36 results on '"Dombrowski AW"'
Search Results
2. Announcing the Early Career Board of ACS Medicinal Chemistry Letters .
- Author
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Baranczak A, Bigi-Botterill SV, Borsari C, Dombrowski AW, Estrada MA, Farrell MP, Riley AP, and Woodland JG
- Published
- 2024
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3. Incorporating Synthetic Accessibility in Drug Design: Predicting Reaction Yields of Suzuki Cross-Couplings by Leveraging AbbVie's 15-Year Parallel Library Data Set.
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Raghavan P, Rago AJ, Verma P, Hassan MM, Goshu GM, Dombrowski AW, Pandey A, Coley CW, and Wang Y
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- Machine Learning, Density Functional Theory, Molecular Structure, Chemistry, Pharmaceutical methods, Small Molecule Libraries chemistry, Small Molecule Libraries chemical synthesis, Drug Design
- Abstract
Despite the increased use of computational tools to supplement medicinal chemists' expertise and intuition in drug design, predicting synthetic yields in medicinal chemistry endeavors remains an unsolved challenge. Existing design workflows could profoundly benefit from reaction yield prediction, as precious material waste could be reduced, and a greater number of relevant compounds could be delivered to advance the design, make, test, analyze (DMTA) cycle. In this work, we detail the evaluation of AbbVie's medicinal chemistry library data set to build machine learning models for the prediction of Suzuki coupling reaction yields. The combination of density functional theory (DFT)-derived features and Morgan fingerprints was identified to perform better than one-hot encoded baseline modeling, furnishing encouraging results. Overall, we observe modest generalization to unseen reactant structures within the 15-year retrospective library data set. Additionally, we compare predictions made by the model to those made by expert medicinal chemists, finding that the model can often predict both reaction success and reaction yields with greater accuracy. Finally, we demonstrate the application of this approach to suggest structurally and electronically similar building blocks to replace those predicted or observed to be unsuccessful prior to or after synthesis, respectively. The yield prediction model was used to select similar monomers predicted to have higher yields, resulting in greater synthesis efficiency of relevant drug-like molecules.
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- 2024
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4. Di(2-picolyl)amines as Modular and Robust Ligands for Nickel-Catalyzed C(sp 2 )-C(sp 3 ) Cross-Electrophile Coupling.
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Rago AJ, Vasilopoulos A, Dombrowski AW, and Wang Y
- Subjects
- Ligands, Catalysis, Nickel, Amines
- Abstract
Ni-catalyzed aryl-alkyl coupling reactions are reliant on using a limited set of commercially available bidentate nitrogenous ligands to enable the reaction, because noncommercial analogues usually entail challenging syntheses. In this work, di(2-picolyl)amines (DPAs) are explored as an alternative modular ligand class for the nickel-catalyzed aryl-alkyl cross-electrophile coupling. Novel DPA ligands were synthesized directly from inexpensive amine and pyridine building blocks in a single step. This facile synthetic route enabled the parallel synthesis of DPA ligands with varied steric and electronic properties. From this collection of ligands, a few robust ligands for C(sp
2 )-C(sp3 ) cross-electrophile coupling were identified and tested in the cross-coupling of a range of diverse molecules, including model examples for late-stage functionalization.- Published
- 2022
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5. The Chosen Few: Parallel Library Reaction Methodologies for Drug Discovery.
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Dombrowski AW, Aguirre AL, Shrestha A, Sarris KA, and Wang Y
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- Drug Discovery
- Abstract
Parallel library synthesis is an important tool for drug discovery because it enables the synthesis of closely related analogues in parallel via robust and general synthetic transformations. In this perspective, we analyzed the synthetic methodologies used in >5000 parallel libraries representing 15 prevalent synthetic transformations. The library data set contains complex substrates and diverse arrays of building blocks used over the last 14 years at AbbVie. The library synthetic methodologies that have demonstrated robustness and generality with proven success are described along with their substrate scopes. The evolution of the synthetic methodologies for library synthesis over the past decade is discussed. We also highlight that the combination of parallel library synthesis with high-throughput experimentation will continue to facilitate the discovery of library-amenable synthetic methodologies in drug discovery.
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- 2022
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6. Rearrangement of 3-Hydroxyazetidines into 2-Oxazolines.
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Ruggeri M, Dombrowski AW, Djuric SW, and Baxendale IR
- Abstract
A novel rearrangement sequence of 3-hydroxyazetidines via a Ritter initiated cascade provides highly substituted 2-oxazolines in high yields. The reaction conditions and substrate scope of the transformation have been studied demonstrating the generality of the process. The derived products can also be functionalized in order to undergo further intramolecular cyclization leading to a new class of macrocycle. The final cyclization step was shown to be a transformation amenable to continuous flow processing allowing for a dramatic reduction in the reaction time and simple scale-up.
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- 2020
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7. Expanding the Medicinal Chemist Toolbox: Comparing Seven C(sp 2 )-C(sp 3 ) Cross-Coupling Methods by Library Synthesis.
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Dombrowski AW, Gesmundo NJ, Aguirre AL, Sarris KA, Young JM, Bogdan AR, Martin MC, Gedeon S, and Wang Y
- Abstract
Despite recent advances in the field of C(sp
2 )-C(sp3 ) cross-couplings and the accompanying increase in publications, it can be hard to determine which method is appropriate for a given reaction when using the highly functionalized intermediates prevalent in medicinal chemistry. Thus a study was done comparing the ability of seven methods to directly install a diverse set of alkyl groups on "drug-like" aryl structures via parallel library synthesis. Each method showed substrates that it excelled at coupling compared with the other methods. When analyzing the reactions run across all of the methods, a reaction success rate of 50% was achieved. Whereas this is promising, there are still gaps in the scope of direct C(sp2 )-C(sp3 ) coupling methods, like tertiary group installation. The results reported herein should be used to inform future syntheses, assess reaction scope, and encourage medicinal chemists to expand their synthetic toolbox., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)- Published
- 2020
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8. Emerging Trends in Flow Chemistry and Applications to the Pharmaceutical Industry.
