pochonin-d has been researched along with monorden* in 5 studies
*monorden: inhibits HSP90 Heat-Shock Proteins, DNA topoisomerase VI and human Topoisomerase II [MeSH]
*monorden: inhibits HSP90 Heat-Shock Proteins, DNA topoisomerase VI and human Topoisomerase II [MeSH]
5 other study(ies) available for pochonin-d and monorden
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Insights into radicicol biosynthesis via heterologous synthesis of intermediates and analogs.
Resorcylic acid lactones are fungal polyketides that display diverse biological activities, with the potent Hsp90 inhibitor radicicol being an important representative member. Two fungal iterative polyketide synthases (IPKSs), Rdc5, the highly reducing IPKS, and Rdc1, the nonreducing IPKS, are required for the biosynthesis of radicicol in Pochonia chlamydosporia. In this study, the complete reconstitution of Rdc5 and Rdc1 activities both in vitro and in Saccharomyces cerevisiae uncovered the earliest resorcylic acid lactone intermediate of the radicicol biosynthetic pathway, (R)-monocillin II. The enzymatic synthesis of (R)-monocillin II confirmed the exquisite timing of the Rdc5 enoyl reductase domain. Using precursor-directed biosynthesis, the chemical modularity of the dual IPKS system was determined. Rdc1 readily accepted an N-acetylcysteamine thioester mimic of the reduced pentaketide product of Rdc5 to synthesize (R)-monocillin II with four additional iterations of polyketide elongation, indicating the C2' ketone group found in (R)-monocillin II is incorporated via the functions of Rdc1 instead of Rdc5. The involvement of the thioesterase domain in Rdc1 in macrolactonization was confirmed through both site-directed mutagenesis and domain deletion. The Rdc1 thioesterase domain was also shown to be tolerant of the opposite stereochemistry of the terminal hydroxyl nucleophile, demonstrated in the precursor-directed synthesis of the enantiomeric (S)-monocillin II. Finally, reconstitution of the halogenase Rdc2 was demonstrated both in vivo and in vitro in the synthesis of pochonin D and a new halogenated analog 6-chloro, 7',8'-dehydrozearalenol. Topics: Biochemistry; Chemistry, Pharmaceutical; Drug Design; Enzymes; Macrolides; Magnetic Resonance Spectroscopy; Models, Chemical; Plasmids; Polyketide Synthases; Protein Interaction Mapping; Protein Structure, Tertiary; Saccharomyces cerevisiae; Zeranol | 2010 |
Divergent synthesis of a pochonin library targeting HSP90 and in vivo efficacy of an identified inhibitor.
Topics: Animals; Antineoplastic Agents; Benzoquinones; Breast Neoplasms; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Macrolides; Mice; Mice, Inbred Strains; Small Molecule Libraries; Structure-Activity Relationship; Xenograft Model Antitumor Assays | 2008 |
Functional characterization of the biosynthesis of radicicol, an Hsp90 inhibitor resorcylic acid lactone from Chaetomium chiversii.
Fungal polyketides with the resorcylic acid lactone (RAL) scaffold are of interest for growth stimulation, the treatment of cancer, and neurodegenerative diseases. The RAL radicicol is a nanomolar inhibitor of the chaperone Hsp90, whose repression leads to a combinatorial blockade of cancer-causing pathways. Clustered genes for radicicol biosynthesis were identified and functionally characterized from the endophytic fungus Chaetomium chiversii, and compared to recently described RAL biosynthetic gene clusters. Radicicol production is abolished upon targeted inactivation of a putative cluster-specific regulator, or either of the two polyketide synthases that are predicted to collectively synthesize the radicicol polyketide core. Genomic evidence supports the existence of flavin-dependent halogenases in fungi: inactivation of such a putative halogenase from the C. chiversii radicicol locus yields dechloro-radicicol (monocillin I). Inactivation of a cytochrome P450 epoxidase furnishes pochonin D, a deepoxy-dihydro radicicol analog. Topics: Chaetomium; Cloning, Molecular; Enzyme Inhibitors; HSP90 Heat-Shock Proteins; Lactones; Macrolides; Models, Biological; Molecular Structure; Multigene Family; Zearalenone | 2008 |
Design, synthesis, and biological evaluation of HSP90 inhibitors based on conformational analysis of radicicol and its analogues.
The molecular chaperone HSP90 is an attractive target for chemotherapy because its activity is required for the functional maturation of a number of oncogenes. Among the known inhibitors, radicicol, a 14-member macrolide, stands out as the most potent. A molecular dynamics/minimization of radicicol showed that there were three low energy conformers of the macrocycle. The lowest of these is the bioactive conformation observed in the cocrystal structure of radicicol with HSP90. Corresponding conformational analyses of several known analogues gave a good correlation between the bioactivity and the energy of the bioactive conformer, relative to other conformers. Based on this observation, a number of proposed analogues were analyzed for their propensity to adopt the bioactive conformation prior to synthesis. This led to the identification of pochonin D, a recently isolated secondary metabolite of Pochonia chlamydosporia, as a potential inhibitor of HSP90. Pochonin D was synthesized using polymer-bound reagents and shown to be nearly as potent an HSP90 inhibitor as radicicol. Topics: Drug Design; HSP90 Heat-Shock Proteins; Lactones; Macrolides; Models, Molecular; Molecular Conformation | 2005 |
Pochonins A-F, new antiviral and antiparasitic resorcylic acid lactones from Pochonia chlamydosporia var. catenulata.
Monorden (1) and the novel resorcylic acid lactones pochonins A (2), B (4), C (6), D (7), and E (8) as well as tetrahydromonorden (5) and pseurotin A (22) were isolated from cultures of the clavicipitaceous hyphomycete Pochonia chlamydosporia var. catenulata strain P 0297. Fermentation of P 0297 in bromide-containing culture media led to a shift in secondary metabolite production and yielded monocillins III (3) and II (9) as major metabolites besides monorden (1) as well as the novel compounds pochonin F (10) and a monocillin II glycoside (11) as minor metabolites. Most of these compounds showed moderate activities in a cellular replication assay against Herpes Simplex Virus 1 (HSV1) and against the parasitic protozoan Eimeria tenella. In contrast to the structurally related zearalenone derivatives none of the metabolites of strain P 0297 were found to be active in a fluorescence polarization assay for determination of modulatory activities on the human estrogenic receptor ERbeta. Beta-zearalenol (17), but not zearalenone (15) and alpha-zearalenol (16), showed antiherpetic effects. We report the production, isolation, and structure elucidation of compounds 1-11 and their biological characterization. Topics: Animals; Antiprotozoal Agents; Antiviral Agents; Eimeria tenella; Germany; Herpesvirus 1, Human; Lactones; Macrolides; Microscopy, Electron, Scanning; Mitosporic Fungi; Molecular Structure; Neurospora; Stereoisomerism | 2003 |