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1.  Synthesis of 3H-Labeled Tetrabenazine (TBZ) 
Tetrabenazine (TBZ) (1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolin-2-one), a vesicular monamine transporter 2 inhibitor, was prepared as a tritium-labeled compound with high specific activity and radiochemical purity. Catalytic hydrogenation of a precursor with the terminal double bond was used to introduce the tritium. This method provides tritium-labeled TBZ with high specific activity and radiochemical purity, which allow the further investigation of a TBZ in the neurological field.
PMCID: PMC3126153  PMID: 21731173
tetrabenazine; TBZ; VMAT2-inhibitor; catalytic tritiation of terminal double bond
2.  A Systematic Screen of FDA-Approved Drugs for Inhibitors of Biological Threat Agents 
PLoS ONE  2013;8(4):e60579.
The rapid development of effective medical countermeasures against potential biological threat agents is vital. Repurposing existing drugs that may have unanticipated activities as potential countermeasures is one way to meet this important goal, since currently approved drugs already have well-established safety and pharmacokinetic profiles in patients, as well as manufacturing and distribution networks. Therefore, approved drugs could rapidly be made available for a new indication in an emergency.
Methodology/Principal Findings
A large systematic effort to determine whether existing drugs can be used against high containment bacterial and viral pathogens is described. We assembled and screened 1012 FDA-approved drugs for off-label broad-spectrum efficacy against Bacillus anthracis; Francisella tularensis; Coxiella burnetii; and Ebola, Marburg, and Lassa fever viruses using in vitro cell culture assays. We found a variety of hits against two or more of these biological threat pathogens, which were validated in secondary assays. As expected, antibiotic compounds were highly active against bacterial agents, but we did not identify any non-antibiotic compounds with broad-spectrum antibacterial activity. Lomefloxacin and erythromycin were found to be the most potent compounds in vivo protecting mice against Bacillus anthracis challenge. While multiple virus-specific inhibitors were identified, the most noteworthy antiviral compound identified was chloroquine, which disrupted entry and replication of two or more viruses in vitro and protected mice against Ebola virus challenge in vivo.
The feasibility of repurposing existing drugs to face novel threats is demonstrated and this represents the first effort to apply this approach to high containment bacteria and viruses.
PMCID: PMC3618516  PMID: 23577127
3.  A Platform for the Detection of Trypanosomes via Selective Small Molecule Recognition 
ACS Medicinal Chemistry Letters  2011;2(7):555-558.
Trypanothione (TSH2), a metabolite unique to trypanosomal parasites, was evaluated as a potential biomarker for trypanosomal infection using fluorescence as the means of detection. Fluoroescein arsenical helix binder (FLASH) was prepared and used to detect TSH2. Since it has low background fluorescence and forms a highly emissive complex with TSH2, it can be used to detect low micromolar concentrations of TSH2 in serum. The large dynamic range of FLASH and its selectivity for detection of the dithiol metabolite indicate that arsenical probes may offer a promising new platform for the diagnosis of trypanosomal infection.
PMCID: PMC4018164  PMID: 24900348
Trypanosomes; trypanothione; Chagas' disease; human African trypanosomiasis; African sleeping sickness; leishmaniasis; diagnostic; fluorescein arsenical helix binder (FLASH)
4.  A High-throughput Fluorescence Polarization Assay for Inhibitors of Gyrase B 
Journal of biomolecular screening  2011;16(2):230-238.
