31 results on '"Timothy R. Ramadhar"'
Search Results
2. A conserved coccidian gene is involved in Toxoplasma sensitivity to the anti-apicomplexan compound, tartrolon E
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Gregory D. Bowden, Patricia M. Reis, Maxwell B. Rogers, Rachel M. Bone Relat, Kelly A. Brayton, Sarah K. Wilson, Bruno Martorelli Di Genova, Laura J. Knoll, Felix J. Nepveux V, Albert K. Tai, Timothy R. Ramadhar, Jon Clardy, and Roberta M. O'Connor more...
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Toxoplasma ,Anti-apicomplexan ,Drug discovery ,CRISPR/Cas9 ,Natural products ,Tartrolon E ,Infectious and parasitic diseases ,RC109-216 - Abstract
New treatments for the diseases caused by apicomplexans are needed. Recently, we determined that tartrolon E (trtE), a secondary metabolite derived from a shipworm symbiotic bacterium, has broad-spectrum anti-apicomplexan parasite activity. TrtE inhibits apicomplexans at nM concentrations in vitro, including Cryptosporidium parvum, Toxoplasma gondii, Sarcocystis neurona, Plasmodium falciparum, Babesia spp. and Theileria equi. To investigate the mechanism of action of trtE against apicomplexan parasites, we examined changes in the transcriptome of trtE-treated T. gondii parasites. RNA-Seq data revealed that the gene, TGGT1_272370, which is broadly conserved in the coccidia, is significantly upregulated within 4 h of treatment. Using bioinformatics and proteome data available on ToxoDB, we determined that the protein product of this tartrolon E responsive gene (trg) has multiple transmembrane domains, a phosphorylation site, and localizes to the plasma membrane. Deletion of trg in a luciferase-expressing T. gondii strain by CRISPR/Cas9 resulted in a 68% increase in parasite resistance to trtE treatment, supporting a role for the trg protein product in the response of T. gondii to trtE treatment. Trg is conserved in the coccidia, but not in more distantly related apicomplexans, indicating that this response to trtE may be unique to the coccidians, and other mechanisms may be operating in other trtE-sensitive apicomplexans. Uncovering the mechanisms by which trtE inhibits apicomplexans may identify shared pathways critical to apicomplexan parasite survival and advance the search for new treatments. more...
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- 2020
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3. The crystalline sponge method: quantum chemical in silico derivation and analysis of guest binding energies
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Timothy R. Ramadhar and Ashley D. Cardenal
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Quantum chemical ,Sponge ,Materials science ,biology ,Chemical physics ,In silico ,Binding energy ,General Materials Science ,General Chemistry ,Crystal structure ,Single point ,Condensed Matter Physics ,biology.organism_classification - Abstract
Previously published crystalline sponge structures were analysed computationally using DFT-D2. Geometry optimisations and single point energy calculations were performed to obtain guest binding energies. Geometry optimisations afforded structures that closely matched experimental crystal structures. Relating binding energies with guest B-factors provided additional means to analyse crystalline sponge host–guest interactions. more...
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- 2021
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4. A symbiotic bacterium of shipworms produces a compound with broad spectrum anti-apicomplexan activity
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Rachel M. Bone Relat, Heather M. Fritz, Fernanda Gimenez, Pradipsinh K. Rathod, Zhenjian Lin, Jon Clardy, Daniel L. Distel, David R. Allred, Felix J.V. Nepveux, John H. White, Gregory D. Bowden, Michael W. Riggs, Jaypee Abenoja, Laura Chery, Timothy R. Ramadhar, Josiah Beaushaw, Eric W. Schmidt, Patricia M. Reis, Iwona M. Driskell, Deborah A. Schaefer, Roberta M. O'Connor, and Striepen, Boris more...
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Toxoplasma Gondii ,Mice ,Theileria ,Medicine and Health Sciences ,2.2 Factors relating to the physical environment ,Aetiology ,Biology (General) ,Protozoans ,0303 health sciences ,biology ,030302 biochemistry & molecular biology ,Eukaryota ,Cryptosporidium ,Animal Models ,Foodborne Illness ,Infectious Diseases ,Cryptosporidium parvum ,Experimental Organism Systems ,5.1 Pharmaceuticals ,Medical Microbiology ,Sarcocystis ,Development of treatments and therapeutic interventions ,Infection ,Toxoplasma ,Gammaproteobacteria ,Biotechnology ,Symbiotic bacteria ,Research Article ,Veterinary parasitology ,QH301-705.5 ,Immunology ,Antiprotozoal Agents ,Mouse Models ,Research and Analysis Methods ,Microbiology ,Vaccine Related ,Apicomplexa ,03 medical and health sciences ,Rare Diseases ,Model Organisms ,Biodefense ,Virology ,Parasite Groups ,parasitic diseases ,Genetics ,Parasitic Diseases ,Animals ,Symbiosis ,Molecular Biology ,030304 developmental biology ,Protozoan Infections ,Prevention ,Host Cells ,Organisms ,Cryptosporidium Parvum ,Biology and Life Sciences ,RC581-607 ,biology.organism_classification ,Veterinary Parasitology ,Parasitic Protozoans ,Bivalvia ,Vector-Borne Diseases ,Emerging Infectious Diseases ,Orphan Drug ,Babesia ,Animal Studies ,Parasitology ,Veterinary Science ,Antimicrobial Resistance ,Immunologic diseases. Allergy ,Parasitic Intestinal Diseases ,Viral Transmission and Infection - Abstract
Apicomplexan parasites cause severe disease in both humans and their domesticated animals. Since these parasites readily develop drug resistance, development of new, effective drugs to treat infection caused by these parasites is an ongoing challenge for the medical and veterinary communities. We hypothesized that invertebrate-bacterial symbioses might be a rich source of anti-apicomplexan compounds because invertebrates are susceptible to infections with gregarines, parasites that are ancestral to all apicomplexans. We chose to explore the therapeutic potential of shipworm symbiotic bacteria as they are bona fide symbionts, are easily grown in axenic culture and have genomes rich in secondary metabolite loci [1,2]. Two strains of the shipworm symbiotic bacterium, Teredinibacter turnerae, were screened for activity against Toxoplasma gondii and one strain, T7901, exhibited activity against intracellular stages of the parasite. Bioassay-guided fractionation identified tartrolon E (trtE) as the source of the activity. TrtE has an EC50 of 3 nM against T. gondii, acts directly on the parasite itself and kills the parasites after two hours of treatment. TrtE exhibits nanomolar to picomolar level activity against Cryptosporidium, Plasmodium, Babesia, Theileria, and Sarcocystis; parasites representing all branches of the apicomplexan phylogenetic tree. The compound also proved effective against Cryptosporidium parvum infection in neonatal mice, indicating that trtE may be a potential lead compound for preclinical development. Identification of a promising new compound after such limited screening strongly encourages further mining of invertebrate symbionts for new anti-parasitic therapeutics., Author summary Apicomplexans are intracellular protozoan parasites that cause significant disease in humans and the livestock we rely on for food. Because these parasites easily develop drug resistance, new drugs are always needed. To identify new anti-apicomplexan drugs, we investigated the compounds produced by symbiotic bacteria of shipworms, marine mollusks that burrow into and eat wood. We screened shipworm symbiotic bacteria for anti-parasitic activity and identified a compound, tartrolon E, with potent, rapid, highly selective and irreversible activity against parasites representing all branches of the apicomplexan tree. This compound was also highly effective in neonatal mice against infection with the intestinal apicomplexan parasite, Cryptosporidium. This study describes the first pan-anti-apicomplexan compound and unveils an unexplored source of anti-parasitic compounds. more...
