Differential binding of inhibitors to active and inactive CDK2 provides insights for drug design

The cyclin-dependent kinases (CDKs) have been characterized in complex with a variety of inhibitors, but the majority of structures solved are in the inactive form. We have solved the structures of six inhibitors in both the monomeric CDK2 and binary CDK2/cyclinA complexes and demonstrate that significant differences in ligand binding occur depending on the activation state. The binding mode of two ligands in particular varies substantially in active and inactive CDK2. Furthermore, energetic analysis of CDK2/cyclin/inhibitors demonstrates that a good correlation exists between the in vitro potency and the calculated energies of interaction, but no such relationship exists for CDK2/inhibitor structures. These results confirm that monomeric CDK2 ligand complexes do not fully reflect active conformations, revealing significant implications for inhibitor design while also suggesting that the monomeric CDK2 conformation can be selectively inhibited.     

Elucidation of interaction between metal-free tetraphenylporphine and surface Ag atoms through temporal fluctuation of surface-enhanced resonance Raman scattering and background-light emission

We have observed simultaneously temporal fluctuation of surface-enhanced resonance Raman scattering (SERRS) and its background-light emission from single Ag nanoaggregates that were adsorbed with metal-free tetraphenylporphine (H(2)TPP) molecules. We found that temporally stable SERRS spectra showed clearly a SERRS band that is attributed to a stretching mode of a chemical bond between a carbon atom and a non-hydrogenated nitrogen atom (C(alpha)-N). This stretching mode was not observed in regular resonance Raman spectra which are free from surface enhancement. On the other hand, we also found that temporally unstable SERRS spectra did not clearly show a C(alpha)-N stretching mode in SERRS bands. Furthermore, temporally stable SERRS spectra were accompanied by temporally stable background-light emission. Kobayashi et al. [J. Phys. Chem. 1985, 89, 5174] reported that formation of an Ag-N bond between surface Ag atoms and non-hydrogenated N atoms in a pyrrole ring enhances the intensity of a C(alpha)-N stretching mode. Thus, the observed relationship between clear appearance of a C(alpha)-N stretching mode and temporal stability of SERRS plus background-light emission strongly suggests that formation of a stable Ag-N bond suppresses fluctuation of both SERRS and background-light emission. Furthermore, the observed relationship implies that chemical contribution to SERRS is stabilization of H(2)TPP molecules that are adsorbed on SERRS-active sites by formation of Ag-N bonds. Additionally, we attributed background-light emission to luminescence of complexes between H(2)TPP molecules and surface Ag atoms considering possible formation of Ag-N bonds, synchronized SERRS intensity with background-light emission intensity, blue-shifted background-light emission maxima from normal fluorescence maxima, and previous reports related to electronic structures of H(2)TPP molecules on Ag surfaces.     

Upward Three-Dimensional Grid Drawings of Graphs

A three-dimensional grid drawing of a graph is a placement of the vertices at distinct points with integer coordinates, such that the straight line segments representing the edges do not cross. Our aim is to produce three-dimensional grid drawings with small bounding box volume. Our first main result is that every -vertex graph with bounded degeneracy has a three-dimensional grid drawing with volume. This is the largest known class of graphs that have such drawings. A three-dimensional grid drawing of a directed acyclic graph (dag) is upward if every arc points up in the -direction. We prove that every dag has an upward three-dimensional grid drawing with volume, which is tight for the complete dag. The previous best upper bound was . Our main result concerning upward drawings is that every -colourable dag ( constant) has an upward three-dimensional grid drawing with volume. This result matches the bound in the undirected case, and improves the best known bound from for many classes of dags, including planar, series parallel, and outerplanar. Improved bounds are also obtained for tree dags. We prove a strong relationship between upward three-dimensional grid drawings, upward track layouts, and upward queue layouts. Finally, we study upward three-dimensional grid drawings with bends in the edges.Research of Vida Dujmovi is supported by NSERC. Research of David Wood is supported by the Government of Spain grant MEC SB2003-0270 and by the projects MCYT-FEDER BFM2003-00368 and Gen. Cat 2001SGR00224.     

