Assessing the folding propensity of aliphatic units within helical aromatic oligoamide foldamers

Great attention is devoted to hybrid foldamers composed of more than one type of monomers. The folding of such hybrids requires units that may possess very different structures to be compatible. A method to assess this compatibility consists in studying the behavior of a monomer of one type within a sequence of another type of monomer. We have prepared and investigated the structure of flexible aliphatic monomers in the context of the rigid helices of quinoline-carboxamides. NMR and X-ray crystallography show that the rigid helical backbones may impart defined conformation into otherwise flexible units and that compatible folding modes exist between very different monomers.     

Aggregation and assembly of crescent foldamers

Recent studies have started to provide initial insights into the aggregation and assembly of two classes of back-rigidified foldamers with flat,curved backbones consisting of aromatic residues.With their persistent shape that presents large,well-defined aromatic surface areas,these crescent foldamers were found to undergo size-dependent aggregation in solution and pack into 1D assemblies in the solid state.Crescent aromatic oligoamides undergo stacking interactions not only in polar solvents but also in non...     

Synthesis of new ethynylene-containing aromatic polyamides by palladium-catalyzed polycondensation of aromatic diiodides with aromatic diethynyl compounds having amide units

New ethynylene-containing aromatic polymides were synthesized by the carbon–carbon crosscoupling polycondensation of aromatic diiodides with aromatic amide-bearing diethynyl compounds in the presence of a palladium catalyst, cuprous iodide, and an organic base. The polymers having sulfone linkages were soluble in various organic solvents and their weight average molecular weights were in the range of 12,500 and 26,500. The polymers with the highest inherent viscosity were obtained, when the monomer ratio of a diethynyl compound to a diiodide was 1.01. The polymers showed no detectable glass transition temperature and no weight loss up to around 300° C in nitrogen. The thermal crosslinking of the polymers occurred at 280°C through the existing internal ethynylene group. © 1995 John Wiley & Sons, Inc.     

Protein folding using fragment assembly and physical energy function

We perform a systematic study of the effects of sequence-independent backbone interactions and sequence-dependent side-chain interactions on protein folding using fragment assembly and physical energy function. Structures for ten proteins belonging to various structural classes are predicted only with Lennard-Jones interaction between backbone atoms. We find nativelike structures for beta proteins, suggesting that for proteins in this class, the global tertiary structures can be determined mainly by sequence-independent backbone interactions. On the other hand, for alpha proteins, nonlocal hydrophobic side-chain interaction is also required to obtain nativelike structures.     

Hydrogen bonded aromatic hydrazide foldamers for the self-assembly of vesicles and gels

This paper describes an investigation of the structural and side-chain factors for the formation of vesicles and gels by hydrogen bonding-mediated aromatic hydrazide foldamers. Six foldamers and one straight analog that bear discrete side chains have been synthesized. SEM and AFM studies reveal that the molecules with the appended 2-(2-(dialkyl-amino)-2-oxoethylamino)-2-oxoethoxyl chains form vesicles, hydrogels or organogels, depending on the solvents. Both the inner amide units and the terminal N,N-dialkylamide units in the chains are revealed to play essential roles in controlling the self-assembly. The former facilitates it by forming the intermolecular hydrogen bonding, while the latter modulates it by providing solubility and balancing the hydrophobicity of the whole molecules in solvents of varying polarity.     

Density functional theory calculations and vibrational circular dichroism of aromatic foldamers

Ab initio calculations together with vibrational circular dichroism (VCD) have been used for studying the conformations of a quinoline-derived oligoamide bearing a terminal chiral residue. Three helically folded conformers of the dimer, trimer, and tetramer forms of the oligomer were optimized at the density functional theory (DFT) level using the B3LYP functional and the 6-31G* basis set. For each form, the three conformers differ in their helical handedness and in the conformation of the chiral end group. The calculated structures of the tetramer and also the proportions predicted between them based on their calculated Gibbs free energies differences match remarkably well with experimental data collected on an octamer. Specifically, a R-phenethyl terminal group gives rise to a 91:9 ratio between left handed and right handed helices. The predicted VCD spectrum calculated from the Boltzmann population of the individual conformer reproduces very well the experimental VCD spectrum of the tetramer in CDCl3 solution. The DFT calculations performed for the trimer also allow one to assess the preferred handedness of the helix and the conformation of the chiral end group, but the calculated relative populations differ slightly from experimental data. Finally, this study shows that the dimer fragment is not sufficient to obtain valuable information on the conformation of this aromatic oligoamide foldamer.     

Preferential solvation within hydrophilic nanocavities and its effect on the folding of cholate foldamers

The conformations of three cholate foldamers and one molecular basket were studied by fluorescence and NMR spectroscopy. In nonpolar solvents (e.g., hexane/ethyl acetate or ethyl acetate) mixed with a small amount of a polar solvent (e.g., alcohol or DMSO), the cholate oligomer folded into a helix with the hydrophilic faces of the cholates turned inward. Folding created a hydrophilic nanocavity preferentially solvated by the entrapped polar solvent concentrated from the bulk. This microphase separation of the polar solvent was critical to the folding process. Folding was favored by larger-sized polar solvent molecules, as fewer such molecules could occupy and solvate the nanocavity, thus requiring a smaller extent of phase separation during folding. Folding was also favored by smaller/acyclic nonpolar solvent molecules, probably because they could avoid contact with the OH/NH groups within the nanocavity better than larger/cyclic nonpolar solvent molecules.     

