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Jianping Wen - One of the best experts on this subject based on the ideXlab platform.
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enhanced Ascomycin production in streptomyces hygroscopicus var ascomyceticus by employing polyhydroxybutyrate as an intracellular carbon reservoir and optimizing carbon addition
Microbial Cell Factories, 2021Co-Authors: Pan Wang, Ying Yin, Xin Wang, Jianping WenAbstract:Ascomycin is a multifunctional antibiotic produced by Streptomyces hygroscopicus var. ascomyceticus. As a secondary metabolite, the production of Ascomycin is often limited by the shortage of precursors during the late fermentation phase. Polyhydroxybutyrate is an intracellular polymer accumulated by prokaryotic microorganisms. Developing polyhydroxybutyrate as an intracellular carbon reservoir for precursor synthesis is of great significance to improve the yield of Ascomycin. The fermentation characteristics of the parent strain S. hygroscopicus var. ascomyceticus FS35 showed that the accumulation and decomposition of polyhydroxybutyrate was respectively correlated with cell growth and Ascomycin production. The co-overexpression of the exogenous polyhydroxybutyrate synthesis gene phaC and native polyhydroxybutyrate decomposition gene fkbU increased both the biomass and Ascomycin yield. Comparative transcriptional analysis showed that the storage of polyhydroxybutyrate during the exponential phase accelerated biosynthesis processes by stimulating the utilization of carbon sources, while the decomposition of polyhydroxybutyrate during the stationary phase increased the biosynthesis of Ascomycin precursors by enhancing the metabolic flux through primary pathways. The comparative analysis of cofactor concentrations confirmed that the biosynthesis of polyhydroxybutyrate depended on the supply of NADH. At low sugar concentrations found in the late exponential phase, the optimization of carbon source addition further strengthened the polyhydroxybutyrate metabolism by increasing the total concentration of cofactors. Finally, in the fermentation medium with 22 g/L starch and 52 g/L dextrin, the Ascomycin yield of the co-overexpression strain was increased to 626.30 mg/L, which was 2.11-fold higher than that of the parent strain in the initial medium (296.29 mg/L). Here we report for the first time that polyhydroxybutyrate metabolism is beneficial for cell growth and Ascomycin production by acting as an intracellular carbon reservoir, stored as polymers when carbon sources are abundant and depolymerized into monomers for the biosynthesis of precursors when carbon sources are insufficient. The successful application of polyhydroxybutyrate in increasing the output of Ascomycin provides a new strategy for improving the yields of other secondary metabolites.
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increasing the Ascomycin yield by relieving the inhibition of acetyl propionyl coa carboxylase by the signal transduction protein glnb
Frontiers in Microbiology, 2021Co-Authors: Pan Wang, Ying Yin, Xin Wang, Wei Tan, Wenting Gao, Jianping WenAbstract:Ascomycin (FK520) is a multifunctional antibiotic produced by Streptomyces hygroscopicus var. ascomyceticus. In this study, we demonstrated that the inactivation of GlnB, a signal transduction protein belonging to the PII family, can increase the production of Ascomycin by strengthening the supply of the precursors malonyl-CoA and methylmalonyl-CoA, which are produced by acetyl-CoA carboxylase and propionyl-CoA carboxylase, respectively. Bioinformatics analysis showed that Streptomyces hygroscopicus var. ascomyceticus contains two PII family signal transduction proteins, GlnB and GlnK. Protein co-precipitation experiments demonstrated that GlnB protein could bind to the α subunit of acetyl-CoA carboxylase, and this binding could be disassociated by a sufficient concentration of 2-oxoglutarate. Coupled enzyme activity assays further revealed that the interaction between GlnB protein and the α subunit inhibited both the activity of acetyl-CoA carboxylase and propionyl-CoA carboxylase, and this inhibition could be relieved by 2-oxoglutarate in a concentration-dependent manner. Because GlnK protein can act redundantly to maintain metabolic homeostasis under the control of the global nitrogen regulator GlnR, the deletion of GlnB protein enhanced the supply of malonyl-CoA and methylmalonyl-CoA by restoring the activity of acetyl-CoA carboxylase and propionyl-CoA carboxylase, thereby improving the production of Ascomycin to 390 ± 10 mg/L. On this basis, the co-overexpression of the β and e subunits of propionyl-CoA carboxylase further increased the Ascomycin yield to 550 ± 20 mg/L, which was 1.9-fold higher than that of the parent strain FS35 (287 ± 9 mg/L). Taken together, this study provides a novel strategy to increase the production of Ascomycin, providing a reference for improving the yield of other antibiotics.