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- 2020
5. GABA Modulating Bacteria of the Human Gut Microbiota
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Asama Lekbua, Philip Strandwitz, Rob Knight, Marc J. Dubin, Jack A. Gilbert, Conor Liston, Darya Terekhova, Karsten Zengler, Ki Hyun Kim, Jennifer Levering, Anukriti Sharma, Timothy R. Ramadhar, Nader Mroue, Jon Clardy, Joanne K. Liu, Eric J. Stewart, David Dietrich, Kim Lewis, and Daniel McDonald more...
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Microbiology (medical) ,Adult ,Male ,medicine.medical_treatment ,Immunology ,Microbial metabolism ,Gut flora ,Applied Microbiology and Biotechnology ,Microbiology ,Article ,Transcriptome ,Cohort Studies ,03 medical and health sciences ,Feces ,Young Adult ,Genetics ,medicine ,Bacteroides ,Humans ,gamma-Aminobutyric Acid ,030304 developmental biology ,Aged ,2. Zero hunger ,0303 health sciences ,Depressive Disorder, Major ,biology ,Bacteria ,Whole Genome Sequencing ,030306 microbiology ,Depression ,Growth factor ,Gene Expression Profiling ,Brain ,Cell Biology ,Middle Aged ,biology.organism_classification ,Magnetic Resonance Imaging ,Gastrointestinal Microbiome ,Gene expression profiling ,Gastrointestinal Tract ,Female ,Bacteroides fragilis - Abstract
The gut microbiota affects many important host functions, including the immune response and the nervous system1. However, while substantial progress has been made in growing diverse microorganisms of the microbiota2, 23-65% of species residing in the human gut remain uncultured3,4, which is an obstacle for understanding their biological roles. A likely reason for this unculturability is the absence in artificial media of key growth factors that are provided by neighbouring bacteria in situ5,6. In the present study, we used co-culture to isolate KLE1738, which required the presence of Bacteroides fragilis to grow. Bioassay-driven purification of B. fragilis supernatant led to the isolation of the growth factor, which, surprisingly, is the major inhibitory neurotransmitter GABA (γ-aminobutyric acid). GABA was the only tested nutrient that supported the growth of KLE1738, and a genome analysis supported a GABA-dependent metabolism mechanism. Using growth of KLE1738 as an indicator, we isolated a variety of GABA-producing bacteria, and found that Bacteroides ssp. produced large quantities of GABA. Genome-based metabolic modelling of the human gut microbiota revealed multiple genera with the predicted capability to produce or consume GABA. A transcriptome analysis of human stool samples from healthy individuals showed that GABA-producing pathways are actively expressed by Bacteroides, Parabacteroides and Escherichia species. By coupling 16S ribosmal RNA sequencing with functional magentic resonance imaging in patients with major depressive disorder, a disease associated with an altered GABA-mediated response, we found that the relative abundance levels of faecal Bacteroides are negatively correlated with brain signatures associated with depression. more...
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- 2018
6. Tundrenone: An Atypical Secondary Metabolite from Bacteria with Highly Restricted Primary Metabolism
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Emily Mevers, Daniel Petras, Jon Clardy, Pieter C. Dorrestein, Darren Liu, Mary E. Lidstrom, Peter Greenberg, Aaron W. Puri, Joern Piel, and Timothy R. Ramadhar
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0301 basic medicine ,Metabolite ,030106 microbiology ,Secondary Metabolism ,Secondary metabolite ,Biochemistry ,Genome ,Catalysis ,03 medical and health sciences ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,Gene cluster ,medicine ,Secondary metabolism ,biology ,Communication ,Computational Biology ,General Chemistry ,biology.organism_classification ,Biosynthetic Pathways ,3. Good health ,Quorum sensing ,Indenes ,chemistry ,13. Climate action ,Multigene Family ,Hydroxy Acids ,Energy source ,Methane ,Methylobacteriaceae ,Genome, Bacterial ,Bacteria ,medicine.drug - Abstract
Methane-oxidizing bacteria, aerobes that utilize methane as their sole carbon and energy source, are being increasingly studied for their environmentally significant ability to remove methane from the atmosphere. Their genomes indicate that they also have a robust and unusual secondary metabolism. Bioinformatic analysis of the Methylobacter tundripaludum genome identified biosynthetic gene clusters for several intriguing metabolites, and this report discloses the structural and genetic characterization of tundrenone, one of these metabolites. Tundrenone is a highly oxidized metabolite that incorporates both a modified bicyclic chorismate-derived fragment and a modified lipid tail bearing a β,γ-unsaturated α-hydroxy ketone. Tundrenone has been genetically linked to its biosynthetic gene cluster, and quorum sensing activates its production. M. tundripaludum’s genome and tundrenone’s discovery support the idea that additional studies of methane-oxidizing bacteria will reveal new naturally occurring molecular scaffolds and the biosynthetic pathways that produce them., Journal of the American Chemical Society, 140 (6), ISSN:0002-7863, ISSN:1520-5126 more...