Solid phase synthesis of aromatic oligoamides: application to helical water-soluble foldamers

Synthetic helical aromatic amide foldamers and in particular those based on quinolines have recently attracted much interest due to their capacity to adopt bioinspired folded conformations that are highly stable and predictable. Additionally, the introduction of water-solubilizing side chains has allowed to evidence promising biological activities. It has also created the need for methods that may allow the parallel synthesis and screening of oligomers. Here, we describe the application of solid phase synthesis to speed up oligomer preparation and allow the introduction of various side chains. The synthesis of quinoline-based monomers bearing protected side chains is described along with conditions for activation, coupling, and deprotection on solid phase, followed by resin cleavage, side-chain deprotection, and HPLC purification. Oligomers having up to 8 units were thus synthesized. We found that solid phase synthesis is notably improved upon reducing resin loading and by applying microwave irradiation. We also demonstrate that the introduction of monomers bearing benzylic amines such as 6-aminomethyl-2-pyridinecarboxylic acid within the sequences of oligoquinolines make it possible to achieve couplings using a standard peptide coupling agent and constitute an interesting alternative to the use of acid chloride activation required by quinoline residues. The synthesis of a tetradecameric sequence was thus smoothly carried out. NMR solution structural studies show that these alternate aminomethyl-pyridine residues do not perturb the canonical helix folding of quinoline monomers in protic solvents, contrary to what was previously observed in nonprotic solvents.     

Laser photochemistry of aromatic substituted cyclobutanes and cyclobutenes

The photochemical ring opening and ring cleavage reactions of 6b,8a-dihydrocyclobut[a]acenaphthylene (1) and two similar compounds are described. These reactions occur at room temperature only if the irradiating light intensity is greater than MW/cm², easily obtained with excimer and dye lasers. This is rationalized in terms of a consecutive two-photon absorption to reach higher-lying reactive states. The mechanism proposed for the reaction of 1 also describes the product distribution, which depends on irradiation parameters such as laser pulse length, wavelength, intensity, and oxygen content of the solvent.     

Conformation of S-shaped aromatic imide foldamers and their induced circular dichroism

Conformation of aromatic foldamers possessing three aromatic rings in a sequence of anthracene-phenylene-anthracene linked with iminodicarbonyl was examined. Their folding structures were confirmed by single crystal X-ray analysis. Two conformations, straight-zigzag and helically-zigzag conformations, were found depending on the substituents at the imide nitrogen atom. Induced circular dichroism originated in the interaction of the upper and bottom anthracene moieties was observed both in solution and in the solid state.     

Interfacial assembly of a series of cinnamoyl-containing bolaamphiphiles: spacer-controlled packing, photochemistry, and odd-even effect

A series of bolaamphiphiles with 4-hydroxycinnamoyl head groups and different length of the alkyl spacers (n = 6-12) were designed to investigate their photochemistry in the organized films obtained from the air/water interface. It has been found that both the length and odd-even number of the spacers can finely tune the molecular packing as well as the photochemistry. When the spacer length was changed from 6 to 12 methylene units, the assemblies changed from J aggregate to H aggregate. The molecules with even-numbered polymethylene spacer tend to form three-dimensional nanorod structure at the air/water interface. For the assembly of derivatives with odd-numbered spacers, diverse morphologies such as nanospirals and nanofibers were observed depending on the chain length and the surface pressures. The different packing of bolaamphiphiles could subsequently affect the photochemistry of the cinnamoyl groups in the organized films. The spacer effect in the assembly can be understood from the cooperation between H-bond of the phenolic hydroxyl and the amide groups, π-π stacking as well as the hydrophobic interactions of the alkyl spacer. A packing model was proposed to explain the phenomenon.     

Triplet state deactivation and photochemistry of aromatic thioketones in solution: xanthione

The decay of triplet xanthione has been studied by means of the phosphorescence decay kinetics and the photodecomposition quantum yields φ_x measured in a variety of solvents at room temperature. Both the triplet decay and φ_x are strongly dependent not only on the solvent but also on the xanthione concentration. Based on these results a mechanism for the photochemical transformation of xanthione is proposed which features a primary photochemical step involving hydrogen abstraction from the solvent and the formation of a solvent-caged radical pair. Following these steps there is a competition between the recombination of the caged radicals and the reaction of the thioketyl radical with a xanthione ground state molecule. The reaction scheme is supported by quantitative calculation of the yields.     