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Identification of the regulon FkbN for Ascomycin biosynthesis and its interspecies conservation analysis as LAL family regulator
Biochemical Engineering Journal, 2019Co-Authors: Yue Zhang, Hong Chen, Pan Wang, Jianping WenAbstract:Abstract Ascomycin is a 23-membered polyketide macrolide with high immunosuppressant activity, produced by Streptomyces hygroscopicus var. ascomyceticus. However, the specific regulatory mechanism of the Ascomycin biosynthesis pathway remains poorly understood. Here, we show that FkbN is a pathway-specific positive regulator for the Ascomycin biosynthesis. Inactivation of fkbN led to a complete loss of Ascomycin production ability. Compared with the parental strain, the Ascomycin yield of a constructed fkbN overexpression strain increased by 400%–1800 mg/L. Transcriptional levels of the genes of encoding precursor, PKS (polyketide synthase) and NRPS (nonribosomal peptide synthetases) were blocked in the fkbN in-frame deletion strain and greatly upregulated in the fkbN overexpression strain. Electrophoretic mobility shift assays (EMSAs) revealed that FkbN-DBD protein specifically bound to the intergenic regions of fkbR1-fkbE and fkbB-fkbO. To explore the high conservation among regulators homologous to FkbN, EMSAs showed that the FkbN-DBD protein directly bound to the putative promoters of different macrolide biosynthetic gene clusters. We did further study in the fkbN deletion strain by heterologous genetic complementation with single copy of the homologous LAL family regulators. Results showed that all the heterologous complementation strains restored the production of Ascomycin. Introduction of a single copy of fkbN into the tacrolimus producing strain S. tsukubaensis or rapamycin producing strain S. hygroscopicus, respectively, both enhanced the yields of the corresponding antibiotics.
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metabolic network model guided engineering ethylmalonyl coa pathway to improve Ascomycin production in streptomyces hygroscopicus var ascomyceticus
Microbial Cell Factories, 2017Co-Authors: Junhua Wang, Kejing Song, Cheng Wang, Jianping WenAbstract:Ascomycin is a 23-membered polyketide macrolide with high immunosuppressant and antifungal activity. As the lower production in bio-fermentation, global metabolic analysis is required to further explore its biosynthetic network and determine the key limiting steps for rationally engineering. To achieve this goal, an engineering approach guided by a metabolic network model was implemented to better understand Ascomycin biosynthesis and improve its production. The metabolic conservation of Streptomyces species was first investigated by comparing the metabolic enzymes of Streptomyces coelicolor A3(2) with those of 31 Streptomyces strains, the results showed that more than 72% of the examined proteins had high sequence similarity with counterparts in every surveyed strain. And it was found that metabolic reactions are more highly conserved than the enzymes themselves because of its lower diversity of metabolic functions than that of genes. The main source of the observed metabolic differences was from the diversity of secondary metabolism. According to the high conservation of primary metabolic reactions in Streptomyces species, the metabolic network model of Streptomyces hygroscopicus var. ascomyceticus was constructed based on the latest reported metabolic model of S. coelicolor A3(2) and validated experimentally. By coupling with flux balance analysis and using minimization of metabolic adjustment algorithm, potential targets for Ascomycin overproduction were predicted. Since several of the preferred targets were highly associated with ethylmalonyl-CoA biosynthesis, two target genes hcd (encoding 3-hydroxybutyryl-CoA dehydrogenase) and ccr (encoding crotonyl-CoA carboxylase/reductase) were selected for overexpression in S. hygroscopicus var. ascomyceticus FS35. Both the mutants HA-Hcd and HA-Ccr showed higher Ascomycin titer, which was consistent with the model predictions. Furthermore, the combined effects of the two genes were evaluated and the strain HA-Hcd-Ccr with hcd and ccr overexpression exhibited the highest Ascomycin production (up to 438.95 mg/L), 1.43-folds improvement than that of the parent strain FS35 (305.56 mg/L). The successful constructing and experimental validation of the metabolic model of S. hygroscopicus var. ascomyceticus showed that the general metabolic network model of Streptomyces species could be used to analyze the intracellular metabolism and predict the potential key limiting steps for target metabolites overproduction. The corresponding overexpression strains of the two identified genes (hcd and ccr) using the constructed model all displayed higher Ascomycin titer. The strategy for yield improvement developed here could also be extended to the improvement of other secondary metabolites in Streptomyces species.