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- 2018
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7. Sequential O-Arylation/Lanthanide(III)-Catalyzed [3,3]-Sigmatropic Rearrangement of Bromo-Substituted Allylic Alcohols
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Jun-ichi Kawakami, Timothy R. Ramadhar, and Robert A. Batey
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Lanthanide ,Allylic rearrangement ,010405 organic chemistry ,Chemistry ,Aryl ,Organic Chemistry ,Ether ,Sigmatropic reaction ,010402 general chemistry ,01 natural sciences ,Medicinal chemistry ,0104 chemical sciences ,Catalysis ,chemistry.chemical_compound ,Nucleophilic aromatic substitution ,Organic chemistry ,Mitsunobu reaction - Abstract
Lanthanide(III)-catalyzed aryl-Claisen rearrangement of substrates bearing halo-substituted allyl groups, specifically 2-bromoallyl aryl ethers, afford ortho-2-bromoallylphenols. Aryl ether substrates were synthesized from brominated allylic alcohols via Mitsunobu reaction, Cu(II)-catalyzed arylation using potassium aryltrifluoroborate salts, or SNAr reaction. Aryl-Claisen rearrangements proceeded in moderate to excellent yields using Eu(III) catalysis. The alkenylbromide functionality remains intact, illustrating the compatibility of synthetically important alkenylhalides during C–O/C–C σ-bond migration processes. Subsequent derivatization of the ortho-2-bromoallylphenol products through O-alkylation or C-arylation/alkenylation via Suzuki–Miyaura cross-coupling demonstrate the potential to access densely-functionalized molecules. more...
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- 2017
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8. Macrotermycins A–D, Glycosylated Macrolactams from a Termite-Associated Amycolatopsis sp. M39
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Yanpeng Hou, Shugeng Cao, Tim S. Bugni, Cameron R. Currie, Thomas P. Wyche, Jonathan L. Klassen, Michael Poulsen, Timothy R. Ramadhar, Ki-Hyun Kim, Christine Beemelmanns, and Jon Clardy
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0301 basic medicine ,Antifungal ,Glycosylation ,medicine.drug_class ,Isoptera ,medicine.disease_cause ,01 natural sciences ,Biochemistry ,Genome ,Article ,Microbiology ,03 medical and health sciences ,Polyketide ,Amycolatopsis sp. M39 ,Actinomycetales ,Gene cluster ,medicine ,Animals ,Parasite hosting ,Physical and Theoretical Chemistry ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Anti-Bacterial Agents ,0104 chemical sciences ,030104 developmental biology ,Staphylococcus aureus ,Antibacterial activity - Abstract
Bioassay-guided metabolomic analyses led to the characterization of four new 20-membered glycosylated polyketide macrolactams, macrotermycins A-D, from a termite-associated actinomycete, Amycolatopsis sp. M39. M39's sequenced genome revealed the macrotermycin's putative biosynthetic gene cluster. Macrotermycins A and C had antibacterial activity against human-pathogenic Staphylococcus aureus and, of greater ecological relevance, they also had selective antifungal activity against a fungal parasite of the termite fungal garden. more...
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- 2017
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9. Homodimericin A: A Complex Hexacyclic Fungal Metabolite
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Jon Clardy, R. Thomas Williamson, Emily Mevers, Josep Saurí, Maria Varlan, Timothy R. Ramadhar, Yizhou Liu, Arvin Moser, and Gary E. Martin
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Models, Molecular ,Antifungal Agents ,Magnetic Resonance Spectroscopy ,Stereochemistry ,Metabolite ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Catalysis ,Actinobacteria ,Stereocenter ,Deoxyribonuclease (Pyrimidine Dimer) ,Viral Proteins ,chemistry.chemical_compound ,Polyketide ,Colloid and Surface Chemistry ,Molecule ,Trichoderma ,Molecular Structure ,biology ,010405 organic chemistry ,Chemistry ,Communication ,General Chemistry ,biology.organism_classification ,Small molecule ,Up-Regulation ,3. Good health ,0104 chemical sciences ,Monomer ,13. Climate action ,Polyketides ,Racemic mixture - Abstract
Microbes sense and respond to their environment with small molecules, and discovering these molecules and identifying their functions informs chemistry, biology, and medicine. As part of a study of molecular exchanges between termite-associated actinobacteria and pathogenic fungi, we uncovered a remarkable fungal metabolite, homodimericin A, which is strongly upregulated by the bacterial metabolite bafilomycin C1. Homodimericin A is a hexacyclic polyketide with a carbon backbone containing eight contiguous stereogenic carbons in a C20 hexacyclic core. Only half of its carbon atoms have an attached hydrogen, which presented a significant challenge for NMR-based structural analysis. In spite of its microbial production and rich stereochemistry, homodimericin A occurs naturally as a racemic mixture. A plausible nonenzymatic reaction cascade leading from two identical achiral monomers to homodimericin A is presented, and homodimericin A's formation by this path, a six-electron oxidation, could be a response to oxidative stress triggered by bafilomycin C1. more...
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- 2016
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10. Identification of a Dual Inhibitor of Janus Kinase 2 (JAK2) and p70 Ribosomal S6 Kinase1 (S6K1) Pathways
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Ki Won Lee, N. R. Thimmegowda, Semi Lim, Ji Young Mun, Seung-Ho Shin, Sanguine Byun, Ki Hyun Kim, Timothy R. Ramadhar, Sam W. Lee, Hyong Joo Lee, Jon Clardy, David A. Frank, and Lee Farrand
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Cell signaling ,Programmed cell death ,Janus kinase 2 ,biology ,Kinase ,Ribosomal Protein S6 Kinases, 70-kDa ,Cancer ,Molecular Bases of Disease ,Apoptosis ,P70-S6 Kinase 1 ,Cell Biology ,Janus Kinase 2 ,medicine.disease ,Biochemistry ,Cell biology ,Diarylheptanoids ,Cell Line, Tumor ,Cancer cell ,biology.protein ,Cancer research ,medicine ,Humans ,Enzyme Inhibitors ,Molecular Biology - Abstract
Bioactive phytochemicals can suppress the growth of malignant cells, and investigation of the mechanisms responsible can assist in the identification of novel therapeutic strategies for cancer therapy. Ginger has been reported to exhibit potent anti-cancer effects, although previous reports have often focused on a narrow range of specific compounds. Through a direct comparison of various ginger compounds, we determined that gingerenone A selectively kills cancer cells while exhibiting minimal toxicity toward normal cells. Kinase array screening revealed JAK2 and S6K1 as the molecular targets primarily responsible for gingerenone A-induced cancer cell death. The effect of gingerenone A was strongly associated with relative phosphorylation levels of JAK2 and S6K1, and administration of gingerenone A significantly suppressed tumor growth in vivo. More importantly, the combined inhibition of JAK2 and S6K1 by commercial inhibitors selectively induced apoptosis in cancer cells, whereas treatment with either agent alone did not. These findings provide rationale for dual targeting of JAK2 and S6K1 in cancer for a combinatorial therapeutic approach. more...