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Bogdan AR and Dombrowski AW
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- Chemistry Techniques, Synthetic methods, Chemistry, Pharmaceutical instrumentation, Chemistry, Pharmaceutical methods, Cold Temperature, Drug Industry instrumentation, Drug Industry methods, Equipment Design, Hot Temperature, Pharmaceutical Preparations chemistry, Small Molecule Libraries chemistry, Chemistry Techniques, Synthetic instrumentation, Pharmaceutical Preparations chemical synthesis, Small Molecule Libraries chemical synthesis
- Abstract
The field of flow chemistry has garnered considerable attention over the past 2 decades. This Perspective highlights many recent advances in the field of flow chemistry and discusses applications to the pharmaceutical industry, from discovery to manufacturing. From a synthetic perspective, a number of new enabling technologies are providing more rationale to run reactions in flow over batch techniques. Additionally, highly automated flow synthesis platforms have been developed with broad applicability across the pharmaceutical industry, ranging from advancing medicinal chemistry programs to self-optimizing synthetic routes. A combination of simplified and automated systems is discussed, demonstrating how flow chemistry solutions can be tailored to fit the specific needs of a project.
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- 2019
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9. High-Throughput Reaction Screening with Nanomoles of Solid Reagents Coated on Glass Beads.
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Tu NP, Dombrowski AW, Goshu GM, Vasudevan A, Djuric SW, and Wang Y
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Technologies that enable rapid screening of diverse reaction conditions are of critical importance to methodology development and reaction optimization, especially when molecules of high complexity and scarcity are involved. The lack of a general solid dispensing method for chemical reagents on micro- and nanomole scale prevents the full utilization of reaction screening technologies. We herein report the development of a technology in which glass beads coated with solid chemical reagents (ChemBeads) enable the delivery of nanomole quantities of solid chemical reagents efficiently. By exploring the concept of preferred screening sets, the flexibility and generality of this technology for high-throughput reaction screening was validated., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
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- 2019
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10. Correction to Tissue-Factor Targeted Peptide Amphiphile Nanofibers as an Injectable Therapy To Control Hemorrhage.
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Morgan CE, Dombrowski AW, Rubert Peŕez CM, Bahnson ESM, Tsihlis ND, Jiang W, Jiang Q, Vercammen JM, Prakash VS, Pritts TA, Stupp SI, and Kibbe MR
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- 2018
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11. High-Temperature Boc Deprotection in Flow and Its Application in Multistep Reaction Sequences.
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Bogdan AR, Charaschanya M, Dombrowski AW, Wang Y, and Djuric SW
- Abstract
A simplified Boc deprotection using a high-temperature flow reactor is described. The system afforded the qualitative yield of a wide variety of deprotected substrates within minutes using acetonitrile as the solvent and without the use of acidic conditions or additional workups. Highly efficient, multistep reaction sequences in flow are also demonstrated wherein no extraction or isolation was required between steps.
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- 2016
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12. Tissue-Factor Targeted Peptide Amphiphile Nanofibers as an Injectable Therapy To Control Hemorrhage.
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Morgan CE, Dombrowski AW, Rubert Pérez CM, Bahnson ES, Tsihlis ND, Jiang W, Jiang Q, Vercammen JM, Prakash VS, Pritts TA, Stupp SI, and Kibbe MR
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- Amino Acid Sequence, Animals, Blood Vessels injuries, Fluorenes chemistry, Hemorrhage pathology, Injections, Intralesional, Liver blood supply, Liver injuries, Male, Molecular Sequence Data, Molecular Targeted Therapy, Nanofibers chemistry, Peptides chemical synthesis, Peptides metabolism, Peptides pharmacokinetics, Protein Binding, Rats, Rats, Sprague-Dawley, Thromboplastin pharmacokinetics, Blood Vessels drug effects, Hemorrhage drug therapy, Liver drug effects, Nanofibers therapeutic use, Peptides pharmacology, Thromboplastin metabolism
- Abstract
Noncompressible torso hemorrhage is a leading cause of mortality in civilian and battlefield trauma. We sought to develop an i.v.-injectable, tissue factor (TF)-targeted nanotherapy to stop hemorrhage. Tissue factor was chosen as a target because it is only exposed to the intravascular space upon vessel disruption. Peptide amphiphile (PA) monomers that self-assemble into nanofibers were chosen as the delivery vehicle. Three TF-binding sequences were identified (EGR, RLM, and RTL), covalently incorporated into the PA backbone, and shown to self-assemble into nanofibers by cryo-transmission electron microscopy. Both the RLM and RTL peptides bound recombinant TF in vitro. All three TF-targeted nanofibers bound to the site of punch biopsy-induced liver hemorrhage in vivo, but only RTL nanofibers reduced blood loss versus sham (53% reduction, p < 0.05). Increasing the targeting ligand density of RTL nanofibers yielded qualitatively better binding to the site of injury and greater reductions in blood loss in vivo (p < 0.05). In fact, 100% RTL nanofiber reduced overall blood loss by 60% versus sham (p < 0.05). Evaluation of the biocompatibility of the RTL nanofiber revealed that it did not induce RBC hemolysis, did not induce neutrophil or macrophage inflammation at the site of liver injury, and 70% remained intact in plasma after 30 min. In summary, these studies demonstrate successful binding of peptides to TF in vitro and successful homing of a TF-targeted PA nanofiber to the site of hemorrhage with an associated decrease in blood loss in vivo. Thus, this therapeutic may potentially treat noncompressible hemorrhage.
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- 2016
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13. The "FERMEX" method for metabolite-enriched fungal extracts.