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integration of parallel 13 c labeling experiments and in silico pathway analysis for enhanced production of Ascomycin
Biotechnology and Bioengineering, 2017Co-Authors: Kejing Song, Jianping WenAbstract:Herein, the hyper-producing strain for Ascomycin was engineered based on 13 C-labeling experiments and elementary flux modes analysis (EFMA). First, the metabolism of non-model organism Streptomyces hygroscopicus var. ascomyceticus SA68 was investigated and an updated network model was reconstructed using 13 C- metabolic flux analysis. Based on the precise model, EFMA was further employed to predict genetic targets for higher Ascomycin production. Chorismatase (FkbO) and pyruvate carboxylase (Pyc) were predicted as the promising overexpression and deletion targets, respectively. The corresponding mutant TD-FkbO and TD-ΔPyc exhibited the consistency effects between model prediction and experimental results. Finally, the combined genetic manipulations were performed, achieving a high-yield Ascomycin engineering strain TD-ΔPyc-FkbO with production up to 610 mg/L, 84.8% improvement compared with the parent strain SA68. These results manifested that the integration of 13 C-labeling experiments and in silico pathway analysis could serve as a promising concept to enhance Ascomycin production, as well as other valuable products. Biotechnol. Bioeng. 2017;114: 1036-1044. © 2016 Wiley Periodicals, Inc.
Gerhard Schulz - One of the best experts on this subject based on the ideXlab platform.
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synthetic modifications of Ascomycin v access to novel Ascomycin derivatives by replacement of the cyclohexylvinylidene subunit
Croatica Chemica Acta, 2005Co-Authors: Reinhold Zimmer, Karl Baumann, Gerhard Schulz, Ewald Haidl, Hildegard Sperner, Maximilian GrassbergerAbstract:Starting from the easily accessible 24-O-tert-butyldimethylsilyl-22(R)-dihydro-28-oxoAscomycin, methodologies that allow replacement of the cyclohexylvinylidene moiety of Ascomycin by various other substituents are described. In addition, a so far unknown reactivity of the masked tricarbonyl moiety of Ascomycin towards a stabilized Wittig reagent is reported.
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novel analogues of Ascomycin with modifications in the amino acid unit through photochemistry the synthesis of 5 6 dehydroAscomycin sdz asq 871
Tetrahedron Letters, 2004Co-Authors: Murty A. R. C. Bulusu, Gerhard Schulz, Peter Waldstatten, Maximilian GrassbergerAbstract:Abstract Irradiation of Ascomycin 1a and its derivatives in MeOH, EtOH and propanol resulted in alkoxylation of the pipecolic acid moiety in the e-position with concomitant reduction in the tricarbonyl region leading to 6-alkoxy-9-hydroxy derivatives in high stereoselectivities and good yields. The products, after reoxidation of the C(9)-OH, afforded the 6-alkoxy analogues of the parent compounds. Elimination of MeOH from the photoproducts, followed by oxidation gave the corresponding 5,6-dehydro amino acid analogues. Similarly, starting from the proline analogue 7 modifications in the pyrrolidine moiety could be achieved.
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selective photochemical cleavage of an α ketoamide in a highly functionalised macrolide Ascomycin
Tetrahedron Letters, 2004Co-Authors: Murty A. R. C. Bulusu, Peter Waldstatten, Thomas Tricotett, Gerhard SchulzAbstract:A novel photochemical amide cleavage reaction of (6S)-methoxyAscomycin opening a pathway for the selective cleavage of the pipecolic acid, is described. The scope of this reaction with several analogues carrying suitable protecting groups is examined.
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nmr study on 9 s and 9 r oxirane derivatives of Ascomycin
Magnetic Resonance in Chemistry, 2002Co-Authors: Karl Baumann, Gerhard Schulz, Klemens Hogenauer, Andrea SteckAbstract:Structure elucidation of 9-S and 9-R oxirane derivatives of Ascomycin, a 23-membered immunomodulating macrolactam, was performed using NMR spectroscopy. The total 1H and 13C signal assignments required the gradient-selected versions of COSY (gs-COSY), heteronuclear multiple quantum-correlation spectroscopy (gs-HSQC), heteronuclear multiple-bond correlation spectroscopy (gs-HMBC), and nuclear Overhauser methods. The data sets then were used to examine the dependence of ketone–hemiketal and cis–trans amide equilibria on the substitution pattern and the absolute configuration of the chiral oxirane. Copyright © 2002 John Wiley & Sons, Ltd.