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- 2015
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11. The crystalline sponge method: MOF terminal ligand effects
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Timothy R. Ramadhar, Shao-Liang Zheng, Yu-Sheng Chen, and Jon Clardy
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Ligand ,fungi ,Inorganic chemistry ,Metals and Alloys ,chemistry.chemical_element ,General Chemistry ,Zinc ,Chloride ,Catalysis ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,chemistry.chemical_compound ,chemistry ,Bromide ,Zinc iodide ,Polymer chemistry ,Materials Chemistry ,Ceramics and Composites ,medicine ,Molecule ,Metal-organic framework ,Group 2 organometallic chemistry ,medicine.drug - Abstract
Bromide and chloride analogs of the commonly used zinc iodide-based metal organic framework for the crystalline sponge method were synthesized and evaluated. Inclusion of (1R)-(–)-menthyl acetate into these MOFs was analysed using third-generation synchrotron radiation, and the effects and potential benefits of varying the MOF terminal ligand are discussed. more...
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- 2015
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12. Analysis of rapidly synthesized guest-filled porous complexes with synchrotron radiation: practical guidelines for the crystalline sponge method
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Jon Clardy, Shao-Liang Zheng, Timothy R. Ramadhar, and Yu-Sheng Chen
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Models, Molecular ,Diffraction ,Synchrotron radiation ,Crystallography, X-Ray ,Biochemistry ,law.invention ,metal–organic framework ,Inorganic Chemistry ,Crystal ,Structural Biology ,law ,crystalline sponge method ,General Materials Science ,Physical and Theoretical Chemistry ,Porosity ,X-ray crystallography ,Physics ,Crystallography ,biology ,synchrotron radiation ,Data Collection ,single-crystal-to-single-crystal transformation ,Condensed Matter Physics ,biology.organism_classification ,Research Papers ,Synchrotron ,Sponge ,Solvents ,Anisotropy ,Thermodynamics ,Metal-organic framework ,Synchrotrons - Abstract
This report describes complete practical guidelines and insights for the crystalline sponge method, which have been derived through the first use of synchrotron radiation on these systems, and includes a procedure for faster synthesis of the sponges. These guidelines will be applicable to crystal sponge data collected at synchrotrons or in-house facilities, and will allow researchers to obtain reliable high-quality data and construct chemically and physically sensible models for guest structural determination., A detailed set of synthetic and crystallographic guidelines for the crystalline sponge method based upon the analysis of expediently synthesized crystal sponges using third-generation synchrotron radiation are reported. The procedure for the synthesis of the zinc-based metal–organic framework used in initial crystal sponge reports has been modified to yield competent crystals in 3 days instead of 2 weeks. These crystal sponges were tested on some small molecules, with two being unexpectedly difficult cases for analysis with in-house diffractometers in regard to data quality and proper space-group determination. These issues were easily resolved by the use of synchrotron radiation using data-collection times of less than an hour. One of these guests induced a single-crystal-to-single-crystal transformation to create a larger unit cell with over 500 non-H atoms in the asymmetric unit. This led to a non-trivial refinement scenario that afforded the best Flack x absolute stereochemical determination parameter to date for these systems. The structures did not require the use of PLATON/SQUEEZE or other solvent-masking programs, and are the highest-quality crystalline sponge systems reported to date where the results are strongly supported by the data. A set of guidelines for the entire crystallographic process were developed through these studies. In particular, the refinement guidelines include strategies to refine the host framework, locate guests and determine occupancies, discussion of the proper use of geometric and anisotropic displacement parameter restraints and constraints, and whether to perform solvent squeezing/masking. The single-crystal-to-single-crystal transformation process for the crystal sponges is also discussed. The presented general guidelines will be invaluable for researchers interested in using the crystalline sponge method at in-house diffraction or synchrotron facilities, will facilitate the collection and analysis of reliable high-quality data, and will allow construction of chemically and physically sensible models for guest structural determination. more...
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- 2015
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13. The Crystalline Sponge Method: A Solvent-Based Strategy to Facilitate Noncovalent Ordered Trapping of Solid and Liquid Organic Compounds
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Jon Clardy, Yu-Sheng Chen, Shao-Liang Zheng, and Timothy R. Ramadhar
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Trifluoromethyl ,010405 organic chemistry ,Intermolecular force ,Ether ,General Chemistry ,010402 general chemistry ,Condensed Matter Physics ,01 natural sciences ,Article ,0104 chemical sciences ,Solvent ,Crystallography ,chemistry.chemical_compound ,chemistry ,Phenyl azide ,Intramolecular force ,Molecule ,General Materials Science ,Solvent effects - Abstract
A strategy that leverages solvent effects to noncovalently trap solid and unstable liquid organic compounds within a crystalline sponge ({[(ZnI2)3(tris(4-pyridyl)-1,3,5-triazine)2]·x(CHCl3)}n) in a simple, mild, and efficient fashion for target molecule structure determination via X-ray diffraction is disclosed. Host-guest structures were obtained using third-generation synchrotron radiation, and new beamline hardware allowed rapid data collection in ~5–24 minutes. This is 40–90% faster than previously reported crystalline sponge synchrotron datasets collected by us, and approximately a 150–720–fold decrease in time versus using a typical in-house diffractometer, effectively enabling the potential for high-throughput analysis. The new target molecule inclusion method using methyl tert-butyl ether (MTBE) solvent was demonstrated by trapping (E)-stilbene, vanillin, 4-(trifluoromethyl)phenyl azide, and (+)-artemisinin (an antimalarial drug). The potential of guests to maximize intermolecular interactions with the crystalline sponge framework at the expense of attenuating intramolecular interactions (e.g., π-conjugation) was observed for (E)-stilbene. Trapping of vanillin and (+)-artemisinin elicited single-crystal-to-single-crystal transformations where space group symmetry reduced from C2/c to P1̄ and C2, respectively, and the absolute configuration of (+)-artemisinin was determined through anomalous dispersion. more...
