Constraining Cyclic Peptides To Mimic Protein Structure Motifs

Many proteins exert their biological activities through small exposed surface regions called epitopes that are folded peptides of well‐defined three‐dimensional structures. Short synthetic peptide sequences corresponding to these bioactive protein surfaces do not form thermodynamically stable protein‐like structures in water. However, short peptides can be induced to fold into protein‐like bioactive conformations (strands, helices, turns) by cyclization, in conjunction with the use of other molecular constraints, that helps to fine‐tune three‐dimensional structure. Such constrained cyclic peptides can have protein‐like biological activities and potencies, enabling their uses as biological probes and leads to therapeutics, diagnostics and vaccines. This Review highlights examples of cyclic peptides that mimic three‐dimensional structures of strand, turn or helical segments of peptides and proteins, and identifies some additional restraints incorporated into natural product cyclic peptides and synthetic macrocyclic peptidomimetics that refine peptide structure and confer biological properties.     

Organolanthanide-based synthesis of 1,2,3-triazoles from nitriles and diazo compounds

The reaction of [(C5Me5)2Ln][(mu-Ph)2BPh2] complexes with the lithium salt of (trimethylsilyl)diazomethane, Li[Me3SiCN2], gave products formulated as the dimeric isocyanotrimethylsilyl amide complexes {(C5Me5)2Ln[mu-N(SiMe3)NC]}2 (Ln = Sm, 1; La, 2). Reactions of (C5Me5)2Sm and [(C5Me5)2Sm(mu-H)]2 with Me3SiCHN2 also form 1. Complexes 1 and 2 react with Me3CCN to form the 1,2,3-triazolato complexes (C5Me5)2Ln(NCCMe3)[NNC(SiMe3)C(CMe3)N] (Ln = Sm, 3; La, 4). Complex 2 reacts with Me3SiN3 to make the isocyanide ligated azide complex {(C5Me5)2La[CNN(SiMe3)2](mu-N3)}3, 5.     

Modulated potential electrogenerated chemiluminescence of luminol and Ru(bpy) 3 2+

Chemiluminescence emission intensity is modulated by modulating the potential of a working electrode which is used to generate a key species in the electrogenerated Chemiluminescence (ECL) reaction. The emission is monitored synchronously using a lock-in amplifier. The reactions used in the characterization are luminol with hydrogen peroxide and tris(2,2-bipyridyl)ruthenium (II) (or Ru(bpy) ₃ ²⁺ ) with oxalate. Modulation widths of ± 50 mV yield maximum signals for luminol when centered at 0.45 V (vs Ag/AgCl) and for Ru(bpy) ₃ ²⁺ when centered at 1.05 V. The resulting signal decreases with increasing modulation frequency and shows that luminol/H₂O₂ is a faster ECL system than Ru(bpy) ₃ ²⁺ /oxalate. Working curves for luminol and for oxalate have essentially the same linear range and slope with the modulated potential approach as with a DC electrode potential. This approach provides capability for differentiating the analytical signal from constant background emission or stray light.     

Block copolymer micelle shuttles with tunable transfer temperatures between ionic liquids and aqueous solutions

Four poly((1,2-butadiene)- block-ethylene oxide) (PB-PEO) diblock copolymers were shown to self-assemble into micelles with PB cores and PEO coronas (including spheres, cylinders, and vesicles) in the ionic liquid, 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([EMIM][TFSI]). All four systems exhibited the "micelle shuttle" (He, Y.; Lodge, T. P. J. Am. Chem. Soc. 2006, 128, 12666-12667), whereby PB-PEO micelles transferred, reversibly and with preservation of micelle structure, from an aqueous phase at room temperature to a hydrophobic ionic liquid at high temperature. The micelle size (both mean and distribution) depends on whether it was initially dissolved in water or in the ionic liquid, but the initial micelle structures in the ionic liquid were shown by dynamic light scattering to be preserved during the transfer and persist essentially unchanged for months in both the ionic liquid and water. The transfer was shown to be driven by the deteriorating solvent quality of water for PEO at high temperature, while the ionic liquid remains a good solvent. The transfer temperature could be tuned by adding ionic or nonionic additives to the aqueous phase to change the solvent quality of water for PEO, and by using ionic liquids with different polarity.     

Mechanistic implications of nickel-catalyzed reductive coupling of aldehydes and chiral 1,6-enynes

[reaction: see text]. A study of nickel-catalyzed reductive coupling reactions of aldehydes and chiral 1,6-enynes has provided evidence for three distinct mechanistic pathways that govern regioselectivity in this transformation. In the absence of a phosphine additive, high regioselectivity and high diastereoselectivity are obtained as a direct result of coordination of both the alkyne and the olefin to the metal center during the C-C bond-forming step.     

Tetraaryldimethoxybenziporphyrins. At the edge of carbaporphyrinoid aromaticity

A series of eight dimethoxybenziporphyrins were prepared in three steps from 1,3-dimethoxybenzene or 2,6-dimethoxytoluene. Dibromination, followed by lithium-halogen exchange and reaction with benzaldehyde gave dicarbinol intermediates. These reacted with pyrrole and aryl aldehydes in the presence of BF3.Et2O in chloroform, followed by oxidation with DDQ, to give the benziporphyrins in 15-25% yield. These compounds readily gave nickel(II) and palladium(II) organometallic derivatives and could be selectively reduced with sodium borohydride to give unstable benziphlorins. Regioselective oxidation with silver acetate afforded the related 22-acetoxybenziporphyrins in 52-64% yield. The dimethoxybenziporphyrins showed chemical shifts by proton NMR spectroscopy that were consistent with weakly diatropic macrocycles. However, addition of TFA gave dications that showed far more significant shifts that are attributed to the presence of a more substantial diatropic ring current. The internal CH for 11H2(2+) was observed at 3.5 ppm, but this effect was diminished for the 3-methylbenziporphyrins 12H2(2+) where this resonance appears at 4.7 ppm. Even in the absence of the methoxy substituents, the dication derived from tetraphenylbenziporphyrin 8H2(2+) shows an upfield shift for this resonance to 5.5 ppm. The dications of the 22-acetoxybenziporphyrins also show similar effects despite the presence of an internal ester moiety. These results demonstrate that a spectrum of diatropic character can manifest even in highly crowded benziporphyrin derivatives.     

