Stereocontrolled Synthesis and Pharmacological Evaluation of Azetidine‐2,3‐Dicarboxylic Acids at NMDA Receptors

The four stereoisomers of azetidine‐2,3‐dicaroxylic acid (L ‐trans‐ADC, L ‐cis‐ADC, D ‐trans‐ADC, and D ‐cis‐ADC) were synthesized in a stereocontrolled fashion following two distinct strategies: one providing the two cis‐ADC enantiomers and one giving access to the two trans‐ADC enantiomers. The four azetidinic amino acids were characterized in a radioligand binding assay ([³H]CGP39653) at native NMDA receptors: L ‐trans‐ADC showed the highest affinity (K_i=10 μM ) followed by the D ‐cis‐ADC stereoisomer (21 μM ). In contrast, the two analogues L ‐cis‐ADC and D ‐trans‐ADC were low‐affinity ligands (>100 and 90 μM , respectively). Electrophysiological characterization of the ADC compounds at the four NMDA receptor subtypes NR1/NR2A, NR1/NR2B, NR1/NR2C, and NR1/NR2D expressed in Xenopus oocytes showed that L ‐trans‐ADC displayed the highest agonist potency at NR1/NR2D (EC₅₀=50 μM ), which was 9.4‐, 3.4‐, and 1.9‐fold higher than the respective potencies at NR1/NR2A–C. D ‐cis‐ADC was shown to be a partial agonist at NR1/NR2C and NR1/NR2D with medium‐range micromolar potencies (EC₅₀=720 and 230 μM , respectively). A subsequent in silico ligand–protein docking study suggested an unusual binding mode for these amino acids in the agonist binding site.     

Synthesis and biological evaluation of bicyclic nucleosides as inhibitors of M. tuberculosis thymidylate kinase

Herein we describe the synthesis and conformational analysis of a series of bicyclic thymidine derivatives and their evaluation as inhibitors of thymidine monophosphate kinase from Mycobacterium tuberculosis (TMPKmt), based on previously discovered bicyclic sugar nucleosides. With a K(i) value of 2.3 microm, 1-[3-aminomethyl-3,5-dideoxy-2-O,6-N-(thiocarbonyl)-beta-D-ribofuranosyl]thymine emerged as the most potent TMPK inhibitor of this series. Moreover, this promising compound displays inhibitory potency against Mycobacteria cultures with an IC(99) value of 100 microg mL(-1), thus promoting TMPKmt for the first time as a validated target for further inhibitory design. Attempts to rationalise the observed structure-activity relationship (SAR) involving molecular modelling and conformational analysis are described.     

Small-Angle Neutron Scattering and Photon Correlation Spectroscopy Investigation on Buckminsterfullerene Solutions

Small-Angle Neutron Scattering (SANS) and Photon Correlation Spectroscopy (PCS) findings on Buckminsterfullerene (C₆₀) solutions are presented. The analysis of SANS data allows to characterize the shape and to determine the value of the gyration radius of C₆₀ dissolved in CS₂, a solvent capable to guarantee a good contrast for the neutron probe. We obtained information about the conformation of fullerene in solution, and, by means of comparisons with experimental and theoretical data existing in literature, we found a confirmation that the gyration radius R_g is independent on concentration. PCS measurements were performed on fullerene/organic solvents (toluene, chloroform and CCl₄) solutions. Since the diffusion coefficient is related, through the Stokes-Einstein relation, to the scatterer hydrodynamic radius, R_H, we have obtained information about the conformation of fullerene in solution and about the character of the structural and hydrodynamic interaction.     