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regioselective carbon carbon bond formation in the effector domain of Ascomycin
Tetrahedron, 2000Co-Authors: Horvath Amarylla, Maximilian Grassberger, Gerhard Schulz, Ewald Haidl, Hildegard Sperner, Andrea SteckAbstract:Abstract Starting from 33- O -silyl-protected Ascomycin or its 23,24-dehydration product, regio- and stereo-selective formal aldol reactions under carbon–carbon bond formation at C-22, C-23, or C-24 are demonstrated. Additionally, with the 22-silyl enol ether Ascomycin derivative a rhodium(I)-catalysed shift of the 19,20 double bond into the 19,38 exocyclic position is observed at elevated temperature.
Stephen W. Fesik - One of the best experts on this subject based on the ideXlab platform.
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Retention of immunosuppressant activity in an Ascomycin analogue lacking a hydrogen-bonding interaction with FKBP12.
Journal of Medicinal Chemistry, 1999Co-Authors: Paul E. Wiedeman, Karl W. Mollison, Stephen W. Fesik, Andrew M. Petros, David G. Nettesheim, Benjamin C. Lane, Jay R. LulyAbstract:C24-DeoxyAscomycin was prepared in a two-step process from Ascomycin and evaluated for its immunosuppressant activity relative to Ascomycin and FK506. An intermediate in the synthetic pathway, Δ23,...
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a computer based protocol for semiautomated assignments and 3d structure determination of proteins
Journal of Biomolecular NMR, 1994Co-Authors: Robert P Meadows, Edward T Olejniczak, Stephen W. FesikAbstract:A strategy is presented for the semiautomated assignment and 3D structure determination of proteins from heteronuclear multidimensional Nuclear Magnetic Resonance (NMR) data. This approach involves the computer-based assignment of the NMR signals, identification of distance restraints from nuclear Overhauser effects, and generation of 3D structures by using the NMR-derived restraints. The protocol is described in detail and illustrated on a resonance assignment and structure determination of the FK506 binding protein (FKBP, 107 amino acids) complexed to the immunosuppressant, Ascomycin. The 3D structures produced from this automated protocol attained backbone and heavy atom rmsd of 1.17 and 1.69 A, respectively. Although more highly resolved structures of the complex have been obtained by standard interpretation of NMR data (Meadows et al. (1993) Biochemistry, 32, 754–765), the structures generated with this automated protocol required minimal manual intervention during the spectral assignment and 3D structure calculations stages. Thus, the protocol may yield an approximate order of magnitude reduction in the time required for the generation of 3D structures of proteins from NMR data.
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1h 13c and 15n assignments and secondary structure of the fk506 binding protein when bound to Ascomycin
Biopolymers, 1993Co-Authors: David G. Nettesheim, Edward T Olejniczak, Robert P Meadows, Gerd Gemmecker, Stephen W. FesikAbstract:The 1H, 13C, and 15N resonances of FKBP when bound to the immunosuppressant, Ascomycin, were assigned using a computer-aided analysis of heteronuclear double and triple resonance three-dimensional nmr spectra of [U-15N]FKBP/Ascomycin and [U-15N,13C]FKBP/Ascomycin. In addition, from a preliminary analysis of two heteronuclear four-dimensional data sets, 3JHN,H alpha coupling constants, amide exchange data, and the differences between the C alpha and C beta chemical shifts of FKBP to random coil values, the secondary structure of FKBP when bound to Ascomycin was determined. The secondary structure of FKBP when bound to Ascomycin in solution closely resembled the x-ray structure of the FKBP/FK506 complex but differed in some aspects from the structure of uncomplexed FKBP in solution.