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- 2017
14. Natalamycin A, an ansamycin from a termite-associated Streptomyces sp
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Timothy R. Ramadhar, Michael Poulsen, Cameron R. Currie, Christine Beemelmanns, Jon Clardy, Shugeng Cao, and Ki Hyun Kim
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Antifungal ,biology ,medicine.drug_class ,Stereochemistry ,Ansamycin ,Geldanamycin analog ,General Chemistry ,Nuclear magnetic resonance spectroscopy ,biology.organism_classification ,Streptomyces ,Article ,Biochemistry ,Macrotermes natalensis ,polycyclic compounds ,medicine ,Streptomyces strain ,Nest (protein structural motif) - Abstract
We report a preliminary functional and complete structural characterization of a highly unusual geldanamycin analog, natalamycin A, that was isolated from Streptomyces strain M56 recovered from a South African nest of Macrotermes natalensis termites. Bioassay-guided fractionation based on antifungal activity led to the isolation of natalamycin A, and a combination of NMR spectroscopy and X-ray crystallographic analysis, including highly-accurate quantum-chemical NMR calculations on the largest and most conformationally-flexible system to date, revealed natalamycin A’s three-dimensional solid- and solution-state structure. This structure along with the structures of related compounds isolated from the same source suggest a geldanamycin-like biosynthetic pathway with unusual post-PKS modifications. more...
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- 2014
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15. Accurate prediction of experimental free energy of activation barriers for the aliphatic-Claisen rearrangement through DFT calculations
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Robert A. Batey and Timothy R. Ramadhar
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Claisen rearrangement ,Pericyclic reaction ,Chemistry ,Computational chemistry ,Kinetic isotope effect ,Activation energy ,Physical and Theoretical Chemistry ,Sigmatropic reaction ,Condensed Matter Physics ,Biochemistry ,Basis set - Abstract
A benchmarking study was performed to determine DFT methods that can accurately predict free energy of activation barriers (ΔG‡) for the aliphatic-Claisen rearrangement. Accurate experimental ΔG‡ values from eight gas-phase literature reactions were used for validation. Previously applied density functionals for this system and its variants, along with the Minnesota 2005/2006/2008 functionals, were tested using the 6-31+G** basis set. On B3LYP/6-31+G** geometries, M08-HX afforded the best results and gave a sevenfold increase in accuracy over the energies predicted by the robust B3LYP functional, which is routinely used for Claisen rearrangements. An investigation of whether improvements in ΔG‡ predictions could occur by optimizing structures with newer functionals then became of interest. For geometry validation, optimization and Bigeleisen–Mayer KIE calculations with M05/6-31+G** and M05-2X/6-31+G** for the rearrangement of allyl vinyl ether were performed and compared to previous experimental data, and both were found to predict new valid Claisen transition structures. All structures were then reoptimized, and it was found that M05-2X/6-31+G** geometries afforded worthwhile enhancement, where M08-HX/6-31+G**//M05-2X/6-31+G** yielded the most accurate and reliable results with a mean unsigned error (MUE) of 0.3 kcal/mol relative to experimental ΔG‡ values. These results should prove useful for Claisen rearrangement studies, and this is the first instance that the Minnesota 2008 functionals have been applied to the study of sigmatropic reactions. more...
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- 2011
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16. Allylation of Imines and Their Derivatives with Organoboron Reagents: Stereocontrolled Synthesis of Homoallylic Amines
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Timothy R. Ramadhar and Robert A. Batey
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Allylic rearrangement ,Chemistry ,Organic Chemistry ,Imine ,chemistry.chemical_element ,Chemical synthesis ,Combinatorial chemistry ,Catalysis ,chemistry.chemical_compound ,Organotrifluoroborate ,Amine gas treating ,Chemoselectivity ,Palladium - Abstract
Homoallylic amines serve as important precursors for the synthesisof a variety of natural products and pharmaceutically relevant compounds.One widely used strategy for homoallylic amine synthesis is theaddition of allylic metal or metalloid derivatives to imines orrelated functional groups. The use of allylic boron compounds forthese reactions has emerged as an important synthe-ticapproach, providing a robust and chemoselective method for efficientand stereocontrolled access to various homoallylic amines. In thisreview, a comprehensive and critical analysis of imine allyl-borationand crotylboration methods using organoborane, organoboronate andpotassium organotrifluoroborate reagents is provided. These approachesinclude direct methods that accomplish diastereo- or enantiocontrolledaddition of the organoboron species. Additionally, organoboron-basedtransition-metal-catalyzed allylation of imines and their respectivesurrogates using copper, indium, iridium, palladium or zinc catalysisis discussed. Finally, coverage on the use of allenyl- and propargylboroncompounds and their application for the synthesis of homopropargylicand homoallenyl amines is provided. 1 Introduction 2 Organoborane Reagents 3 Organoboronic Acid and Ester Reagents 4 Potassium Organotrifluoroborate Reagents 5 Organoboron-Based Transition-Metal-Catalyzed Allylation 5.1 Copper Catalysis 5.2 Indium Catalysis 5.3 Iridium Catalysis 5.4 Palladium Catalysis 5.5 Zinc Catalysis 6 Allenylation and Propargylation Reactions 7 Concluding Remarks more...
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- 2011
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17. Stereocontrolled Synthesis of Contiguous C(sp3)−C(aryl) Bonds by Lanthanide(III)-Catalyzed Domino Aryl-Claisen [3,3]-Sigmatropic Rearrangements
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Jun-ichi Kawakami, Robert A. Batey, Alan J. Lough, and Timothy R. Ramadhar
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Models, Molecular ,Lanthanide ,Molecular Structure ,Chemistry ,Stereochemistry ,Aryl ,Organic Chemistry ,Cycloparaffins ,Stereoisomerism ,Alkenes ,Sigmatropic reaction ,Crystallography, X-Ray ,Lanthanoid Series Elements ,Biochemistry ,Catalysis ,Domino ,chemistry.chemical_compound ,Stereospecificity ,Nucleophilic aromatic substitution ,Yield (chemistry) ,Physical and Theoretical Chemistry ,Ethers - Abstract
A domino [3,3]-sigmatropic aryl-Claisen rearrangement of cyclic and acyclic bisaryloxy-substituted alkenes can be performed in high yield by using Ln(fod)(3) catalysis to obtain bisphenolic products incorporating two contiguous aryl-C(sp(3)) bonds. Stereospecific rearrangement was observed for cyclic substrates. The precursor diaryl ethers were typically synthesized from the corresponding diols by double arylation procedures using either copper catalyzed coupling of aryltrifluoroborate salts or by S(N)Ar reaction. more...