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Bills GF, Dombrowski AW, and Goetz MA
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- Fermentation, Biological Products isolation & purification, Culture Techniques methods, Fungi growth & development, Fungi metabolism
- Abstract
The FERMEX (Fermentation Extract) program was a highly successful source of microbial natural product molecules for pharmaceutical lead discovery. The program was based on the observation that solid fermentations of fungi generally exhibited more complex metabolite profiles than when the same strains were grown on liquid medium. To produce interference-free fermentations and improve organic product recovery, fungi colonized homogeneous media-saturated vermiculite thus promoting cellular and metabolic differentiation. Secondary metabolites in fungal cells were extracted from the substratum and medium with methyethylketone to generate metabolite-enriched screening samples. The necessary equipment, protocol, and media recipes are described along with examples of bioactive fungal metabolites produced in this system.
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- 2012
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14. Isolation, structure, and coccidiostat activity of coccidiostatin A.
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Jayasuriya H, Guan Z, Dombrowski AW, Bills GF, Polishook JD, Jenkins RG, Koch L, Crumley T, Tamas T, Dubois M, Misura A, Darkin-Rattray SJ, Gregory L, and Singh SB
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- Animals, Coccidiosis etiology, Molecular Structure, Coccidiostats chemistry, Coccidiostats isolation & purification, Coccidiostats pharmacology, Eimeria drug effects, Heterocyclic Compounds, Bridged-Ring chemistry, Heterocyclic Compounds, Bridged-Ring isolation & purification, Heterocyclic Compounds, Bridged-Ring pharmacology, Penicillium chemistry
- Abstract
Coccidiosis is one of the more common and costly diseases in poultry that is caused by various Eimeria species. In our quest to discover coccidiostats from natural products, we discovered a microbial fermentation extract that exhibited in vivo anticoccidial activity. Fractionation of this extract led to the discovery of two potent antiprotozoals, emecorrugatin A (1) and coccidiostatin A (2). The former compound exhibited only in vitro activity, whereas the latter new compound exhibited in vivo activity against Eimeria species in chickens at 150 ppm dosed in chicken feed. The isolation, structure elucidation, relative configuration, and activity of coccidiostatin A (2) are described.
- Published
- 2007
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15. Isolation and insecticidal/anthelmintic activity of xanthonol, a novel bis-xanthone, from a non-sporulating fungal species.
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Ondeyka JG, Dombrowski AW, Polishook JP, Felcetto T, Shoop WL, Guan Z, and Singh SB
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- Anthelmintics chemistry, Anthelmintics pharmacology, Gas Chromatography-Mass Spectrometry, Insecticides chemistry, Insecticides pharmacology, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Optical Rotation, Spectrometry, Mass, Electrospray Ionization, Xanthones chemistry, Anthelmintics isolation & purification, Fungi chemistry, Insecticides isolation & purification, Xanthones isolation & purification, Xanthones pharmacology
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Xanthonol, a novel dimeric xanthone, was isolated from a fermentation broth of a non-sporulating fungal species using Sephadex LH20 followed by HPLC and the structure elucidated by spectral analysis. Xanthonol exhibited insecticidal and anthelmintic activities against larvae of Lucilia sericata, Aedes aegypti, and Haemonchus contortus with LD90 of 33, 8, and 50 microg/ml, respectively.
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- 2006
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16. Isolation and structures of novel fungal metabolites as chemokine receptor (CCR2) antagonists.
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Herath KB, Jayasuriya H, Ondeyka JG, Polishook JD, Bills GF, Dombrowski AW, Cabello A, Vicario PP, Zweerink H, Guan Z, and Singh SB
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- Anti-Inflammatory Agents, Non-Steroidal chemistry, Cell Membrane metabolism, Cells, Cultured, Chemokine CCL2 metabolism, Cytochalasins chemistry, Cytochalasins isolation & purification, Cytochalasins pharmacology, Disulfides chemistry, Disulfides isolation & purification, Disulfides pharmacology, Fungi metabolism, Humans, Indole Alkaloids chemistry, Indole Alkaloids isolation & purification, Indole Alkaloids pharmacology, Molecular Structure, Monocytes drug effects, Peptide Fragments metabolism, Piperazines chemistry, Piperazines isolation & purification, Piperazines pharmacology, Receptors, CCR2, Receptors, Chemokine metabolism, Anti-Inflammatory Agents, Non-Steroidal isolation & purification, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Fungi chemistry, Receptors, Chemokine antagonists & inhibitors
- Abstract
The chemokine receptor, CCR2, is predominantly expressed on monocytes/macrophages, and on a subset of memory T cells. It binds to several CC type chemokines of the monocyte chemoattractant protein (MCP) family of which MCP-1 exhibits the highest affinity. CCR2/MCP-1 expression/association in monocyte/macrophage/T cells has been associated with inflammatory processes such as rheumatoid arthritis, multiple sclerosis and atherosclerosis. Neutralization of CCR2 with either a peptide or receptor antagonist results in the prevention of joint swelling in rodent models of arthritis. In this paper, bioassay-guided discovery of CCR2 receptor antagonists derived from natural product extracts are reported. These antagonists belong to two main classes exemplified by bisthiodiketopiperazines and cytochalasins. Six compounds, including emestrin, two new emestrin analogs, and chaetomin represent the first group of compounds. These compounds inhibited the binding of MCP-1 to CCR2 (CHO membrane) with IC50 values of 0.8 to 9 microM and exhibited good activity in a whole cell assay using MCP-1 and human monocytes with IC50's ranging from 4-9 microM. Cytochalasins A and B represented the second group and inhibited the binding activity with IC50 values of 5 and 188 microM, respectively. This is the first report of natural product antagonists of the CCR2 receptor.
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- 2005
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17. Steroidal and triterpenoidal fungal metabolites as ligands of liver X receptors.