Synthesis and characterization of acetylene-terminated aromatic amide resin precursors

A series of 10 acetylene-terminated aromatic amide monomers was synthesized by the triethylamine-promoted reaction of bis[p-(m-chlorocarbonylphenoxy)phenyl] sulfone or bis[p-(m-chlorocarbonylphenoxyl)phenyl]ketone with o- or p-ethynyl- and o- or p-trimethylsilylethynylaniline. Yields were essentially quantitative. Structures were verified by infrared and nuclear magnetic resonance spectroscopy and mass spectral data. Thermal characteristics of the monomers were investigated by means of differential scanning calorimetry and thermogravimetric analysis. The initial glass transition temperatures were generally well below the onset of cure which occurred in the 160–225°C range for the terminal ethynyl monomers and in the 260–295°C range for their trimethylsilylethynyl analogs. Onset of decomposition in air for the resinified terminal ethynyl monomers took place in the 400–485°C range, while resins from the trimethylsilylethynyl monomers underwent breakdown at substantially lower temperatures.     

Efficient molecular mechanics simulations of the folding,orientation, and assembly of peptides in lipid bilayers using an implicit atomic solvation model

Membrane proteins comprise a significant fraction of the proteomes of sequenced organisms and are the targets of approximately half of marketed drugs. However, in spite of their prevalence and biomedical importance, relatively few experimental structures are available due to technical challenges. Computational simulations can potentially address this deficit by providing structural models of membrane proteins. Solvation within the spatially heterogeneous membrane/solvent environment provides a major component of the energetics driving protein folding and association within the membrane. We have developed an implicit solvation model for membranes that is both computationally efficient and accurate enough to enable molecular mechanics predictions for the folding and association of peptides within the membrane. We derived the new atomic solvation model parameters using an unbiased fitting procedure to experimental data and have applied it to diverse problems in order to test its accuracy and to gain insight into membrane protein folding. First, we predicted the positions and orientations of peptides and complexes within the lipid bilayer and compared the simulation results with solid-state NMR structures. Additionally, we performed folding simulations for a series of host–guest peptides with varying propensities to form alpha helices in a hydrophobic environment and compared the structures with experimental measurements. We were also able to successfully predict the structures of amphipathic peptides as well as the structures for dimeric complexes of short hexapeptides that have experimentally characterized propensities to form beta sheets within the membrane. Finally, we compared calculated relative transfer energies with data from experiments measuring the effects of mutations on the free energies of translocon-mediated insertion of proteins into lipid bilayers and of combined folding and membrane insertion of a beta barrel protein.     

Expanding the scope of aromatic polyketides by combinatorial biosynthesis

Combinatorial biosynthesis is a technology for mixing genes responsible for the biosynthesis of secondary metabolites, in order to generate products for compound libraries serendipitously or to cause desired modifications to natural products. Both of these approaches are extremely useful in drug discovery. Streptomyces and related species are abundant in bioactive secondary metabolites and were therefore the first microbes to be used for combinatorial biosynthesis. Polyketides are the most abundant medicinal agents among natural products. Structural diversity and a wide scope of bioactivities are typical of the group. However, the common feature of polyketides is a biosynthetic process from simple carboxylic acid residues. In molecular genetics, polyketides are sub-classified as types I and II, called modular and aromatic polyketides respectively. The best-known bioactivities of aromatic polyketides are their antibacterial and antitumor effects. Genetic analysis of aromatic polyketides has resulted in almost 30 cloned and identified biosynthetic gene clusters. Several biosynthetic enzymes are flexible enough to allow their use in combinatorial biosynthesis to create high diversity compound libraries. This review describes the state of the art of combinatorial biosynthesis, giving anthracyclines as examples. Contiguous DNA sequences for antibiotics, cloned from four different anthracycline producers, provide tools for rapid lead optimization or other structural modification processes, and not only for anthracyclines. Two gene cassettes enabling fast and flexible structural modification of polyketides are introduced in this paper.     

Helical aromatic oligoamides: reliable, readily predictable folding from the combination of rigidified structural motifs

Factors responsible for the folding of aromatic oligoamides with backbones rigidified by local three-center H-bonds were investigated. The stability of the three-center H-bonds was quantified by the half-lives of amide proton-deuterium exchange reactions, which show that the three-center H-bonds were largely intact at room temperature in the oligomer examined. This result is consistent with our current and previous 2D NMR studies. The overall helical conformation of nonamer 1 was found by variable-temperature NOESY studies to be dynamic. As temperature rose, the end-to-end NOEs rapidly disappeared, while the amide side chain NOEs were still readily detectable, corresponding to the "breath" and stretching of the helix by slightly twisting the local H-bonded rings. Based on the simple repetition of the same structural motif and local conformational preference, undecamer 2 was found to fold into well-defined helical conformation. The predictability of the folding of these backbone-rigidified aromatic oligoamides was demonstrated by a simple modeling method using structural parameters from oligomers with known crystal structures. The reliability and generality of the modeling methods were shown by the excellent agreement between the modeled structures corresponding to 1 and 2 and data from NOESY studies.     

Surface photochemistry: The photo-chlorination of aromatic hydrocarbons with ferric chloride on alumina

Irradiation of a number of aromatic hydrocarbons adsorbed on alumina in the presence of ferric chloride leads to monochlorination.