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- 2010
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18. Cyclobutanone Mimics of Penicillins: Effects of Substitution on Conformation and Hemiketal Stability
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Darryl P. Evanoff, Gerald Lange, Abdeljalil Assoud, Gary I. Dmitrienko, Nicholas J. Taylor, Timothy R. Ramadhar, Marc E. Savard, and Jarrod W. Johnson
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Models, Molecular ,Substitution reaction ,Magnetic Resonance Spectroscopy ,Anomeric effect ,Bicyclic molecule ,Stereochemistry ,Organic Chemistry ,Molecular Conformation ,Substituent ,Stereoisomerism ,Penicillins ,Sulfuryl chloride ,Reference Standards ,Crystallography, X-Ray ,Ring (chemistry) ,chemistry.chemical_compound ,Models, Chemical ,chemistry ,Alkoxy group ,Quantum Theory ,Computer Simulation ,Tetrahydrothiophene ,Cyclobutanes - Abstract
The tendency for carbocyclic analogues of penicillins to undergo hydrate and hemiketal formation is central to their ability to function as beta-lactamase inhibitors. 2-Thiabicyclo[3.2.0]heptan-6-one-4-carboxylates with alkoxy functionality at C3 have been prepared through two complementary diastereoselective substitution reactions following a highly stereoselective chlorination with sulfuryl chloride. We have found that carbocyclic analogues with 3beta substituents favor an endo envelope conformation in solution, the solid state, and the gas phase, whereas those with 3alpha substituents adopt an exo envelope. Evidence from X-ray crystal structures and ab initio calculations suggests that an anomeric effect contributes to the large conformational preference of the tetrahydrothiophene ring that favors the C3 substituent in an axial orientation. In addition, the envelope conformation of the bicycle, which is determined by the stereochemistry of the C3 substituent, has a dramatic effect on the ability of the cyclobutanone to undergo hemiketal formation in methanol-d4. more...
- Published
- 2008
- Full Text
- View/download PDF
19. Inverse H-Cex situHRMAS NMR experiments for solid-phase peptide synthesis
- Author
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Fernando Amador, Michael J. T. Ditty, William P. Power, and Timothy R. Ramadhar
- Subjects
Hrmas nmr ,Phase transition ,Protein Conformation ,Phase (waves) ,Inverse ,General Chemistry ,Carbon ,Phase Transition ,Homonuclear molecule ,chemistry.chemical_compound ,Nuclear magnetic resonance ,chemistry ,Heteronuclear molecule ,Magic angle spinning ,Peptide synthesis ,General Materials Science ,Nuclear Magnetic Resonance, Biomolecular ,Oligopeptides ,Hydrogen - Abstract
The growing importance of solid-phase peptide synthesis (SPPS) has necessitated the development of spectroscopic experiments that can be used to obtain structural and conformational information on resin-bound peptides. Despite the utility of two-dimensional high-resolution magic angle spinning (HRMAS) NMR experiments that provide homonuclear shift correlations, experiments that provide heteronuclear shift correlations are necessary for complex conformational and structural elucidatory problems. Here we report the optimization and implementation of non-gradient inverse NMR experiments for acquiring the 1H-13C shift correlations of resin-bound peptides. The use of non-gradient experiments is advantageous as many magic angle spinning (MAS) probes do not possess gradient coils. An HRMAS BIRD-HMQC experiment with a reduced 1JCH constant has proven very suitable for obtaining one-bond correlations. Long-range correlations can be interpolated by using a non-gradient HRMAS CT-HMBC-1 experiment where the resulting data is processed with forward linear prediction. It has been shown that removing the effects of 1H-1H J-modulation is crucial in order to view cross peaks that correspond to long-range correlations. Additionally, both experiments prove extremely useful over routine one-dimensional 13C HRMAS experiments for extracting carbon chemical shift data. The non-gradient HRMAS BIRD-HMQC and CT-HMBC-1 experiments can be used to assist in conformational analysis and to identify and deconvolute situations where accidental equivalence and seemingly correlated isochronous signals arise. more...
- Published
- 2007
- Full Text
- View/download PDF
20. Variable genetic architectures produce virtually identical molecules in bacterial symbionts of fungus-growing ants
- Author
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Antonio C. Ruzzini, Jon Clardy, Ethan B. Van Arnam, Timothy R. Ramadhar, Clarissa S. Sit, and Cameron R. Currie
- Subjects
Multidisciplinary ,food.ingredient ,Trachymyrmex ,Ants ,Molecular Sequence Data ,Fungi ,Biology ,biology.organism_classification ,Genome ,Corrections ,Actinobacteria ,food ,Plasmid ,Evolutionary biology ,Genes, Bacterial ,Pseudonocardia ,Horizontal gene transfer ,Botany ,Physical Sciences ,Fungus-growing ants ,Animals ,Escovopsis ,Symbiosis - Abstract
Small molecules produced by Actinobacteria have played a prominent role in both drug discovery and organic chemistry. As part of a larger study of the actinobacterial symbionts of fungus-growing ants, we discovered a small family of three previously unreported piperazic acid-containing cyclic depsipeptides, gerumycins A–C. The gerumycins are slightly smaller versions of dentigerumycin, a cyclic depsipeptide that selectively inhibits a common fungal pathogen, Escovopsis. We had previously identified this molecule from a Pseudonocardia associated with Apterostigma dentigerum, and now we report the molecule from an associate of the more highly derived ant Trachymyrmex cornetzi. The three previously unidentified compounds, gerumycins A–C, have essentially identical structures and were produced by two different symbiotic Pseudonocardia spp. from ants in the genus Apterostigma found in both Panama and Costa Rica. To understand the similarities and differences in the biosynthetic pathways that produced these closely related molecules, the genomes of the three producing Pseudonocardia were sequenced and the biosynthetic gene clusters identified. This analysis revealed that dramatically different biosynthetic architectures, including genomic islands, a plasmid, and the use of spatially separated genetic loci, can lead to molecules with virtually identical core structures. A plausible evolutionary model that unifies these disparate architectures is presented. more...
- Published
- 2015
21. ChemInform Abstract: Natalamycin A, an Ansamycin from a Termite-Associated Streptomyces sp
- Author
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Ki Hyun Kim, Shugeng Cao, Jon Clardy, Michael Poulsen, Cameron R. Currie, Timothy R. Ramadhar, and Christine Beemelmanns
- Subjects
Antifungal ,biology ,medicine.drug_class ,Chemistry ,Stereochemistry ,Ansamycin ,Geldanamycin analog ,General Medicine ,Nuclear magnetic resonance spectroscopy ,biology.organism_classification ,Streptomyces ,Macrotermes natalensis ,polycyclic compounds ,medicine ,Streptomyces strain ,Nest (protein structural motif) - Abstract
We report a preliminary functional and complete structural characterization of a highly unusual geldanamycin analog, natalamycin A, that was isolated from Streptomyces strain M56 recovered from a South African nest of Macrotermes natalensis termites. Bioassay-guided fractionation based on antifungal activity led to the isolation of natalamycin A, and a combination of NMR spectroscopy and X-ray crystallographic analysis, including highly-accurate quantum-chemical NMR calculations on the largest and most conformationally-flexible system to date, revealed natalamycin A's three-dimensional solid- and solution-state structure. This structure along with the structures of related compounds isolated from the same source suggest a geldanamycin-like biosynthetic pathway with unusual post-PKS modifications. more...