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Ondeyka JG, Jayasuriya H, Herath KB, Guan Z, Schulman M, Collado J, Dombrowski AW, Kwon SS, McCallum C, Sharma N, MacNaul K, Hayes N, Menke JG, and Singh SB
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- DNA-Binding Proteins metabolism, Fungi chemistry, Inhibitory Concentration 50, Ligands, Liver metabolism, Liver X Receptors, Orphan Nuclear Receptors, Receptors, Cytoplasmic and Nuclear metabolism, Steroids chemistry, Steroids pharmacology, Triterpenes chemistry, Triterpenes pharmacology, DNA-Binding Proteins agonists, Fungi metabolism, Receptors, Cytoplasmic and Nuclear agonists, Steroids isolation & purification, Triterpenes isolation & purification
- Abstract
Cholesterol homeostasis is tightly controlled process that involves a variety of regulators including liver X receptors (LXR). Agonists of LXR are expected to increase cholesterol efflux, lower LDL, and raise HDL levels. Screening of a natural product library of microbial extracts using a LXR-scintillation proximity assay (SPA) binding assay and bioassay-guided fractionation of a number of fungal extracts led to the isolation of five ergostane and a cycloartane derivative. These compounds exhibited IC50 value ranging 0.5 approximately 9 microM in the binding assay for a-receptor and a number of these showed in vitro agonist activity in the coactivator association assays but lacked the cell based LXR activation. The isolation and LXR activity of these compounds are described.
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- 2005
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18. Discovery of structurally diverse natural product antagonists of chemokine receptor CXCR3.
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Ondeykal JG, Herath KB, Jayasuriya H, Polishook JD, Bills GF, Dombrowski AW, Mojena M, Koch G, DiSalvo J, DeMartino J, Guan Z, Nanakorn W, Morenberg CM, Balick MJ, Stevenson DW, Slattery M, Borris RP, and Singh SB
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- Animals, Bacteriocins, Cell Line, Tumor, Diosgenin isolation & purification, Diosgenin pharmacology, Fatty Acids isolation & purification, Fatty Acids pharmacology, Models, Molecular, Molecular Conformation, Peptides isolation & purification, Peptides pharmacology, Rats, Receptors, CXCR3, Biological Factors pharmacology, Diosgenin analogs & derivatives, Receptors, Chemokine antagonists & inhibitors
- Abstract
The chemokines (CXCL9, CXCL10 and CXCL11) and associated CXCR3 receptor are expressed during the inflammatory process from multiple sclerosis, atherosclerosis or organ transplantation resulting in the recruitment of lymphocytes leading to tissue damage. It is hypothesized that blocking of the ligand/CXCR3 receptor interaction has potential to provide opportunity for development of agents that would block tissue rejection. In this paper, four classes of natural product inhibitors (IC50 ranging 0.1-41 microM) have been described that block the CXCR3 receptor interaction of IP-10 ligand. These include a cyclic thiopeptide (duramycin), polyketide glycosides (roselipins), steroidal glycosides (hypoglausin A and dioscin) and a novel alkyl pyridinium alkaloid that were isolated by bioassay-guided fractionation of the organic extracts derived from actinomycete, fungal, plant and marine sources and discovered using 125I IP-10/CXCR3 binding assay. Duramycin was the most potent with an IC50 of 0.1 microM. Roselipins 2A, 2B and 1A showed IC50 values of 14.6, 23.5, and 41 microM, respectively. Diosgenin glycosides dioscin, hypoglaucin A and kallstroemin D exhibited IC50 values of 2.1, 0.47 and 3 microM, respectively. A novel cyclic 3-alkyl pyridinium salt isolated from a sponge displayed a binding IC50 of 0.67 microM.
- Published
- 2005
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19. Identification of diverse microbial metabolites as potent inhibitors of HIV-1 Tat transactivation.
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Jayasuriya H, Zink DL, Polishook JD, Bills GF, Dombrowski AW, Genilloud O, Pelaez FF, Herranz L, Quamina D, Lingham RB, Danzeizen R, Graham PL, Tomassini JE, and Singh SB
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- Bacteria chemistry, Cell Line, Fungi chemistry, Gene Products, tat genetics, Gene Products, tat metabolism, Humans, Molecular Structure, Anti-HIV Agents metabolism, Anti-HIV Agents pharmacology, Bacteria metabolism, Fungi metabolism, Gene Expression Regulation, Viral drug effects, Gene Products, tat antagonists & inhibitors, Transcriptional Activation drug effects
- Abstract
HIV-1 Tat is one of six regulatory proteins that are required for viral replication and is an attractive target for the development of new anti-HIV agents. Screening of microbial extracts using a whole cell Tat-dependent transactivation assay, which guided the separation of the active broths, led to the identification of five structurally diverse classes (M(R) range 232-1126) of natural products. These include i) three sesquiterpenoids, namely, sporogen-AO1, petasol, and 6-dehydropetasol, ii) two resorcylic 14-membered lactones, namely monorden and monocillin IV, iii) a ten-membered lactone, iv) a quinoline and quinoxiline bicyclic octadepsipeptides, namely echinomycin and UK-63598, and v) a cyclic heptapeptide, ternatin. These compounds displayed varying degrees of potencies with IC50 values ranging from 0.0002 to 100 microM. The most active compound was the quinoxiline bicyclic octadepsipeptides, UK-63598, which inhibited Tat-dependent transactivation with an IC50 value of 0.2 nM and exhibited a 100-fold therapeutic window with respect to toxicity. In a single-cycle antiviral assay, UK-6358 inhibited viral replication with an IC50 value of 0.5 nM; however, it appeared to be equally toxic at that concentration. Monocillin IV was significantly less active (Tat transactivation inhibitory IC50 of 5 microM) but was not toxic at 100 microM in an equivalent cytotoxicity assay. The compound exhibited antiviral activity with an IC50 value of 6.2 microM in the single-cycle antiviral assay and a sixfold therapeutic window. Details of the isolation, fermentation, and biological activities of these structurally diverse natural products are described.
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- 2005
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20. Isolation and structure of antagonists of chemokine receptor (CCR5).
