Deorphaning the Macromolecular Targets of the Natural Anticancer Compound Doliculide

The cyclodepsipeptide doliculide is a marine natural product with strong actin‐polymerizing and anticancer activities. Evidence for doliculide acting as a potent and subtype‐selective antagonist of prostanoid E receptor 3 (EP3) is presented. Computational target prediction suggested that this membrane receptor is a likely macromolecular target and enabled immediate in vitro validation. This proof‐of‐concept study demonstrates the in silico deorphanization of phenotypic screening hits as a viable concept for future natural‐product‐inspired chemical biology and drug discovery efforts.     

A study of T1-weighted 31phosphorus MR-spectroscopy from patients with focal and diffuse liver disease.

³¹P-MR-Spectroscopy was performed in 28 patients with focal (n = 23) and diffuse (n = 5) liver disease and in 18 healthy volunteers. The spectra were obtained with a whole body scanner operating at 1.5 T by using a surface coil. To get T₁-weighted ³¹P-spectra a short TR of 600 msec was taken, because T₁-weighted spectra of focal liver disease were more significantly different from spectra from healthy volunteers than density weighted ones. The VOI from patients with focal superficial alterations showed a mean volume of 172 ml, with diffuse liver disease 196 ml, and from volunteers 158 ml. Focal tumors filled up the VOI on an average of 70%. This investigation demonstrated that PME/β-ATP- and PDE/β-ATP-ratios were sensitive indicators for focal liver disease. As a result of this study we could establish a significant increase of PME/β-ATP- (0.75 ± 0.30) and PDE/β-ATP-ratios (1.68 ± 0.62) in patients with superficial focal liver metastases (n = 19) compared to the control group (PME/β-ATP: 0.49 ± 0.17, PDE/β-ATP: 1.24 ± 0.24; t-test: p < 0.02). Patients with a hemangioma (n = 1), liver infarction (n = 1), empyema of gallbladder (n = 1) and a hepatic involvement by a malignant lymphoma (n = 1) showed a similar increase of PME/β-ATP and/or PDE/β-ATP. Up to now spectral changes seemed to be non-specific. The ratios of ³¹P metabolites of the cirrhoses (n = 4) and the fatty liver (n = 1) did not show any characteristic changes versus the volunteers.     

A collection of robust organic synthesis reactions for in silico molecule design

A focused collection of organic synthesis reactions for computer-based molecule construction is presented. It is inspired by real-world chemistry and has been compiled in close collaboration with medicinal chemists to achieve high practical relevance. Virtual molecules assembled from existing starting material connected by these reactions are supposed to have an enhanced chance to be amenable to real chemical synthesis. About 50% of the reactions in the dataset are ring-forming reactions, which fosters the assembly of novel ring systems and innovative chemotypes. A comparison with a recent survey of the reactions used in early drug discovery revealed considerable overlaps with the collection presented here. The dataset is available encoded as computer-readable Reaction SMARTS expressions from the Supporting Information presented for this paper.     

Infrared diode-laser spectrum of the CH3CN ν2 band: Analysis of local resonances with ν6±1 + 2ν8±2, ν4 + ν7±1 + ν8±1, ν4 + ν6±1, ν4 + ν7±1, and 2ν70 + ν8±1 states

Fifty-one sections of infrared diode-laser spectra of acetonitrile have been measured in the region from 2283.5 to 2235.7 cm^?1. About 450 transitions belonging to the ν₂ band have been assigned for K ≦ 7 and J ≦ 44. Anomalies found in the rotational structure have been proven to be due to five local resonances. Observed transition frequencies have been fitted by a least-squares method to a model which includes Fermi-type resonances (Δk = 0, Δ? = ± 3n) with ν₆^±1 + 2ν₈^±2 and ν₄ + ν₇^±1 + ν₈^±1 states, x, y-type Coriolis resonances (Δk = ±1, Δ? = ?3n ± 1) with ν₄ + ν₆^±1 and ν₄ + ν₇^±1 + ν₈^±1 states, and a centrifugal-distortion-type resonance (Δk = ±2, Δ? = ?3n ± 2) with a 2ν₇⁰ + ν₈^±1 state. The 11 × 11 dimensional energy matrix has been diagonalized in order to obtain the perturbed energy levels. The standard deviation for the fit is 1.075 × 10^?3 cm^?1. The molecular constants determined are also listed.     

Millimeter-wave spectrum and internal rotation of 1-silylpropyne,CH3CCSiH3

Rotational transitions of CH₃CCSiH₃ have been observed in the millimeter-wave region using a computer-controlled source-frequency modulation spectrometer with a 1.8-m-long free space absorption cell. The observed spectrum clearly showed the effect of internal rotation with a small potential barrier. It has been analyzed by calculating the torsion-rotation energies on the basis of torsional wave functions obtained by diagonalizing the torsional part of the Hamiltonian. The least-squares analysis has yielded the rotational constant B = 2068.2817(4) MHz and a few centrifugal distortion constants. The barrier height to internal rotation has been determined to be 3.77(70) cm^?1 from the contour map of the standard deviation. Also, the A rotational constant of the silyl group around the symmetry axis has been estimated by fixing the A constant of the methyl group to the value of CH₃CCH.     

Unimolecular ethyl loss from metastable 13C labelled [C5H10O]+˙ ions with the oxygen on the middle carbon: An example for incomplete energy randomization?

The investigation of ¹³C labelled 3-pentanone cation radicals generated via isomerization of the corresponding [C₅H₁₀O]^+˙ enol cation radicals demonstrates unambiguously that, in contrast to previous investigations, unimolecular ethyl loss from ¹³C labelled 3-pentanone cation radicals is preceded by complete energy randomization.