- Published
- 2015
- Full Text
- View/download PDF
22. Resolving the mechanistic origins of E/Z-selectivity differences for the ortho-aryl-Claisen [3,3]-sigmatropic rearrangement through DFT calculations
- Author
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Timothy R. Ramadhar and Robert A. Batey
- Subjects
chemistry.chemical_compound ,chemistry ,Computational chemistry ,Stereochemistry ,Aryl ,Product (mathematics) ,Physical and Theoretical Chemistry ,Sigmatropic reaction ,Condensed Matter Physics ,Selectivity ,Biochemistry ,Transition state ,Cope rearrangement - Abstract
The mechanistic origins of E / Z -product selectivity differences for the synthetically important thermal ortho -aryl-Claisen [3,3]-sigmatropic rearrangement is resolved through a computational study. The formation of E - and Z -products has previously been proposed to occur as a result of reaction via different chair-like transition states or through chair- and boat-like transition states. Using DFT B3LYP/6-31G * calculations on a previously reported experimental system, it has been determined that differences in E / Z -product selectivities primarily arise by progression through different chair-like transition states. more...
- Published
- 2011
- Full Text
- View/download PDF
23. Bacterial symbionts in agricultural systems provide a strategic source for antibiotic discovery
- Author
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Christine Beemelmanns, Cameron R. Currie, Timothy R. Ramadhar, and Jon Clardy
- Subjects
Antifungal ,medicine.drug_class ,Antibiotics ,Isoptera ,Biology ,Article ,Beta-lactam ,chemistry.chemical_compound ,Antibiotic resistance ,Drug Discovery ,Drug Resistance, Bacterial ,medicine ,Animals ,Humans ,Symbiosis ,Pharmacology ,Biological Products ,Ecology ,business.industry ,Ants ,fungi ,Fungi ,Agriculture ,Biotechnology ,Anti-Bacterial Agents ,Coleoptera ,chemistry ,Drug Design ,business - Abstract
As increased antibiotic resistance erodes the efficacy of currently used drugs, the need for new candidates with therapeutic potential grows. Although the majority of antibiotics in clinical use originated from natural products, mostly from environmental actinomycetes, high rediscovery rates, among other factors, have diminished the enthusiasm for continued exploration of this historically important source. Several well-studied insect agricultural systems have bacterial symbionts that have evolved to produce small molecules that suppress environmental pathogens. These molecules represent an underexplored reservoir of potentially useful antibiotics. This report describes the multilateral symbioses common to insect agricultural systems, the general strategy used for antibiotic discovery and pertinent examples from three farming systems: fungus-farming ants, southern pine beetles (SPBs) and fungus-growing termites. more...
- Published
- 2013
24. ChemInform Abstract: Mild Double Allylboration Reactions of Nitriles and Acid Anhydrides Using Potassium Allyltrifluoroborate
- Author
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Timothy R. Ramadhar, Jazmin Bansagi, and Robert A. Batey
- Subjects
chemistry.chemical_compound ,Chemistry ,Organotrifluoroborate ,Reagent ,Potassium ,Electrophile ,food and beverages ,Organic chemistry ,chemistry.chemical_element ,General Medicine ,Chemoselectivity ,Boron trifluoride - Abstract
The double allylboration of nitriles and acid anhydrides to form bis-allyl amines and esters, respectively, can be achieved through the use of potassium allyltrifluoroborate in the presence of boron trifluoride etherate at room temperature. The method described is relatively mild, exhibits chemoselectivity to other electrophiles present, avoids the use of metals, and features the use of an operationally stable and robust potassium organotrifluoroborate reagent. more...
- Published
- 2013
- Full Text
- View/download PDF
25. Mild double allylboration reactions of nitriles and acid anhydrides using potassium allyltrifluoroborate
- Author
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Timothy R. Ramadhar, Robert A. Batey, and Jazmin Bansagi
- Subjects
chemistry.chemical_compound ,Chemistry ,Organotrifluoroborate ,Potassium ,Reagent ,Organic Chemistry ,Electrophile ,food and beverages ,chemistry.chemical_element ,Organic chemistry ,Chemoselectivity ,Boron trifluoride - Abstract
The double allylboration of nitriles and acid anhydrides to form bis-allyl amines and esters, respectively, can be achieved through the use of potassium allyltrifluoroborate in the presence of boron trifluoride etherate at room temperature. The method described is relatively mild, exhibits chemoselectivity to other electrophiles present, avoids the use of metals, and features the use of an operationally stable and robust potassium organotrifluoroborate reagent. more...
- Published
- 2012
26. Recent Advances in Nucleophilic Addition Reactions of Organoboronic Acids and Their Derivatives to Unsaturated CN Functionalities
- Author
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Robert A. Batey and Timothy R. Ramadhar
- Subjects
Nucleophilic addition ,Cascade reaction ,Chemistry ,Organic chemistry - Published
- 2011
- Full Text
- View/download PDF
27. ChemInform Abstract: Cyclobutanone Mimics of Penicillins: Effects of Substitution on Conformation and Hemiketal Stability
- Author
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Marc E. Savard, Nicholas J. Taylor, Gerald Lange, Jarrod W. Johnson, Timothy R. Ramadhar, Abdeljalil Assoud, Gary I. Dmitrienko, and Darryl P. Evanoff
- Subjects
Substitution reaction ,chemistry.chemical_compound ,Anomeric effect ,Chemistry ,Stereochemistry ,Alkoxy group ,Substituent ,Stereoselectivity ,General Medicine ,Sulfuryl chloride ,Ring (chemistry) ,Tetrahydrothiophene - Abstract
The tendency for carbocyclic analogues of penicillins to undergo hydrate and hemiketal formation is central to their ability to function as β-lactamase inhibitors. 2-Thiabicyclo[3.2.0]heptan-6-one-4-carboxylates with alkoxy functionality at C3 have been prepared through two complementary diastereoselective substitution reactions following a highly stereoselective chlorination with sulfuryl chloride. We have found that carbocyclic analogues with 3β substituents favor an endo envelope conformation in solution, the solid state, and the gas phase, whereas those with 3α substituents adopt an exo envelope. Evidence from X-ray crystal structures and ab initio calculations suggests that an anomeric effect contributes to the large conformational preference of the tetrahydrothiophene ring that favors the C3 substituent in an axial orientation. In addition, the envelope conformation of the bicycle, which is determined by the stereochemistry of the C3 substituent, has a dramatic effect on the ability of the cyclobuta... more...