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Jayasuriya H, Herath KB, Ondeyka JG, Polishook JD, Bills GF, Dombrowski AW, Springer MS, Siciliano S, Malkowitz L, Sanchez M, Guan Z, Tiwari S, Stevenson DW, Borris RP, and Singh SB
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- Cytochalasins chemistry, Cytochalasins pharmacology, Humans, Inhibitory Concentration 50, Molecular Structure, Pyridines chemistry, Pyridines pharmacology, Sesterterpenes, Terpenes chemistry, Terpenes isolation & purification, Terpenes pharmacology, CCR5 Receptor Antagonists, CD4 Antigens metabolism, Cytochalasins isolation & purification, Fungi chemistry, HIV Envelope Protein gp120 metabolism, Lauraceae chemistry, Pyridines isolation & purification
- Abstract
Human CCR5 is a G-coupled receptor that binds to the envelope protein gp120 and CD4 and mediates the HIV-1 viral entry into the cells. The blockade of this binding by a small molecule receptor antagonist could lead to a new mode of action agent for HIV-1 and AIDS. Screening of natural product extracts led to the identification of anibamine (1), a novel pyridine quaternary alkaloid as a TFA salt, from Aniba sp.; ophiobolin C from fermentation extracts of fungi Mollisia sp.; and 19,20-epoxycytochalasin Q from Xylaria sp. Formation of the TFA salt of anibamine is plausibly an artifact of the isolation. The identity of the natural counterion is unknown. Anibamine.TFA competed for the binding of 125I-gp120 to human CCR5 with an IC50 of 1 microM. Ophiobolin C and 19,20-epoxycytochalasin Q exhibited binding IC50) values of 40 and 60 microM, respectively.
- Published
- 2004
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21. Isolation, structure, absolute stereochemistry, and HIV-1 integrase inhibitory activity of integrasone, a novel fungal polyketide.
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Herath KB, Jayasuriya H, Bills GF, Polishook JD, Dombrowski AW, Guan Z, Felock PJ, Hazuda DJ, and Singh SB
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- Bridged Bicyclo Compounds, Heterocyclic chemistry, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Fermentation, Furans chemistry, Furans pharmacology, HIV Integrase Inhibitors chemistry, HIV Integrase Inhibitors pharmacology, Inhibitory Concentration 50, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Stereoisomerism, Bridged Bicyclo Compounds, Heterocyclic isolation & purification, Fungi chemistry, Furans isolation & purification, HIV Integrase metabolism, HIV Integrase Inhibitors isolation & purification, HIV-1 enzymology
- Abstract
HIV-1 integrase is a critical enzyme for replication of HIV, and its inhibition is one of the most promising new drug targets for anti-retroviral therapy with potentially significant advantages over existing therapies. In this Note, the isolation, structure elucidation, and absolute stereochemistry of integrasone, a novel polyketide, derived from an unidentified sterile mycelium have been described. This bicyclic dihydroxy epoxide lactone inhibited the strand transfer reaction of HIV-1 integrase with an IC(50) of 41 microM.
- Published
- 2004
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22. Isolation, structure, and HIV-1-integrase inhibitory activity of structurally diverse fungal metabolites.
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Singh SB, Jayasuriya H, Dewey R, Polishook JD, Dombrowski AW, Zink DL, Guan Z, Collado J, Platas G, Pelaez F, Felock PJ, and Hazuda DJ
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- Alkenes chemistry, Alkenes isolation & purification, Alkenes metabolism, Anthraquinones chemistry, Anthraquinones isolation & purification, Anthraquinones metabolism, Aspergillus metabolism, Biphenyl Compounds chemistry, Biphenyl Compounds isolation & purification, Biphenyl Compounds metabolism, Caffeic Acids chemistry, Caffeic Acids isolation & purification, Caffeic Acids metabolism, Enzyme Inhibitors isolation & purification, Esters chemistry, Esters isolation & purification, Esters metabolism, Fatty Acids chemistry, Fatty Acids isolation & purification, Fatty Acids metabolism, Fermentation, Fungal Proteins isolation & purification, Industrial Microbiology, Monosaccharides chemistry, Monosaccharides isolation & purification, Monosaccharides metabolism, Penicillium metabolism, Pyrones chemistry, Pyrones isolation & purification, Pyrones metabolism, Sesterterpenes, Talaromyces metabolism, Terpenes chemistry, Terpenes isolation & purification, Terpenes metabolism, Terphenyl Compounds chemistry, Terphenyl Compounds isolation & purification, Terphenyl Compounds metabolism, Enzyme Inhibitors chemistry, Enzyme Inhibitors metabolism, Fungal Proteins chemistry, Fungal Proteins metabolism, HIV Integrase metabolism
- Abstract
HIV-1 integrase is a critical enzyme for replication of HIV, and its inhibition is one of the most promising new drug strategies for anti-retroviral therapy, with potentially significant advantages over existing therapies. In this report, a series of HIV-1 inhibitors isolated from the organic extract of fermentations from terrestrial fungi is described. These fungal species, belonging to a variety of genera, were collected from throughout the world following the strict guidelines of Rio Convention on Biodiversity. The polyketide- and terpenoid-derived inhibitors are represented by two naphthoquinones, a biphenyl and two triphenyls, a benzophenone, four aromatics with or without catechol units, a linear aliphatic terpenoid, a diterpenoid, and a sesterterpenoid. These compounds inhibited the coupled and strand-transfer reaction of HIV-1 integrase with an IC(50) value of 0.5-120 micro M. The bioassay-directed isolation, structure elucidation, and HIV-1 inhibitory activity of these compounds are described.
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- 2003
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23. Isolation, structure and HIV-1 integrase inhibitory activity of exophillic acid, a novel fungal metabolite from Exophiala pisciphila.
