Seamless Integration of Dose‐Response Screening and Flow Chemistry: Efficient Generation of Structure–Activity Relationship Data of β‐Secretase (BACE1) Inhibitors

Drug discovery is a multifaceted endeavor encompassing as its core element the generation of structure‐activity relationship (SAR) data by repeated chemical synthesis and biological testing of tailored molecules. Herein, we report on the development of a flow‐based biochemical assay and its seamless integration into a fully automated system comprising flow chemical synthesis, purification and in‐line quantification of compound concentration. This novel synthesis‐screening platform enables to obtain SAR data on b‐secretase (BACE1) inhibitors at an unprecedented cycle time of only 1 h instead of several days. Full integration and automation of industrial processes have always led to productivity gains and cost reductions, and this work demonstrates how applying these concepts to SAR generation may lead to a more efficient drug discovery process.     

Dual picosecond dye lasers synchronously pumped by a mode locked cw yag laser

The performance of a novel dual dye laser system synchronously pumped by the frequency doubled output of a mode-locked CW-YAG laser is evaluated in relation to pulsewidth, pulse substructure, pulse spectral width and timing jitter. The behavior of the system is adequately described by a theoretical model which includes the time dependent gain and losses due to frequency bandwidth, cavity length mismatch and output coupler. The jitter is significantly reduced from that obtained with CW gas laser pumping as a result of the shorter pump pulse (50 ns instead of ≈100 ps). A routine operating condition uses 2-plate birefringen filters, 0.8 W pump power at 532 nm, to yield two 2.0 ps pulses having a cross correlation width of 3.8 ps, and 30 mW average power from each laser.     

Studies of fast inertial and diffusive motions in liquids

Recent studies of quasi-free molecular motion in liquids will be presented. Of particular interest is the inertial regime of motion which occurs significantly only if the free rotational period is comparable with the effective collisional frequency in the liquid. Results on the isomerism of stilbene and on the anisotropy decays for aniline in solution have exposed regions where the motion is nondiffusive. The results are compared with current statistical mechanical theories. This research was supported by grants from NSF, NIH and AROD and by the LRSM program at the University of Pennsylvania.     

Tres forte separation de l'etat fondamental 6S52 DU Mn2+ dans des boracites de Cl,Br et I en phase cubique

A very strong axial Zero Field Splitting is found for the ground state (⁶S_{$\text{5}\text{2}$}) of the Mn²⁺ in the cubic phase of Mg-Cl, Zn-Cl, Zn-Br and Zn-I Boracites going from 1.6 cm^-1 for Zn-Cl to 3.8 cm^-1 for Zn-I.     

Spectral manifestations of nonradiative processes in azulene

The linewidths for S₁ ← S₀ (at 14 652 cm⁻¹) and S₂ ← S₀ (at 28 048 cm⁻¹) of azulene in a naphthalene host crystal at 1.2°K are presented along with measurements of the line narrowing due to perdeuteration of the azulene. The results are related to current ideas of nonradiative processes in azulene and azulene-d₈.     

Radiative decay of benzophenone low pressure gas

The radiative decay of benzophenone low pressure gas was studied subsequent to pulse excitation at several wavelengths. Estimates of the emission rates and quantum yields for the fast and slow decay processes lead to models for the isolated molecule radiationless processes; both somewhat different from that recently proposed by Busch et al. We propose that it is the very rapid intersystem crossing process that produces the non-stationary mixed singlet-triplet levels.     

Design, synthesis, and photochemical validation of peptide linchpins containing the S,S-tetrazine phototrigger

The design, solid-phase synthesis, and photochemical validation of diverse peptide linchpins, containing the S,S-tetrazine phototrigger, have been achieved. Steady state irradiation or femtosecond laser pulses confirm their rapid photofragmentation. Attachment of peptides to the C- and N-termini will provide access to diverse constrained peptide constructs that hold the promise of providing information about early peptide/protein conformational dynamics upon photochemical release.     

Wipe sampling procedure coupled to LC–MS/MS analysis for the simultaneous determination of 10 cytotoxic drugs on different surfaces

A simple wipe sampling procedure was developed for the surface contamination determination of ten cytotoxic drugs: cytarabine, gemcitabine, methotrexate, etoposide phosphate, cyclophosphamide, ifosfamide, irinotecan, doxorubicin, epirubicin and vincristine. Wiping was performed using Whatman filter paper on different surfaces such as stainless steel, polypropylene, polystyrol, glass, latex gloves, computer mouse and coated paperboard. Wiping and desorption procedures were investigated: The same solution containing 20% acetonitrile and 0.1% formic acid in water gave the best results. After ultrasonic desorption and then centrifugation, samples were analysed by a validated liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS) in selected reaction monitoring mode. The whole analytical strategy from wipe sampling to LC–MS/MS analysis was evaluated to determine quantitative performance. The lowest limit of quantification of 10 ng per wiping sample (i.e. 0.1 ng cm⁻²) was determined for the ten investigated cytotoxic drugs. Relative standard deviation for intermediate precision was always inferior to 20%. As recovery was dependent on the tested surface for each drug, a correction factor was determined and applied for real samples. The method was then successfully applied at the cytotoxic production unit of the Geneva University Hospitals pharmacy.     

The polarized charge-transfer spectrum of crystalline anthracene-TNB complex

The intermolecular charge-transfer spectrum of the crystalline anthracene-TNB complex has been measured, using polarized light. The crystal spectrum differs from that of the solution to a much greater degree than is the case for ordinary aromatic systems. The transition is polarized along the intermolecular axis and is blue-shifted with respect to the solution. There is pronounced vibrational structure, including a prominent 250 cm^-1 interval. A Davydov splitting of approximately 200 cm^-1 is observed, and this is shown to be in reasonable agreement with the known crystal structure and with the symmetry assignment of the transition, which is A′ ← A′ for the complex in solution and A ← A in the crystal.     

Resonant non-linear spectroscopy in strong fields

A method is presented to describe multiple resonant non-linear spectra in the presence of strong laser fields. The Liouville equation for the density operator of the molecular system is transformed to a time-independent linear equation system. This can be easily solved rigorously by numerical methods or, after partitioning into a strong-field part and a perturbation, the solution can be obtained analytically by a novel perturbative approach. The results account for power broadening. Rabi splitting of signals, and power-induced extra resonances, the latter being related to the pure dephasing-induced resonances in the weak-field limit. The method can be applied to a large number of multiple resonant non-linear spectroscopies, especially CARS, CSRS, coherent Rayleigh scattering and sum- or difference-frequency generation.