1-Borabarrelene derivatives via Diels-Alder additions to borabenzenes

[reaction: see text] Borabenzene reacts with strong dienophiles such as dimethylacetylenedicarboxylate or benzyne to afford substituted borabarrelenes and borabenzobarrelene, respectively. The resultant Diels-Alder adducts display high stability due to increased Lewis acidity at boron.     

Progress toward the total synthesis of bacchopetiolone: application of a tandem aromatic oxidation/Diels-Alder reaction

A stereoselective synthesis of the bacchopetiolone (1) carbocyclic core using a tandem phenolic oxidation/Diels-Alder reaction is described. [reaction: see text].     

Selective one-pot synthesis of trithiocarbonates, xanthates, and dithiocarbamates for use in RAFT/MADIX living radical polymerizations

[reaction: see text] We report a facile route for the production of chain transfer agents for reversible addition fragmentation chain transfer (RAFT) and macromolecular design via the interchange of xanthates (MADIX) polymerizations, via a one-pot reaction. 1,1'-Thiocarbonyl diimidazole (TCDI) undergoes controlled monosubstitution when reacted with secondary thiols or alcohols. The intermediate S/O-esters of imidazole-N-thionocarboxylic acid react efficiently with a range of primary thiols, alcohols, and amines to form asymmetrical dithiocarbonates, trithiocarbonates, and dithiocarbamates, respectively. The synthesis provides a facile approach to the controlled radical polymerization of vinyl monomers through the reversible addition-fragmentation chain transfer (RAFT) mechanism.     

t-Butyl Chloromethyl Ether

A convenient preparation of t-butyl methylthiomethyl ether (2) and its conversion to t-butyl chloromethyl ether (1) are described. Methylthiomethanol (4), which was previously unknown, was isolated as a by-product from the preparation of (2): it is a stable distillable liquid.     

Calculated and experimental 1H and 13C NMR assignments for cannabicitran

Cannabicitran is an important cannabinoid natural product produced by Cannabis sativa and is often found at surprisingly high levels (up to ~10%) in “purified” commercial cannabidiol (CBD) extract preparations. Despite the prevalence of this molecule in CBD oil and other cannabinoid-related products, and the rapidly expanding interest in cannabinoids for treatment of a wide range of physiological conditions, only unassigned ¹H NMR data and partial unambiguous ¹³C assignments have been published. Herein, we report the complete ¹H and ¹³C NMR assignments of cannabicitran and comparatively evaluate the performance of several density functional theory (DFT) methods with varying levels of theory for the calculation of NMR chemical shifts.     

Electrical characteristics of ion-implanted laser-annealed silicon

The present paper summarizes recent experiments at the JRC, aiming to determine the relative damage effects produced in a-SiO2 by particles of different mass and energy, so as to correlate typical defects with specific production mechanisms. By systematic analysis of optical absorption spectra, the main colour centres that are currently associated with primary irradiation effects were characterized. Centres responsible for the B₂-band (5.04 eV) and E'-band (5.78 eV) were quantitatively investigated with respect to particle type, production yield and saturation behaviour. Arguments taken from energy loss and dpa seem to suggest that the E' centre is based on a stable structural substrate, which is not reconciled with simple ideas of a broken bond. The B₂ centre is confirmed to be associated with atomic defects produced by collisions. New determinations in the vacuum u.v., performed on heavy-ion irradiated samples, seem to put this centre in quantitative relationship to a centre responsible for a 7.15 eV absorption.     

Synthetic studies toward longeracemine: The intramolecular [4+2] cycloaddition of 3H-pyrroles

Model studies to develop a tetracyclization approach mimicking the proposed biosynthesis of the secodaphnane-type alkaloid longeracemine are described. These studies have culminated in the successful implementation of a 3H-pyrrole [4+2] cycloaddition that delivers a longeracemine-like azabicycle containing three contiguous quaternary stereocenters.