Beta strand peptidomimetics as potent PDZ domain ligands

The search for general strategies for inhibiting protein-protein interactions has been stimulated by recognition of the key role they play in virtually every process of living systems. Multiprotein complex assembly and localization by PDZ domain-containing proteins exemplify processes critical to cell physiology and function that are mediated by beta strand association. Here we describe the development of substituted "@-tides," protease-resistant peptidomimetics incorporating conformationally restricted amino acid surrogates that reproduce the hydrogen-bonding pattern and side-chain functionality of a beta strand. The synthetic flexibility and generality of the substituted @-tide design was demonstrated by the synthesis of a panel of ligands for the alpha1-syntrophin PDZ domain. The rational design of a small molecule of unprecedented affinity for the PDZ domain suggests that these peptidomimetics may provide a general method for inhibiting protein-protein interactions involving extended peptide chains.     

Progress in understanding the intramolecular vibrational redistribution dynamics in the S(1) state of para-fluorotoluene

We employ zero-kinetic-energy (ZEKE) photoelectron spectroscopy with nanosecond laser pulses to study intramolecular vibrational redistribution (IVR) in S(1) para-fluorotoluene. The frequency resolution of the probe step is superior to that obtained in any studies on this molecule to date. We focus on the behavior of the 13(1) (C-CH(3) stretch) and 7a(1) (C-F stretch) vibrational states whose dynamics have previously received significant attention, but with contradictory results. We show conclusively that, under our experimental conditions, the 7a(1) vibrational state undergoes significantly more efficient IVR than does the 13(1) state. Indeed, under the experimental conditions used here, the 13(1) state undergoes very little IVR. These two states are especially interesting because their energies are only 36 cm(-1) apart, and the two vibrational modes have the same symmetry. We discuss the role of experimental conditions in observations of IVR in some detail, and thereby suggest explanations for the discrepancies reported to date.     

Highly regioselective synthesis of gem-difluoroallenes through magnesium organocuprate SN2' substitution

[reaction: see text]. The reaction of gem-difluoropropargyl electrophiles with Grignard reagents is complicated by the inherent difficulty of executing nucleophilic substitutions on a CF2 group, and the facile formation of carbenoid intermediates arising from alpha-elimination of fluoride. In the presence of an excess amount of a copper salt, a Grignard reagent reacts with gem-difluoropropargyl bromide via an S(N)2' mechanism to produce gem-difluoroallene in high yield. If desired, the resulting difluoroallene can undergo a second nucleophilic attack on the CF2 terminus to yield a trisubstituted monofluoroallene through an addition-elimination mechanism.     

Schlicht envelopes of holomorphy and topology

Let Ω be a domain in ${\mathbb{C}^{2}}Let Ω be a domain in \mathbbC²{\mathbb{C}^{2}}, and let p: [(W)\tilde]? \mathbbC²{\pi: \tilde{\Omega}\rightarrow \mathbb{C}^{2}} be its envelope of holomorphy. Also let W￠=p([(W)\tilde]){\Omega'=\pi(\tilde{\Omega})} with i: W\hookrightarrow W￠{i: \Omega \hookrightarrow \Omega'} the inclusion. We prove the following: if the induced map on fundamental groups i_*:p₁(W) ? p₁(W￠){i_{*}:\pi_{1}(\Omega) \rightarrow \pi_{1}(\Omega')} is a surjection, and if π is a covering map, then Ω has a schlicht envelope of holomorphy. We then relate this to earlier work of Fornaess and Zame.     

Large scale synthesis of the Cdc42 inhibitor secramine A and its inhibition of cell spreading

We describe a large scale synthesis of secramine A. Consistent with its ability to inhibit activation of the small GTPase Cdc42, we find that secramine A inhibits cell spreading, a process previously shown to be Cdc42-dependent.     

Dynamic mechanical properties of plasticized poly(vinyl chloride). Linear free energy relationship in the poly(vinyl chloride)–ester system

A considerable number of quantitative attempts have been made to predict the properties of solutions containing polar polymers and polar solvents. Thermodynamic approaches have generally failed to accurately describe these systems. This can be be ascribed to the difficulty in determining structural characteristics arising from the variety of secondary interactions present in these highly complex solutions. A linear free energy relationship has been used here to explore changes encountered in solutions of monofunctional esters in poly(vinyl chloride) undergoing mechanical deformation. This treatment appears valid only for the rubbery region of the viscoelastic spectrum of this polymer. The data indicate that the observed changes are a function of corresponding changes in polymer intramolecular interactions.     

Highly ion conductive poly(ethylene oxide)-based solid polymer electrolytes from hydrogen bonding layer-by-layer assembly

We report the development of a solid polymer electrolyte film from hydrogen bonding layer-by-layer (LBL) assembly that outperforms previously reported LBL assembled films and approaches battery integration capability. Films were fabricated by alternating deposition of poly(ethylene oxide) (PEO) and poly(acrylic acid) (PAA) layers from aqueous solutions. Film quality benefits from increasing PEO molecular weight even into the 10(6) range due to the intrinsically low PEO/PAA cross-link density. Assembly is disrupted at pH near the PAA ionization onset, and a potential mechanism for modulating PEO:PAA ratio within assembled films by manipulating pH is discussed. Ionic conductivity of 5 x 10(-5) S/cm is achievable after short exposure to 100% relative humidity (RH) for plasticization. Adding free ions by exposing PEO/ PAA films to lithium salt solutions enhanced conductivity to greater than 10(-5) S/cm at only 52% RH and tentatively greater than 10(-4) S/cm at 100% RH. The excellent stability of PEO/PAA films even when exposed to 1.0 M salt solutions led to an exploration of LBL assembly with added electrolyte present in the adsorption step. Fortuitously, the modulation of PEO/PAA assembly by ionic strength is analogous to that of electrostatic LBL assembly and can be attributed to electrolyte interactions with PEO and PAA. Dry ionic conductivity was enhanced in films assembled in the presence of salt as compared to films that were merely exposed to salt after assembly, implying different morphologies. These results reveal clear directions for the evolution of these promising solid polymer electrolytes into elements appropriate for electrochemical power storage and generation applications.