- Published
- 2008
- Full Text
- View/download PDF
28. The Crystalline Sponge Method: Synthetic and Crystallographic Guidelines
- Author
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Timothy R. Ramadhar, Shao-Liang Zheng, Jon Clardy, and Yu-Sheng Chen
- Subjects
Inorganic Chemistry ,Crystallography ,Sponge ,Materials science ,biology ,Structural Biology ,General Materials Science ,Physical and Theoretical Chemistry ,Condensed Matter Physics ,biology.organism_classification ,Biochemistry - Abstract
Synthetic and crystallographic guidelines for the crystalline sponge method based upon the analysis of rapidly-synthesized crystal sponges using high-flux synchrotron radiation are presented [1]. The synthetic procedure for the zinc-based metal-organic framework (MOF) used in preliminary crystal sponge reports [2, 3] has been modified to afford suitable sponges in 3 days instead of 2 weeks. These sponges were tested on some small molecules, with two being difficult cases for in-house diffraction analysis in regards to data quality and determination of space group. These issues were readily resolved by the use of high-flux synchrotron radiation with more...
- Published
- 2014
- Full Text
- View/download PDF
29. Stereocontrolled Synthesis of Contiguous C(sp3)âC(aryl) Bonds by Lanthanide(III)-Catalyzed Domino Aryl-Claisen [3,3]-Sigmatropic Rearrangements.
- Author
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Timothy R. Ramadhar, Jun-ichi Kawakami, Alan J. Lough, and Robert A. Batey
- Published
- 2010
- Full Text
- View/download PDF
30. Small-Molecule Reactivation of Mutant p53 to Wild-Type-like p53 through the p53-Hsp40 Regulatory Axis
- Author
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Kiki Chu, So-Young Hwang, David J. Newman, Sam W. Lee, Jung Hyun Lee, Masatsugu Hiraki, Shugeng Cao, Jon Clardy, Aditi U. Gurkar, Jianming Zhang, Takushi Namba, Anna Mandinova, Kyoung Wan Yoon, Timothy R. Ramadhar, Maureen E. Murphy, Vihren N. Kolev, Sanguine Byun, Broad Institute of MIT and Harvard, Lee, Samuel W., and Mandinova, Anna more...
- Subjects
Conformational change ,Mutant ,Clinical Biochemistry ,Mice, Nude ,Antineoplastic Agents ,Biology ,medicine.disease_cause ,Biochemistry ,Article ,Indole Alkaloids ,Small Molecule Libraries ,Mice ,Mutant protein ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,Disulfides ,Gene ,Molecular Biology ,Pharmacology ,Mutation ,Wild type ,General Medicine ,HSP40 Heat-Shock Proteins ,HCT116 Cells ,Molecular biology ,Xenograft Model Antitumor Assays ,High-Throughput Screening Assays ,Cell culture ,Cancer cell ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Tumor Suppressor Protein p53 - Abstract
TP53 is the most frequently mutated gene in human cancer, and small-molecule reactivation of mutant p53 function represents an important anticancer strategy. A cell-based, high-throughput small-molecule screen identified chetomin (CTM) as a mutant p53 R175H reactivator. CTM enabled p53 to transactivate target genes, restored MDM2 negative regulation, and selectively inhibited the growth of cancer cells harboring mutant p53 R175H in vitro and in vivo. We found that CTM binds to Hsp40 and increases the binding capacity of Hsp40 to the p53 R175H mutant protein, causing a potential conformational change to a wild-type-like p53. Thus, CTM acts as a specific reactivator of the p53 R175H mutant form through Hsp40. These results provide new insights into the mechanism of reactivation of this specific p53 mutant., United States. National Institutes of Health (GM108415), United States. National Institutes of Health (CA142805), United States. National Institutes of Health (CA149477), United States. National Institutes of Health (CA80058), United States. National Institutes of Health (GM086258) more...
- Full Text
- View/download PDF
31. A symbiotic bacterium of shipworms produces a compound with broad spectrum anti-apicomplexan activity.
- Author
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Roberta M O'Connor, Felix J Nepveux V, Jaypee Abenoja, Gregory Bowden, Patricia Reis, Josiah Beaushaw, Rachel M Bone Relat, Iwona Driskell, Fernanda Gimenez, Michael W Riggs, Deborah A Schaefer, Eric W Schmidt, Zhenjian Lin, Daniel L Distel, Jon Clardy, Timothy R Ramadhar, David R Allred, Heather M Fritz, Pradipsinh Rathod, Laura Chery, and John White more...
- Subjects
Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Apicomplexan parasites cause severe disease in both humans and their domesticated animals. Since these parasites readily develop drug resistance, development of new, effective drugs to treat infection caused by these parasites is an ongoing challenge for the medical and veterinary communities. We hypothesized that invertebrate-bacterial symbioses might be a rich source of anti-apicomplexan compounds because invertebrates are susceptible to infections with gregarines, parasites that are ancestral to all apicomplexans. We chose to explore the therapeutic potential of shipworm symbiotic bacteria as they are bona fide symbionts, are easily grown in axenic culture and have genomes rich in secondary metabolite loci [1,2]. Two strains of the shipworm symbiotic bacterium, Teredinibacter turnerae, were screened for activity against Toxoplasma gondii and one strain, T7901, exhibited activity against intracellular stages of the parasite. Bioassay-guided fractionation identified tartrolon E (trtE) as the source of the activity. TrtE has an EC50 of 3 nM against T. gondii, acts directly on the parasite itself and kills the parasites after two hours of treatment. TrtE exhibits nanomolar to picomolar level activity against Cryptosporidium, Plasmodium, Babesia, Theileria, and Sarcocystis; parasites representing all branches of the apicomplexan phylogenetic tree. The compound also proved effective against Cryptosporidium parvum infection in neonatal mice, indicating that trtE may be a potential lead compound for preclinical development. Identification of a promising new compound after such limited screening strongly encourages further mining of invertebrate symbionts for new anti-parasitic therapeutics. more...
- Published
- 2020
- Full Text
- View/download PDF
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