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three dimensional structure of the fk506 binding protein Ascomycin complex in solution by heteronuclear three and four dimensional nmr
Biochemistry, 1993Co-Authors: Robert P Meadows, Andrew M. Petros, David G. Nettesheim, Edward T Olejniczak, Harriet T Smith, Thomas F Holzman, Jean M Severin, Earl J Gubbins, Stephen W. FesikAbstract:A high-resolution three-dimensional solution structure of the FKBP/Ascomycin complex has been determined using heteronuclear multidimensional nuclear magnetic resonance spectroscopy (NMR) and a distance geometry/simulated annealing protocol. A total of 43 structures of the complex, including 3 tightly bound water molecules, were obtained using 1958 experimental restraints consisting of 1724 nuclear Overhauser effect (NOE) derived distances, 66 chi 1 and 46 phi angular restraints, and 122 hydrogen bond restraints. The root mean square (rms) deviations between the 43 FKBP/Ascomycin solution structures and the mean atomic coordinates were 0.43 +/- 0.08 A for the backbone heavy atoms and 0.80 +/- 0.08 A for all non-hydrogen atoms. Angular order parameters for the family of 43 conformations were calculated to determine dihedral convergence. Order parameters for phi, psi, and chi 1 angles exhibited mean values of 0.98, 0.97, and 0.95, respectively, while the mean of the chi 2 order parameter was 0.63. Comparisons were made between the FKBP/Ascomycin complex and two NMR-derived solution structures of unbound FKBP and the X-ray crystal structure of an FKBP/FK506 complex. Differences were observed between the FKBP/Ascomycin complex and uncomplexed FKBP for residues 33-45 and 78-92. In contrast, the NMR-derived solution structure of the FKBP/Ascomycin complex and the X-ray crystal structure of the FKBP/FK506 complex were very similar. Differences between the two complexes were mainly observed in the conformations of some highly solvent exposed side chains.
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stereospecific assignments and χ1 rotamers for fkbp when bound to Ascomycin from 3jhα hβ and 3jn hβ coupling constants
FEBS Letters, 1992Co-Authors: Edward T Olejniczak, Stephen W. FesikAbstract:3JH alpha,H beta and 3JN,H beta coupling constants were measured for isotopically labeled FKBP when bound to the immunosuppressant, Ascomycin, using a 1H-coupled 3D HCCH-TOCSY and 15N-coupled 3D HSQC-TOCSY experiment, respectively. From an analysis of these two sets of coupling constants, stereospecific beta-proton assignments and chi 1 rotamers for FKBP have been obtained. All of the chi 1 rotamers were consistent with the chi 1 angles measured in the X-ray crystal structure of the FKBP/FK506 complex, suggesting that the structures of the two complexes are similar.
Francis J Dumont - One of the best experts on this subject based on the ideXlab platform.
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preparation and in vitro activities of naphthyl and indolyl ether derivatives of the fk 506 related immunosuppressive macrolide Ascomycin
ChemInform, 2010Co-Authors: Peter J. Sinclair, Mary Jo Staruch, Francis J Dumont, William H Parsons, Frederick Wong, Greg Wiederrecht, Matthew J. WyvrattAbstract:Abstract The synthesis of naphthyl- and indolyl-ethers of the immunosuppressive macrolide Ascomycin using pentavalent bismuth reagents is described. The in vitro activities of the aryl ether analogs are reported. The indole ether analogs show increased immunosuppressive activity in vitro relative to the parent macrolide.
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c32 o phenalkyl ether derivatives of the immunosuppressant Ascomycin a tether length study
Bioorganic & Medicinal Chemistry Letters, 1999Co-Authors: Mark T. Goulet, Mary Jo Staruch, Matthew J. Wyvratt, John G. Cryan, Francis J Dumont, Frederick Wong, Peter J. Sinclair, Gregory J Wiederrecht, William H ParsonsAbstract:A tether length study of C32-O-phenalkyl ether derivatives of Ascomycin was conducted wherein it was determined that a 2-carbon tether provides optimum in vitro immunosuppressive activity. Oxygen-bearing substituents along the 2-carbon tether can further increase the potency of this design.
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Potent immunosuppressive C32-O-arylethyl ether derivatives of Ascomycin with reduced toxicity.
Bioorganic & Medicinal Chemistry Letters, 1999Co-Authors: Helen M. Armstrong, Mary Jo Staruch, Mark T. Goulet, Francis J Dumont, Frederick Wong, Mark A. Holmes, Peter J. Sinclair, Samuel Koprak, Laurence B. Peterson, Ray RosaAbstract:The synthesis of C32-O-arylethyl ether derivatives of Ascomycin that possess equivalent immunosuppressant activity but reduced toxicity, compared to FK-506, is described.