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Ondeyka JG, Zink DL, Dombrowski AW, Polishook JD, Felock PJ, Hazuda DJ, and Singh SB
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- Benzoates chemistry, Benzoates isolation & purification, Chromatography, High Pressure Liquid, Fermentation, Galactosides chemistry, Galactosides isolation & purification, HIV Integrase Inhibitors chemistry, HIV Integrase Inhibitors isolation & purification, Magnetic Resonance Spectroscopy, Molecular Structure, Spectrometry, Mass, Electrospray Ionization, Benzoates pharmacology, Exophiala metabolism, Galactosides pharmacology, HIV Integrase Inhibitors pharmacology, HIV-1 enzymology
- Abstract
HIV-1 integrase is one of the three enzymes that are critical for replication and spread of HIV and its inhibition is one of the most promising new drug targets for anti-retroviral therapy with potential advantage over existing therapies. This paper describes the isolation and structure elucidation of exophillic acid, a novel dimeric 2,4-dihydroxy alkyl benzoic acid, derived from Exophiala pisciphila, a fungus isolated from a soil sample collected in Georgia, USA. Exophillic acid (1) and aquastatin A (2), a related compound, inhibited the strand transfer reaction of HIV-1 integrase with IC50 values of 68 and 50 microM, respectively.
- Published
- 2003
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24. Integracides: tetracyclic triterpenoid inhibitors of HIV-1 integrase produced by Fusarium sp.
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Singh SB, Zink DL, Dombrowski AW, Polishook JD, Ondeyka JG, Hirshfield J, Felock P, and Hazuda DJ
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- Crystallography, X-Ray, Fermentation, Humans, Magnetic Resonance Spectroscopy, Models, Molecular, Spectrometry, Mass, Electrospray Ionization, Fusarium metabolism, HIV Integrase drug effects, HIV Integrase Inhibitors isolation & purification, HIV Integrase Inhibitors pharmacology, Triterpenes chemical synthesis, Triterpenes pharmacology
- Abstract
HIV-1 integrase is a critical enzyme in the replication of HIV-1. It is absent in the host cells and therefore is a good target for treatment of HIV-1 infections. Integracides are members of the tetracyclic triterpenoids family that were isolated from the fermentation broth of a Fusarium sp. Integracide A, a sulfated ester, exhibited significant inhibitory activity against strand transfer reaction of HIV-1 integrase. The discovery, structure elucidation including single crystal X-ray structure and HIV-1 inhibitory activity of these compounds are described.
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- 2003
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25. Isolation, structure, and HIV-1 integrase inhibitory activity of Cytosporic acid, a fungal metabolite produced by a Cytospora sp.
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Jayasuriya H, Guan Z, Polishook JD, Dombrowski AW, Felock PJ, Hazuda DJ, and Singh SB
- Subjects
- Electron Spin Resonance Spectroscopy, Fermentation, HIV Integrase Inhibitors chemistry, HIV Integrase Inhibitors pharmacology, Inhibitory Concentration 50, Molecular Structure, Puerto Rico, Stereoisomerism, Tetrahydronaphthalenes chemistry, Tetrahydronaphthalenes pharmacology, Fungi chemistry, HIV Integrase Inhibitors isolation & purification, HIV-1 enzymology, Tetrahydronaphthalenes isolation & purification
- Abstract
HIV-1 integrase is a critical enzyme for replication of HIV, and its inhibition has the potential to lead to an anti-retroviral therapy that has advantages over existing therapies. Cytosporic acid (1) is a polyketide-derived novel natural product that was isolated from a fermentation broth of the filamentous fungus Cytospora sp. collected from Puerto Rico. It inhibited strand transfer reaction of HIV-1 integrase with an IC(50) of 20 microM. The isolation, structure elucidation, relative stereochemistry, and activity of 1 are described.
- Published
- 2003
- Full Text
- View/download PDF
26. Isolation and insecticidal activity of mellamide from Aspergillus melleus.
- Author
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Ondeyka JG, Dombrowski AW, Polishook JP, Felcetto T, Shoop WL, Guan Z, and Singh SB
- Subjects
- Amides chemistry, Animals, Biological Assay, Culicidae drug effects, Culicidae growth & development, Diptera drug effects, Diptera growth & development, Indoles chemistry, Industrial Microbiology, Insecticides chemistry, Larva drug effects, Amides isolation & purification, Aspergillus chemistry, Indoles isolation & purification, Insecticides isolation & purification
- Abstract
Mellamide, a novel indole amide, was isolated from a fermentation of Aspergillus melleus using silica gel and high-performance liquid chromatographic methods. This allowed its separation from three known antiparasitic compounds (ochratoxin A, viomellin and xanthomegnin) also present in the potent extract. The structure was elucidated by (1)H, (13)C, COSY, DEPT, HMQC and HMBC NMR experiments. HR-FTMS aided in the molecular weight and formula determination. Mellamide showed in vitro insecticidal activity in bioassays against larvae of Lucilia sericata and Aedes egypti with LD(90) of 1,000 and 50 micro g/ml, respectively.
- Published
- 2003
- Full Text
- View/download PDF
27. Novel sesquiterpenoids from the fermentation of Xylaria persicaria are selective ligands for the NPY Y5 receptor.
- Author
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Smith CJ, Morin NR, Bills GF, Dombrowski AW, Salituro GM, Smith SK, Zhao A, and MacNeil DJ
- Subjects
- Animals, Anti-Obesity Agents, Chromatography, High Pressure Liquid, Inhibitory Concentration 50, Mice, Molecular Structure, Neurotransmitter Agents, New Jersey, Nuclear Magnetic Resonance, Biomolecular, Sesquiterpenes chemistry, Sesquiterpenes pharmacology, Ascomycota chemistry, Neuropeptide Y metabolism, Receptors, Neuropeptide Y antagonists & inhibitors, Receptors, Neuropeptide Y drug effects, Sesquiterpenes isolation & purification
- Abstract
Neuropeptide Y (NPY) is a polypeptide found in the peripheral and central nervous system and is involved in the regulation of feeding. Antagonists of NPY receptor activation could therefore have potential for development as antiobesity drugs. Fermentation of an isolate of Xylaria persicaria yielded two novel eremophilane sesquiterpenoids xylarenals A (1) and B (2). These compounds are selective for the NPY Y5 receptor but have only modest affinity. The isolation, structure elucidation, and biological activities of these compounds are described.
