Biomedical subjects
Publications and source records attributed to James P Snyder.
The synthesis of compound 1, a precursor for the synthesis of the oximidine II core structure 2, is described. An undesired C8-C9 isomerization occurred during the intramolecular Castro-Stephens reaction leading to macrocyle 3. The thermodynamic driving force for this unexpected isomerization was established by DFT and MP2 calculations. [reaction: see text]
On the basis of the coordinates of the related Newcastle disease virus (NDV) F protein, Valine-94, a determinant of measles virus (MV) cytopathicity, is predicted to lie in a cylindrical cavity with 10 A diameter located at the F neck. A 16-residue domain around V94 is functionally interchangeable between NDV and MV F, supporting our homology model. Features of the cavity are conserved within the Paramyxovirinae. A hydrophobic base and a hydrophilic residue at the rim are required for surface expression. Small residue substitutions predicted to open the cavity were found to disrupt transport or limit fusogenicity of transport-competent mutants but can be compensated for by simultaneous insertion of larger residues at the opposing wall. Variants containing histidine substitutions mediate fusion at pH 8.5, while at pH 7.2 fusion is blocked, suggesting that functionality requires low charge in the cavity. These results indicate that specific structural features of the cavity are essential for paramyxovirus fusion initiation.
We have discovered a novel and highly diastereoselective synthesis of azetinyl thiazolidine-2-thiones that utilizes additions of the chlorotitanium enolates of N-acyl thiazolidin-2-thiones to O-methyl aldoximes. The "anti" azetines can be subsequently converted to the corresponding alpha,beta-disubstituted beta-amino carbonyl compound with retention of stereochemistry. The formation of azetine and the product of its "hydrolytic" opening has been confirmed by X-ray crystallographic analyses.
The pentapeptide Ac-HAAAH-NH2, cyclized through its imidazoles by PdII to give [Pd(en)(peptide)]2+, has recently been evaluated by 2-D NMR and simulated annealing as a single alpha-helix conformation in solution. In the present work, we have questioned this assumption by developing Pd2+ parameters for AMBER*, performing an extensive conformational search for the [Pd(en)(peptide)]2+, and deconvoluting the averaged NMR data into eight rapidly equilibrating conformations with populations ranging from 2 to 55%. None of the latter correspond to the alpha-helix, although a 3% form possesses a related structure. As a critical component of interpreting an averaged NMR spectrum in terms of a single conformation, we advise testing this assumption with a method that permits conformational deconvolution.
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A previous experimentally defined model for the fibril formed from the core residues of the beta-amyloid (Abeta) peptides of Alzheimer's disease, 10YEVHHQKLVFFAEDVGSNKGAIIGLM, Abeta(10-35) using spectroscopic and scattering analyses reports on the average structure, benefiting immensely from the homogeneous assembly of Abeta(10-35). However, the energetic constraints that contribute to fibril dynamics and stability remain poorly understood. Here we perform molecular dynamics simulations to extend the structural assignment by providing evidence for a dynamic average ensemble with transient backbone H-bonds and internal solvation contributing to the inherent stability of amyloid fibrils.
[structure: see text] DFT and MMFF force field calculations for 2 (R = H) predict that two conformers dominate in water (>/=95%) and both sustain a geometry in which the C-F and H-N dipoles align oppositely in a near-planar arrangement. The (1)H NMR spectra (D(2)O and DMSO-d(6)) and X-ray structure for 2 (R = SO(2)NHEt) confirm the predictions in all essentials. A novel single-conformer system is proposed.
Numerous well-behaved Karplus curves correlating dihedral angle (phi) and NMR coupling constants (3JXY) exist for X-C-Z-Y fragments with X or Y = H, C, F, and P. Absent is the enigmatic F-C-C-F moiety. By calculating the four Ramsey contributions to 3JFF for F-CH2-CH2-F, a pleasing phi/3JFF curve with both positive and negative regions arises. Unlike the H-C-C-H curve, F-C-C-F is PSO vs FC dominated. The latter and the F lone electron pairs cause both the negative J values and the substituent-induced J-leveling effect.
Dicubyl disulfide (1) has been prepared in six steps from commercially available dimethyl-1,4-cubanedicarboxylate in 47% overall yield. In the final step, the previously unknown cubanethiol 2 was oxidized to disulfide 1. X-ray crystallography for 1 reveals the shortest tetragonal C-S bond on record (1.771 A). In contrast to previous generalizations, density functional theory calculations predict a low S-S rotation barrier similar to that for t-BuSSBu-t. Low-temperature (13)C NMR (600 MHz) confirms the prediction.
Taxol (paclitaxel), a complex diterpene obtained from Taxus brevifolia and its semisynthetic analogue Taxotere are two of the most important new drugs for cancer chemotherapy. Their mechanism of cytotoxic action involves stabilization of microtubules leading to mitotic arrest. A similar mechanism has been proposed for an expanding set of other natural products, for instance, the epothilones, eleutherobin, the sarcodictyins, discodermolide, laulimalide, Rhazinilam, WS9885B, certain steroids and a group of polyisoprenyl benzophenones. In this review, we focus on the conformations of small molecule microtubule (MT) stabilizing compounds which have been isolated or synthesized and subjected to structural analysis. NMR and fluorescense spectroscopies, X-ray crystallography, high resolution microscopy (electron crystallography) and theoretical calculations comprise the most common methods used in this context. In particular, we describe how the structures were determined and with what accuracy. We also discuss the conformational diversity apparent from the three dimensional structures and compare the various proposals for bioactive conformations at the target MT binding sites. Of critical importance are the recently disclosed models for Taxol and its biomimetics binding to beta-tubulin. Several different conformational schemes derived from both pharmacophore construction and modeled protein ligand complexes are compared and critically evaluated. Although full consensus has yet to be reached, emphasis is placed on pharmacophore models for the various anti-MT agents that are internally consistent and encompass more than one structural class.
BACKGROUND: Molecular mechanics (MM) and quantum chemical (QM) calculations are widely applied and powerful tools for the stereochemical and conformational investigations of molecules. The same methods have been extensively used to probe the conformational profile of Taxol (Figure 1) both in solution and at the beta-tubulin protein binding site. RESULTS: In the present work, the relative energies of seven conformations of Taxol derived from NMR and X-ray analyses were compared with a set of widely used force fields and semiempirical MO methods coupled to a continuum solvent treatment. The procedures not only diverge significantly in their assessment of relative conformational energies, but none of them provide satisfactory agreement with experiment. CONCLUSIONS: For Taxol, molecular mechanics and semiempirical QM methods are unable to provide a consistent energetic ranking of side-chain conformations. For similar highly polar organic structures, "energy-free" conformational search methods are advised.