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c32 o imidazol 2 yl methyl ether derivatives of the immunosuppressant Ascomycin with improved therapeutic potential
Bioorganic & Medicinal Chemistry Letters, 1998Co-Authors: Mark T. Goulet, Mary Jo Staruch, John G. Cryan, Francis J Dumont, Samuel Koprak, Ray Rosa, Shelli R Mcalpine, Gregory J Wiederrecht, Mary Beth Wilusz, Laurence B. PetersonAbstract:A series of C32-O-aralkyl ether derivatives of the FK-506 related macrolide Ascomycin have been prepared based on an earlier reported C32-O-cinnamyl ether design. In the present study, the nature of the aryl tethering group was varied in an attempt to improve oral activity. An imidazol-2-yl-methyl tether was found to be superior among those investigated and has resulted in an Ascomycin analog, L-733,725, with in vivo immunosuppressive activity comparable to FK-506 but with an improved therapeutic index.
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c32 amino derivatives of the immunosuppressant Ascomycin
ChemInform, 1998Co-Authors: John Szumiloski, Mary Jo Staruch, Mark T. Goulet, Francis J Dumont, Thomas R Beattie, Matthew J. WyvrattAbstract:Abstract Various C32-amino derivatives were investigated as replacements for the C32-hydroxyl group of Ascomycin and its C24-deoxy analog. The syntheses of these amino derivatives and their biological evaluation are reported herein.
Matthew J. Wyvratt - One of the best experts on this subject based on the ideXlab platform.
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preparation and in vitro activities of naphthyl and indolyl ether derivatives of the fk 506 related immunosuppressive macrolide Ascomycin
ChemInform, 2010Co-Authors: Peter J. Sinclair, Mary Jo Staruch, Francis J Dumont, William H Parsons, Frederick Wong, Greg Wiederrecht, Matthew J. WyvrattAbstract:Abstract The synthesis of naphthyl- and indolyl-ethers of the immunosuppressive macrolide Ascomycin using pentavalent bismuth reagents is described. The in vitro activities of the aryl ether analogs are reported. The indole ether analogs show increased immunosuppressive activity in vitro relative to the parent macrolide.
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c32 o phenalkyl ether derivatives of the immunosuppressant Ascomycin a tether length study
Bioorganic & Medicinal Chemistry Letters, 1999Co-Authors: Mark T. Goulet, Mary Jo Staruch, Matthew J. Wyvratt, John G. Cryan, Francis J Dumont, Frederick Wong, Peter J. Sinclair, Gregory J Wiederrecht, William H ParsonsAbstract:A tether length study of C32-O-phenalkyl ether derivatives of Ascomycin was conducted wherein it was determined that a 2-carbon tether provides optimum in vitro immunosuppressive activity. Oxygen-bearing substituents along the 2-carbon tether can further increase the potency of this design.
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c32 amino derivatives of the immunosuppressant Ascomycin
ChemInform, 1998Co-Authors: John Szumiloski, Mary Jo Staruch, Mark T. Goulet, Francis J Dumont, Thomas R Beattie, Matthew J. WyvrattAbstract:Abstract Various C32-amino derivatives were investigated as replacements for the C32-hydroxyl group of Ascomycin and its C24-deoxy analog. The syntheses of these amino derivatives and their biological evaluation are reported herein.
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preparation and in vitro activity of aryl ether derivatives of the fk 506 related immunosuppressive macrolides Ascomycin and l 683 742
Bioorganic & Medicinal Chemistry Letters, 1995Co-Authors: Peter J. Sinclair, Mary Jo Staruch, Matthew J. Wyvratt, Frederick Wong, Francis J DumontAbstract:Abstract The arylation of the immunosuppressive macrolides Ascomycin and L-683,742 using pentavalent bismuth reagents is described. The in vitro activities of the aryl ether analogs are reported.
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Alkyl ether analogs of the FK-506 related, immunosuppressive macrolide L-683,590 (Ascomycin)
Bioorganic & Medicinal Chemistry Letters, 1994Co-Authors: Mark T. Goulet, Mary Jo Staruch, Derek W. Hodkey, John G. Cryan, Francis J Dumont, William H Parsons, Matthew J. WyvrattAbstract:Abstract C32-O-Ether derivatives of L-683,590 have been prepared by alkylation with various alkyl, alkenyl, and alkynyl 2,2,2-trichloroacetimidates. These analogs exhibit good immunosuppressive activity in vitro, as measured in a T cell proliferation assay. In the case of cinnamyl ethers, this activity correlates with the lipophilicity (π value) of the aromatic substituents.
