: Anisomycin; Antifungal Agents; Catalysis; Cyclization; Hydrogenation; Oxazoles; Oxidation-Reduction; Palladium; Phenylalanine; Stereoisomerism

Topics: Animals; Anisomycin; Antifungal Agents; CDC2 Protein Kinase; G1 Phase; Genes, Regulator; Mutation; Rats; Schizosaccharomyces

Topics: Anisomycin; Antifungal Agents; Ascomycota; Candida; Chromatography, Thin Layer; Fermentation; Fungi; Isomerism; Magnetic Resonance Spectroscopy; Molecular Conformation; Molecular Structure; Pyrrolidines

L-657,398 is a broad spectrum antifungal agent isolated from solid fermentation or from the mycelium of the liquid fermentation of Aspergillus ochraceus. Structurally, the compound is a novel pyrollidine related to anisomycin.

Topics: Anisomycin; Antifungal Agents; Aspergillus; Chemical Phenomena; Chemistry; Fermentation; Pyrrolidines