- Published
- 2002
- Full Text
- View/download PDF
28. Integramides A and B, two novel non-ribosomal linear peptides containing nine C(alpha)-methyl amino acids produced by fungal fermentations that are inhibitors of HIV-1 integrase.
- Author
-
Singh SB, Herath K, Guan Z, Zink DL, Dombrowski AW, Polishook JD, Silverman KC, Lingham RB, Felock PJ, and Hazuda DJ
- Subjects
- Chromatography, High Pressure Liquid, Fermentation, Fungi metabolism, Oligopeptides chemistry, HIV Integrase chemistry, HIV Integrase Inhibitors chemical synthesis, Peptides chemistry
- Abstract
[structure: see text]. Integramides A and B are two novel 16-mer linear peptides rich in C(alpha)-methyl amino acids that were isolated from fungal extracts of Dendrodochium sp. by employing a bioassay-guided isolation procedure using recombinant HIV-1 integrase. The structure and stereochemistry were elucidated by a combination of 2D NMR and ESI- and FAB-MS including MS/MS studies and by Marfey's method. Integramides A and B inhibited the coupled reaction of HIV-1 integrase with IC50 values of 17 and 10 microM, respectively.
- Published
- 2002
- Full Text
- View/download PDF
29. Structure and chemistry of apicidins, a class of novel cyclic tetrapeptides without a terminal alpha-keto epoxide as inhibitors of histone deacetylase with potent antiprotozoal activities.
- Author
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Singh SB, Zink DL, Liesch JM, Mosley RT, Dombrowski AW, Bills GF, Darkin-Rattray SJ, Schmatz DM, and Goetz MA
- Subjects
- Antiprotozoal Agents pharmacology, Enzyme Inhibitors pharmacology, Mass Spectrometry, Nuclear Magnetic Resonance, Biomolecular, Peptides, Cyclic pharmacology, Protein Conformation, Stereoisomerism, Antiprotozoal Agents chemistry, Enzyme Inhibitors chemistry, Epoxy Compounds chemistry, Histone Deacetylase Inhibitors, Peptides, Cyclic chemistry
- Abstract
Apicidins are a class of cyclic tetrapeptides that do not contain the classical electrophilic alpha-keto epoxide yet are potent (nM) inhibitors of histone deacetylase and antiprotozoal agents. These compounds showed broad-spectrum activities against the apicomplexan family of protozoa including Plasmodium sp (malarial parasite), Toxoplasma gondii, Cryptosporidium sp., and Eimeria sp. These cyclic peptides contain a beta-turn amino acid (R)-Pip or (R)-Pro, (S)-N-methoxy Trp, (S)-Ile, or (S)-Val, and either (S)-2-amino-8-oxodecanoic acid or a modified (S)-2-amino-8-oxodecanoic acid. The isolation and structure elucidation of new apicidins from two Fusarium species, temperature-dependent NMR studies of apicidin, NMR and molecular modeling based conformation of the 12-membered macrocyclic ring, and selected chemical modifications of apicidin have been detailed in this paper. The cyclic nature of the peptide, the C-8 keto group, and the tryptophan are all critical for the biological activity.
- Published
- 2002
- Full Text
- View/download PDF
30. Structure, histone deacetylase, and antiprotozoal activities of apicidins B and C, congeners of apicidin with proline and valine substitutions.
- Author
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Singh SB, Zink DL, Liesch JM, Dombrowski AW, Darkin-Rattray SJ, Schmatz DM, and Goetz MA
- Subjects
- Amino Acid Substitution, Animals, Antiprotozoal Agents pharmacology, Eimeria tenella drug effects, Histone Deacetylase Inhibitors, Magnetic Resonance Spectroscopy, Molecular Conformation, Parasitic Sensitivity Tests, Peptides, Cyclic pharmacology, Proline chemistry, Sarcocystidae drug effects, Valine chemistry, Antiprotozoal Agents chemistry, Histone Deacetylases metabolism, Peptides, Cyclic chemistry
- Abstract
[structure: see text]. Isolation and structure elucidation of two novel cyclic tetrapeptides that show a variety of potent antiprotozoal activities by reversibly inhibiting HDAC have been reported. These are the new members of a unique family of cyclic tetrapeptides that do not require the electrophilic alpha-epoxyketone moiety of HC-toxin, trapoxin A, or chlamydocin for their potent activities against HDAC and the malarial parasite.
- Published
- 2001
- Full Text
- View/download PDF
31. Dihydrocarbazole alkaloids from Aspergillus tubingensis.
- Author
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Sings HL, Harris GH, and Dombrowski AW
- Subjects
- Alkaloids isolation & purification, Carbazoles isolation & purification, Fermentation, Magnetic Resonance Spectroscopy, Mass Spectrometry, Oxidation-Reduction, Spectrophotometry, Ultraviolet, Alkaloids chemistry, Aspergillus chemistry, Carbazoles chemistry
- Abstract
Investigation of the fungus Aspergillus tubingensis has led to the isolation and identification of two dihydrocarbazole-containing compounds (1 and 2). Details of the purification and structure elucidation of 1 and 2 are described. This is the first known report of dihydrocarbazole-containing compounds to be isolated from a living system.
- Published
- 2001
- Full Text
- View/download PDF
32. Candelalides A-C: novel diterpenoid pyrones from fermentations of Sesquicillium candelabrum as blockers of the voltage-gated potassium channel Kv1.3.