DNA gyrase, a type II topoisomerase that introduces negative supercoils into DNA, is a validated antibacterial drug target. The holoenzyme is composed of 2 subunits, gyrase A (GyrA) and gyrase B (GyrB), which form a functional A2B2 heterotetramer required for bacterial viability. A novel fluorescence polarization (FP) assay has been developed and optimized to detect inhibitors that bind to the adenosine triphosphate (ATP) binding domain of GyrB. Guided by the crystal structure of the natural product novobiocin bound to GyrB, a novel novobiocin–Texas Red probe (Novo-TRX) was designed and synthesized for use in a high-throughput FP assay. The binding kinetics of the interaction of Novo-TRX with GyrB from Francisella tularensis has been characterized, as well as the effect of common buffer additives on the interaction. The assay was developed into a 21-μL, 384-well assay format and has been validated for use in high-throughput screening against a collection of Food and Drug Administration–approved compounds. The assay performed with an average Z′ factor of 0.80 and was able to identify GyrB inhibitors from a screening library.
PMCID: PMC3176662  PMID: 21245469
fluorescence polarization; gyrase; assay development; high-throughput screen; anthracycline
5.  A parallel chiral-achiral liquid chromatographic method for the determination of the stereoisomers of ketamine and ketamine metabolites in the plasma and urine of patients with complex regional pain syndrome 
Talanta  2010;82(5):1892-1904.
A parallel chiral/achiral LC-MS/MS assay has been developed and validated to measure the plasma and urine concentrations of the enantiomers of ketamine, (R)- and (S)-Ket, in Complex Regional Pain Syndrome (CRPS) patients receiving a 5-day continuous infusion of a sub-anesthetic dose of (R,S)-Ket. The method was also validated for the determination of the enantiomers of the Ket metabolites norketamine, (R)-and (S)-norKet and dehydronorketamine, (R)- and (S)-DHNK, as well as the diastereomeric metabolites hydroxynorketamine, (2S,6S)-/(2R,6R)-HNK and two hydroxyketamines, (2S,6S)-HKet and (2S,6R)-Hket. In this method, (R,S)-Ket, (R,S)-norKet and (R,S)-DHNK and the diastereomeric hydroxyl-metabolites were separated and quantified using a C18 stationary phase and the relative enantiomeric concentrations of (R,S)-Ket, (R,S)-norKet and (R,S)-DHNK were determined using an AGP-CSP. The analysis of the results of microsomal incubations of (R)- and (S)-Ket and a plasma and urine sample from a CRPS patient indicated the presence of 10 additional compounds and glucuronides. The data from the analysis of the patient sample also demonstrated that a series of HNK metabolites were the primary metabolites in plasma and (R)- and (S)-DHNK were the major metabolites found in urine. The results suggest that norKet is the initial, but not the primary, metabolite and that downstream norKet metabolites play a role in (R,S)-Ket-related pain relief in CRPS patients.
PMCID: PMC2948022  PMID: 20875593
6.  Synthesis of Tritium Labeled (R,R)-4-Methoxyfenoterol 
The preparation of 2′,4′,6′-[3H3]-(R,R)-4-methoxyfenoterol, a tritium-labeled derivative of (R,R)-4-methoxyfenoterol was demonstrated on a 15 mCi scale providing material with a specific activity of 57 Ci/mmol.
PMCID: PMC2835161  PMID: 20228869
7.  Comparative Molecular Field Analysis of Fenoterol Derivatives: A Platform Towards Highly Selective and Effective β2 Adrenergic Receptor Agonists 
Bioorganic & medicinal chemistry  2009;18(2):728-736.
to use a previously developed CoMFA model to design a series of new structures of high selectivity and efficacy towards the β2 adrenergic receptor.
Out of 21 computationally designed structures 6 compounds were synthesized and characterized for β2-AR binding affinities, subtype selectivities and functional activities.
the best compound is (R,R)-4-methoxy-1-naphthylfelnoterol with Kiβ2-AR = 0.28 µM, Kiβ1-AR/Kiβ2-AR = 573, EC50cAMP = 3.9 nM, EC50cardio = 16 nM. The CoMFA model appears to be an effective predictor of the cardiomocyte contractility of the studied compounds which are targeted for use in congestive heart failure.
PMCID: PMC2832585  PMID: 20036561
comparative molecular fields analysis; β2 selective agonist; drug design

Results 1-7 (7)