Synthesis of Phenanthro[9,10-c]thiophenes by 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-Promoted Cyclo-Oxidation.

A new method to prepare phenanthro[9,10-c]thiophenes has been developed. In the presence of triflic acid, 3,4-diaryl thiophenes undergo 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-promoted cyclo-oxidation. NMR and computational studies indicate that protonation of the thiophene plays a key role in this reaction.

Progression from latent infection to active disease in dynamic tuberculosis transmission models: a systematic review of the validity of modelling assumptions.

Mathematical modelling is commonly used to evaluate infectious disease control policy and is influential in shaping policy and budgets. Mathematical models necessarily make assumptions about disease natural history and, if these assumptions are not valid, the results of these studies can be biased. We did a systematic review of published tuberculosis transmission models to assess the validity of assumptions about progression to active disease after initial infection (PROSPERO ID CRD42016030009).

Role of Molecular Recognition in l-Cystine Crystal Growth Inhibition.

l-Cystine kidney stones-aggregates of single crystals of the hexagonal form of l-cystine-afflict more than 20 000 individuals in the United States alone. Current therapies are often ineffective and produce adverse side effects. Recognizing that the growth of l-cystine crystals is a critical step in stone pathogenesis, real-time in situ atomic force microscopy of growth on the (0001) face of l-cystine crystals and measurements of crystal growth anisotropy were performed in the presence of prospective inhibitors drawn from a 31-member library.

Regioselective Synthesis of Substituted Cyclopenta[l]phenanthrenes.

A simple and efficient synthesis of cyclopenta[l]phenanthrenes from substituted acetophenones provides access to polycyclic aromatics with a variety of substitution patterns. The synthesis requires only three steps from a silyl enol ether: a Mukaiyama aldol reaction followed by McMurry coupling and then Mallory photocyclooxidation to give the target phenanthrenes. Photocyclization conditions have been found that give regioselective formation of 2,7-phenanthrenes from bis(meta-substituted) stilbenes.

Inhibition of envelope-mediated CD4+-T-cell depletion by human immunodeficiency virus attachment inhibitors.

Human immunodeficiency virus type 1 (HIV-1) envelope (Env) binding induces proapoptotic signals in CD4(+) T cells without a requirement of infection. Defective virus particles, which represent the majority of HIV-1, usually contain a functional Env and therefore represent a potentially significant cause of such CD4(+)-T-cell loss. We reasoned that an HIV-1 inhibitor that prohibits Env-host cell interactions could block the destructive effects of defective particles.

Multiplexing a high-throughput liability assay to leverage efficiencies.

In order to identify potential cytochrome P-450 3A4 (drug-metabolizing enzyme) inducers at an early stage of the drug discovery process, a cell-based transactivation high-throughput luciferase reporter assay for the human pregnane X receptor (PXR) in HepG2 cells has been implemented and multiplexed with a viability end point for data interpretation, as part of a Lead Profiling portfolio of assays. As a routine part of Lead Profiling operations, assays are periodically evaluated for utility as well as for potential improvements in technology or process. We used a recent evaluation of our PXR-transactivation assay as a model for the application of Lean Thinking-based process analysis to lab-bench assay optimization and automation.

Multiplexed assay panel of cytotoxicity in HK-2 cells for detection of renal proximal tubule injury potential of compounds.

Proximal tubules of the kidneys are one of the most common targets of nephrotoxic drugs and chemicals. Screens to predict nephrotoxic potential of compounds with insights to mechanisms of toxicity facilitate lead optimization, guide structure-activity relationships, minimize risks of clinical nephrotoxicity and therefore are valuable in the process of drug discovery. We developed and characterized an in vitro assay multiplexed to measure several endpoints of cytotoxicity using HK-2 cells.

Use of cryopreserved transiently transfected cells in high-throughput pregnane X receptor transactivation assay.

Cryopreserved, transiently transfected HepG2 cells were compared to freshly transfected HepG2 cells for use in a pregnane X receptor (PXR) transactivation assay. Assay performance was similar for both cell preparations; however, cryopreserved cells demonstrated less interassay variation. Validation with drugs of different PXR activation potencies and efficacies demonstrated an excellent correlation (r(2) > 0.