Modulation of Multiscale 3D Lattices through Conformational Control: Painting Silk Inverse Opals with Water and Light

Structural proteins from naturally occurring materials are an inspiring template for material design and synthesis at multiple scales. The ability to control the assembly and conformation of such materials offers the opportunity to define fabrication approaches that recapitulate the dimensional hierarchy and structure–function relationships found in nature. A simple and versatile directed assembly method of silk fibroin, which allows the design of structures across multiple dimensional scales by generating and tuning structural color in large‐scale, macro defect‐free colloidally assembled 3D nanostructures in the form of silk inverse opals (SIOs) is reported. This approach effectively combines bottom‐up and top‐down techniques to obtain control on the nanoscale (through silk conformational changes), microscale (through patterning), and macroscale (through colloidal assembly), ultimately resulting in a controllable photonic lattice with predefined spectral behavior, with a resulting palette spanning almost the entire visible range. As a demonstration of the approach, examples of “multispectral” SIOs, paired with theoretical calculations and analysis of their response as a function of changes of lattice constants and refractive index contrast are illustrated.     

环己烷衍生物和γ-内酯衍生物的构象分析

构象分析是50年代有机立体化学的重大进展。用环己烷衍生物和γ-内酯衍生物的构象分析说明构象分析的重要性。     

Cooperative relaxation processes in polymers

The basic mode of relaxation in polymer molecules involves the rotation of a conformer, with a time scale of the order of picoseconds. This fast relaxation process, however, cannot take place easily in the condensed state crowded by densely packed conformers, necessitating the intermolecular cooperativity among them. The domain of cooperativity grows at lower temperatures, towards the infinite size at the Kauzman zero entropy temperature, though the system deviates from the equilibrium as the glass transition intervenes at about 50°C above that temperature. From the temperature dependence of the domain size, the well-known Vogel equation is derived, which we consider is the basic origin of the empirical WLF and free volume equations. The molar volume is a crucial factor in determining molar free volume. The molecular weight of a conformer with a density correction, therefore, can be used as a parameter in determining the T_g of liquids and amorphous polymers. A larger size conformer means a higher glass transition temperature. A conformer at the chain end, on the other hand, has a higher enthalpy, i.e., a smaller effective size for that conformer. If a conformer is reacted trifunctionally, the resulting conformer is a combination of the two conformers and T_g increases, but a further addition of another conformer to that branch point reduces the average size of the conformers, so T_g decreases. The model for cooperative relaxation can be directly applied to predicting T_gs from the chemical structure of polymers, the kinetics and T_gs of thermosets during the crosslinking reaction, the distribution of relaxation times from the domain size distribution at a given temperature, the dynamics of the physical aging process, and other complex behaviors of polymers and liquids near the glass transition temperature. © 1997 John Wiley & Sons, Inc. J Appl Polym Sci 64: 77–93, 1997     

Classifying the Binding Modes of Disordered Proteins

Disordered proteins often act as interaction hubs in cellular pathways, via the specific recognition of a distinguished set of partners. While disordered regions can adopt a well-defined conformation upon binding, the coupled folding to binding model does not explain how interaction versatility is achieved. Here, I present a classification scheme for the binding modes of disordered protein regions, based on their conformational heterogeneity in the bound state. Binding modes are defined as (i) disorder-to-order transitions leading to a well-defined bound state, (ii) disordered binding leading to a disordered bound state and (iii) fuzzy binding when the degree of disorder in the bound state may vary with the partner or cellular conditions. Fuzzy binding includes polymorphic bound structures, conditional folding and dynamic binding. This classification scheme describes the structural continuum of complexes involving disordered regions as well as their context-dependent interaction behaviors.     

Two Opposing d‐Amino Acids Give Zigzag Hairpin Epitopes an Additional Kink to Create Antibody‐Selective Peptide Antigens

We have developed peptides that are able to distinguish between subgroups of polyclonal antibodies. These β‐hairpin peptides act as conformational epitopes with specific shape and flexibility; they have been analyzed by NMR and CD spectroscopy, and have been shown to identify known disease markers. As a standalone mini β‐sheet, a hairpin is stabilized by alternating pairs of hydrogen‐bonded and non‐bonded amino acids on its two opposing peptide strands. A single d mutation disrupts this secondary structure, the correlated double‐d mutation of two opposing amino acids compensates for this destabilizing effect. The designed kink was introduced into both hydrogen‐bonded and ‐non‐bonded positions of an all‐l hairpin that is a known conformational epitope in molecular recognition. Our peptides enabled the discrimination of different human rheumatoid arthritis autoantibodies in an ELISA assay.