DFT study on the radical scavenging activity of β,β-dimethylacrylalkannin derivatives

The radical scavenging activity of β,β-dimethylacrylalkannin derivatives has been studied by using density functional theory. The hydrogen bond property of the studied structures was investigated using the atoms in molecules theory. It turned out that the hydrogen bond is important for good radical scavenging activity. The hydrogen atom transfer for β,β-dimethylacrylalkannin derivatives is difficult to occur compared with the zero compound phenol. However, β,β-dimethylacrylalkannin derivatives appear to be good candidates for the one-electron transfer, particularly for β,β-dimethylacrylalkannin derivatives with electron-donating groups. Their naphthoquinone planar conformation and the extended electronic delocalisation between adjacent substituent groups determine low adiabatic ionisation potential (IP_a) values. The IP_a values of β,β-dimethylacrylalkannin derivatives with –NHPh, –N(CH₃)Ph, –N(CH₂CH₂)O and –N(CH₃)₂ groups are lower than that of the parent compound β,β-dimethylacrylalkannin, suggesting that these derivatives are expected to be the promising candidates for radical scavenging activity compounds. Taking this system as an example, we present an efficient method for the investigation of radical scavenging activity from theoretical point of view.     

Monitoring intra-annual cambial activity based on the periodic collection of twigs – A feasibility study

This study aims at monitoring the cambial activity and xylogenesis along the growing season under Mediterranean climate using a newly designed sampling method based on the periodic collection of twigs from the crown, in order to test its efficacy. Ten species were selected; seven hardwood (Acer pseudoplatanus L., Ceratonia siliqua L., Schinus terebinthifolius Raddi, Olea europaea L., Fraxinus angustifolia Vahl, Populus alba L., Quercus suber L.) and three softwood species (Abies alba Mill., Cupressus sempervirens L., Pinus pinea L.). The twigs were collected monthly during one year. After microtome sectioning and staining, the sections were photographed and analyzed to monitor ring development and the period of cambial activity.The twigs revealed large differences in radial growth, within and among species, which might be associated to their particular position in the tree, to the effect of the different crown microclimates, and/or to the crown conformation and type of leaves. The method showed effectiveness in the study of cambial activity, but limitations in the study of ring development due to impossibility of comparing samples. Improvements to the method are proposed, aiming essentially at minimizing the variability among samples.     

A study of staining for electron microscopy using collagen as a model system—VIII. Simulation of the negative staining pattern

Simulated negative staining patterns of collagen fibrils were prepared for visual display by a graphical procedure in which amino acid side-chains along the staggered molecules were weighted according to their stain-excluding capacity. The simulated patterns were then compared directly with electron-optical images of collagen fibrils negatively stained with sodium phosphotungstate or lithium tungstate. These visual comparisons confirm previous observations that satisfactory matching occurs when side-chains are weighted according to their ‘bulkiness’ (average cross-sectional area or ‘plumpness’). Optimal matching at the edges of the overlap zones occurred when a hairpin-like conformation was assumed for the N-terminal telopeptides and a condensed conformation for the hydrophobic part of the C-terminal telopeptides. The negative staining pattern is known to include some element of positive staining; visual matching suggests that this additional uptake of positive staining ions occurs predominantly in the more accessible gap zone in a fibril D-period. A slight mismatching between observed and simulated patterns can be understood if the gap zone suffers greater axial shrinkage than the overlap zone when specimens are prepared for electron microscopy.     

Discovery of substituted 4-anilino-2-arylpyrimidines as a new series of apoptosis inducers using a cell- and caspase-based high throughput screening assay. 2. Structure–activity relationships of the 2-aryl group

As a continuation of our efforts to discover and develop the apoptosis inducing 4-anilino-2-(2-pyridyl)pyrimidines as potential anticancer agents, we explored replacing the 2-pyridyl group by other aryl groups. SAR studies showed that the 2-pyridyl group can be replaced by a 3-pyridyl, 4-pyridyl and 2-pyrazinyl group, and that the SAR for the anilino group was similar to that of the 2-pyridyl series. However, replacement of the 2-pyridyl group by a phenyl group, a 3,5-dichloro-4-pyridyl group, or a saturated ring led to inactive compounds. Several potent compounds, including 2f, 3d, 3j and 4a, with EC₅₀ values of 0.048–0.024 μM in the apoptosis induction assay against T47D cells, were identified through the SAR studies. In a tubulin polymerization assay, compound 2f, which was active against all the three cell lines tested (T47D, HTC116 and SNU398), inhibited tubulin polymerization with an IC₅₀ value of 0.5 μM, while compound 2a, which was active against T47D cells but not active against HTC116 and SNU398 cells, was not active in the tubulin assay at up to 50 μM.     

Discovery of N-aryl-9-oxo-9H-fluorene-1-carboxamides as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 1. Structure–activity relationships of the carboxamide group

N-(2-Methylphenyl)-9-oxo-9H-fluorene-1-carboxamide (2a) was identified as a novel apoptosis inducer through our caspase- and cell-based high-throughput screening assay. Compound 2a was found to be active with sub-micromolar potencies for both caspase induction and growth inhibition in T47D human breast cancer, HCT116 human colon cancer, and SNU398 hepatocellular carcinoma cancer cells. It arrested HCT116 cells in G₂/M followed by apoptosis as assayed by the flow cytometry. Structure–activity relationship (SAR) studies of the carboxamide group identified the lead compound N-(2-(1H-pyrazol-1-yl)phenyl)-9-oxo-9H-fluorene-1-carboxamide (6s). Compound 6s, with increased aqueous solubility, was found to retain the broad activity in the caspase activation assay and in the cell growth inhibition assay with sub-micromolar EC₅₀ and GI₅₀ values in T47D, HCT116, and SNU398 cells, respectively.