- Author
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Singh SB, Zink DL, Dombrowski AW, Dezeny G, Bills GF, Felix JP, Slaughter RS, and Goetz MA
- Subjects
- Animals, CHO Cells, Cricetinae, Diterpenes chemistry, Diterpenes pharmacology, Fermentation, Hypocreales growth & development, Immunosuppressive Agents chemical synthesis, Immunosuppressive Agents chemistry, Immunosuppressive Agents pharmacology, Kv1.1 Potassium Channel, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Conformation, Pyrones chemistry, Pyrones pharmacology, Recombinant Proteins antagonists & inhibitors, Diterpenes chemical synthesis, Potassium Channel Blockers, Potassium Channels, Potassium Channels, Voltage-Gated, Pyrones chemical synthesis
- Abstract
[figure: see text] Blockers of the voltage-gated potassium channel Kv1.3 are potential immunosuppressants. Candelalides A-C are three novel diterpenoid pyrones that block this channel. The structure, stereochemistry, and activity against Kv1.3 are described.
- Published
- 2001
- Full Text
- View/download PDF
33. Resorcylic acid lactones: naturally occurring potent and selective inhibitors of MEK.
- Author
-
Zhao A, Lee SH, Mojena M, Jenkins RG, Patrick DR, Huber HE, Goetz MA, Hensens OD, Zink DL, Vilella D, Dombrowski AW, Lingham RB, and Huang L
- Subjects
- Adenosine Triphosphate pharmacology, Humans, Lymphocyte Specific Protein Tyrosine Kinase p56(lck) antagonists & inhibitors, Enzyme Inhibitors pharmacology, Lactones pharmacology, MAP Kinase Kinase Kinase 1, Protein Serine-Threonine Kinases antagonists & inhibitors, Resorcinols pharmacology
- Abstract
A resorcylic acid lactone, L-783,277, isolated from a Phoma sp. (ATCC 74403) which came from the fruitbody of Helvella acetabulum, is a potent and specific inhibitor of MEK (Map kinase kinase). L-783,277 inhibits MEK with an IC50 value of 4 nM. It weakly inhibits Lck and is inactive against Raf, PKA and PKC. L-783,277 is an irreversible inhibitor of MEK and is competitive with respect to ATP. L-783,290, the trans-isomer of L-783,277, was isolated from the same culture and evaluated together with several semi-synthetic resorcylic acid lactone analogs. A preliminary structure-activity relationship is presented. Several independent cell-based assays have been carried out to study the biological activities of these resorcylic acid lactone compounds and a brief result summary from these studies is presented.
- Published
- 1999
- Full Text
- View/download PDF
34. Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase.
- Author
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Darkin-Rattray SJ, Gurnett AM, Myers RW, Dulski PM, Crumley TM, Allocco JJ, Cannova C, Meinke PT, Colletti SL, Bednarek MA, Singh SB, Goetz MA, Dombrowski AW, Polishook JD, and Schmatz DM
- Subjects
- Animals, Eimeria tenella drug effects, Female, Humans, Kinetics, Mice, Mice, Inbred BALB C, Neospora drug effects, Peptides, Cyclic therapeutic use, Plasmodium falciparum drug effects, Protein Binding, Protozoan Infections drug therapy, Structure-Activity Relationship, Toxoplasma drug effects, Antiprotozoal Agents pharmacology, Enzyme Inhibitors pharmacology, Eukaryota drug effects, Histone Deacetylase Inhibitors, Malaria drug therapy, Peptides, Cyclic pharmacology, Plasmodium berghei
- Abstract
A novel fungal metabolite, apicidin [cyclo(N-O-methyl-L-tryptophanyl-L -isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)], that exhibits potent, broad spectrum antiprotozoal activity in vitro against Apicomplexan parasites has been identified. It is also orally and parenterally active in vivo against Plasmodium berghei malaria in mice. Many Apicomplexan parasites cause serious, life-threatening human and animal diseases, such as malaria, cryptosporidiosis, toxoplasmosis, and coccidiosis, and new therapeutic agents are urgently needed. Apicidin's antiparasitic activity appears to be due to low nanomolar inhibition of Apicomplexan histone deacetylase (HDA), which induces hyperacetylation of histones in treated parasites. The acetylation-deacetylation of histones is a thought to play a central role in transcriptional control in eukaryotic cells. Other known HDA inhibitors were also evaluated and found to possess antiparasitic activity, suggesting that HDA is an attractive target for the development of novel antiparasitic agents.
- Published
- 1996
- Full Text
- View/download PDF
35. A cofactor for thienamycin biosynthesis produced by a blocked mutant of Streptomyces cattleya.
- Author
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Chen TS, Arison BH, Ruby CL, Dombrowski AW, and Inamine ES
- Subjects
- Fermentation, Mutation, Streptomyces genetics, Streptomyces enzymology, Thienamycins biosynthesis, Vitamin B 12 physiology
- Published
- 1993
- Full Text
- View/download PDF
36. L-696,474, a novel cytochalasin as an inhibitor of HIV-1 protease. I. The producing organism and its fermentation.
- Author
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Dombrowski AW, Bills GF, Sabnis G, Koupal LR, Meyer R, Ondeyka JG, Giacobbe RA, Monaghan RL, and Lingham RB
- Subjects
- Cytochalasins pharmacology, Fermentation, Isoindoles, Ascomycota chemistry, Cytochalasins isolation & purification, HIV Protease Inhibitors
- Abstract
A novel cytochalasin, L-696,474, (18-dehydroxy cytochalasin H) that inhibits HIV-1 protease was discovered in fermentations of a bark-inhabiting Ascomycete, Hypoxylon fragiforme. The product was first identified from extracts of an agar medium. Fermentation studies on a number of media indicated that the product can be made on several solid and liquid media. Optimum production was obtained from growth in a complex medium composed of glycerol, glucose, citrate, Ardamine, soybean meal, tomato paste, and inorganic salts. Other Hypoxylon spp., related species of Xylariales, and other fungi known to produce cytochalasins, were also surveyed for their ability to make L-696,474. Only one other Hypoxylon fragiforme isolate was found to make this novel cytochalasin; none of the other cultures surveyed made L-696,474 or any other compounds which inhibit HIV-1 protease.
- Published
- 1992
- Full Text
- View/download PDF
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