Electronic structure of carbon trioxide and vibronic interactions involving Jahn-Teller states

The electronic structure of CO3 is characterized by equation-of-motion and coupled-cluster methods. C(2v) and D(3h) isomers are considered. Vertical excitation energies, transition dipoles, and the molecular orbital character of the excited states are presented for singlet and triplet manifolds. Ground-state equilibrium structures and frequencies are strongly affected by vibronic interactions with low-lying excited states. At D(3h) geometries, the vibronic interactions are enhanced by the Jahn-Teller character of the excited states. The curvature of the potential energy surface and the existence of the D(3h) minimum are very sensitive to the correlation treatment and the basis set. The correlation effects are stronger at D(3h), in agreement with a smaller HOMO-LUMO gap.     

Theoretical investigation of lone pair inversions, ring openings, and hydride shifts in O-methylated epoxides

Mechanisms associated with the isomerization of the O-methylethylene oxonium ion and its tetramethyl-substituted analogue have been explored using correlated electronic structure calculations. The minima and transition states associated with inversion at the oxygen atom, as well as those associated with opening of the epoxide ring, have been characterized. The calculated barrier to inversion at the oxygen atom for the O-methylethylene oxonium ion, 15.7 kcal/mol, agrees well with the experimentally determined value, 10+/-2 kcal/mol. Our calculations indicate that a significantly higher barrier exists for the ring-opening mechanism that leads to more thermodynamically stable structures. This work includes the first known calculations on the O-methyl-2,3-dimethyl-2-butene oxonium ion along with transition states and intermediates associated with ring opening and inversion at the oxygen atom. Results show that there is a significantly lower barrier to ring opening as compared to the O-methylethylene oxonium ion species, leading to a lower probability of isolating this species. The effects of basis sets and correlation techniques on these ions were also analyzed in this work. Our results indicate that the B3LYP/6-31G* level is reliable for obtaining molecular geometries for both minima and transition states on the C3H7O+ and C7H15O+ potential energy surfaces.     

Swelling and network parameters of crosslinked thermoreversible hydrogels of poly(N-ethylacrylamide)

Samples of Poly(N-ethylacrylamide) (PEA) have been synthesized by free radical polymerization in water using N,N′-methylene bis-acrylamide (BIS) as crosslinker. Hydrogels obtained by swelling them in water, 15 wt% KCl and 1 wt% sodium dodecyl sulphate (SDS) were examined by gravimetric, dimensional and compression-strain measurements to afford values of swelling ratio, polymer-solvent interaction parameters, elastic moduli and effective crosslinking density ν_e. Crosslinking inefficiency is evidenced by the low value (0.23) of ν_e relative to the theoretical crosslinking density ν_t based on the content of BIS in the synthesis. A small but finite extrapolated value of ν_e at ν_t = 0 is indicative of hydrophobic physical interactions. In water at 298 K increasing the content of BIS leads to a decrease in swelling and increases in values of elastic moduli and polymer-water interaction parameter. At a fixed content of BIS the values of ν_e and the elastic moduli exhibit an unusual increase with temperature, the crosslinking thus being thermally reversible. It is proposed that this results from a balance between hydrophobic interaction and breakage of hydrophilic hydrogen bonding. Although KCl in the medium decreases the swelling compared with that in water, the opposite effect occurs on incorporation of SDS, which is assumed to confer some polyelectrolyte character to the PEA chains. The finding, that these two swelling media reduce the values of ν_e and elastic moduli cf the value in water, has not been resolved satisfactorily.     

Isomolar semigrand ensemble molecular dynamics: development and application to liquid-liquid equilibria

An extended system molecular dynamics method for the isomolar semigrand ensemble (fixed number of particles, pressure, temperature, and fugacity fraction) is developed and applied to the calculation of liquid-liquid equilibria (LLE) for two Lennard-Jones mixtures. The method utilizes an extended system variable to dynamically control the fugacity fraction xi of the mixture by gradually transforming the identity of particles in the system. Two approaches are used to compute coexistence points. The first approach uses multiple-histogram reweighting techniques to determine the coexistence xi and compositions of each phase at temperatures near the upper critical solution temperature. The second approach, useful for cases in which there is no critical solution temperature, is based on principles of small system thermodynamics. In this case a coexistence point is found by running N-P-T-xi simulations at a common temperature and pressure and varying the fugacity fraction to map out the difference in chemical potential between the two species A and B (mu(A)-mu(B)) as a function of composition. Once this curve is known the equal-distance/equal-area criterion is used to determine the coexistence point. Both approaches give results that are comparable to those of previous Monte Carlo (MC) simulations. By formulating this approach in a molecular dynamics framework, it should be easier to compute the LLE of complex molecules whose intramolecular degrees of freedom are often difficult to properly sample with MC techniques.