Novel zwitterionic complexes arising from the coordination of an ambiphilic phosphorus-aluminum ligand to gold.

Coordination of Mes2PC(=CHPh)AltBu2 to metal chlorides has been studied. Bridging P→M-Cl→Al coordinations were observed with Rh and Pd fragments, while chloride abstraction systematically occurred with gold. The resulting zwitterionic complexes have been fully characterized and analyzed by DFT calculations.

An Al/P-based frustrated Lewis pair as an efficient ambiphilic ligand: coordination of boron trihalides, rearrangement, and formation of HBX2 complexes (X = Br, I).

The Al/P-based frustrated Lewis pair (FLP) Mes2P-C(═CH-Ph)-Al(CMe3)2 (1) reacted with boron halides BX3 (X = F, Cl, Br, I) as an ambiphilic ligand to form complexes (2-5) in which the boron atoms were coordinated to phosphorus and one of the halogen atoms to aluminum. Nonplanar five-membered heterocycles resulted that had five different ring atoms (AlCPBX). The distance of the bridging halogen atoms to the AlCPB plane increased steadily with the radius of the halogen atoms. Only the BF3 adduct showed a dynamic behavior in solution at room temperature with equivalent tert-butyl or mesityl groups in the NMR spectra, while in other cases, the rigid conformation led to the magnetic inequivalence of the substituents at Al and P with well-resolved signals for each group. The BBr3 and BI3 complexes underwent in solution at room temperature a spontaneous stereoselective rearrangement with the concomitant release of isobutene. The obtained products, Mes2P-(µ-C═CH-Ph)(µ-HBX2)-AlX(CMe3) (6 and 7) may be viewed as unique adducts of a modified new Al/P-based FLP, Mes2P-C(═CH-Ph)-AlX(CMe3) (X = Br, I), with dihalogenboranes, HBX2. The trapped boranes are either completely unknown (X = I) or unstable in the free form. Quantum-chemical calculations suggest an ionic rearrangement mechanism via the formation of a borenium cation, ß-hydride elimination, and hydride transfer. The bromine migration from boron to aluminum corresponds to a formal suprafacial 1,3-sigmatropic rearrangement.

Dimeric aluminum-phosphorus compounds as masked frustrated Lewis pairs for small molecule activation.

Hydroalumination of aryldialkynylphosphines RP(C≡C-(t)Bu)(2) (R = Ph, Mes) with equimolar quantities of diethylaluminum hydride afforded mixed alkenyl-alkynyl cyclic dimers in which the dative aluminum-phosphorus bonds are geminal to the exocyclic alkenyl groups. Addition of triethylaluminum to isolated 1 (R = Ph) or to the in situ generated species (R = Mes) caused diethylaluminum ethynide elimination to yield the arylethylphosphorus dimers 2 and 3. These possess a chair-like Al(2)C(2)P(2) heterocycle with intermolecular Al-P interactions. The boat conformation (4) was obtained by the reaction of (t)Bu-P(C≡C-(t)Bu)(2) with di(tert-butyl)aluminum hydride. Despite being dimeric, 2 behaves as a frustrated Lewis pair and activates small molecules. The reaction with carbon dioxide gave cis/trans isomeric AlPC(2)O heterocycles that differ only by the configuration of the exocyclic alkenyl unit. Four isomers resulted from the reaction with phenyl isocyanate. This is caused by cis/trans isomerization of the initial C=O adduct and subsequent rearrangement to the AlPC(2)N heterocycle, being the C=N adduct.

Biosynthetic gene cluster of the non-ribosomally synthesized cyclodepsipeptide skyllamycin: deciphering unprecedented ways of unusual hydroxylation reactions.

The cyclic depsipeptide skyllamycin A is a potent inhibitor of the platelet-derived growth factor (PDGF) signaling pathway by inhibiting binding of homodimeric PDGF BB to the PDGF ß-receptor. Its structure contains a cinnamoyl side chain and shows a high amount of ß-hydroxylated amino acids as well as an unusual α-hydroxyglycine moiety as a rare structural modification. The skyllamycin biosynthetic gene cluster was cloned and sequenced from Streptomyces sp. Acta 2897. Its analysis revealed the presence of open reading frames encoding proteins for fatty acid precursor biosynthesis, non-ribosomal peptide synthetases, regulators, and transporters along with other modifying enzymes. Specific in-frame mutagenesis of these tailoring enzymes resulted in the production of novel skyllamycin derivatives revealing that ß-hydroxy groups in skyllamycin A are introduced by a promiscuous cytochrome P450 monooxygenase, whereas a two-component flavin-dependent monooxygenase is involved in α-hydroxylation.

Design, synthesis, structure and binding properties of PDZ binding, cyclic beta-finger peptides.

Protein interaction domains (PIDs) play a critical role in signal transduction. One PID of great interest is the PDZ domain, a 100 amino-acid-residue domain. Most PDZ domains recognize short, C-terminal peptide motives. In the heterodimer of the nNOS-PDZ domain and the alpha-syntrophin-PDZ domain, however, one PDZ domain forms a beta-finger that binds to the other PDZ domain. We show here that cyclic peptides derived from the beta-finger of the nNOS-PDZ domain can bind the syntrophin-PDZ domain in the same manner as the whole domain. The structure of three "finger-peptides" of different size has been determined and the binding investigated using calorimetry and NMR-titration experiments.

Structures of cyclic, antimicrobial peptides in a membrane-mimicking environment define requirements for activity.

New antimicrobial compounds are of major importance because of the growing problem of bacterial resistance. In this context, antimicrobial peptides have received a lot of attention. Their mechanism of action, however, is often obscure. Here, the structures of two cyclic, antimicrobial peptides from the family of arginine- and tryptophan-rich peptides determined in a membrane-mimicking environment are described. The sequence of the peptides has been obtained from a cyclic parent peptide by scrambling the amino acids. While the activity of the peptides is similar to that of the parent peptide, the structures are not. The peptides do, however, all adopt an amphiphilic structure. A comparison between the structures helps to define the requirements for the activity of these peptides.

Design of antimicrobial compounds based on peptide structures.

New antimicrobial compounds are of major importance because of the growing problem of bacterial resistance and antimicrobial peptides have been gaining a lot of interest. Their mechanism of action, however, is often obscure. Here a set of non-peptidic compounds with antimicrobial activity are presented that have been designed based on criteria derived from three-dimensional structures of antimicrobial peptides. Even though only a small set of compounds has been designed, the activity immediately matches that of the original peptides, supporting the proposed criteria for activity, i.e. not the peptidic nature of antimicrobial peptides is responsible for their activity but rather the proper arrangement of the relevant functional groups.

Structure of the antimicrobial, cationic hexapeptide cyclo(RRWWRF) and its analogues in solution and bound to detergent micelles.

Antimicrobial, cationic peptides are abundant throughout nature as part of many organisms' defence against microorganisms. They exhibit a large variety of sequences and structural motifs and are thought to act by rupturing the bacterial membrane. Several models based on biophysical experiments have been proposed for their mechanism of action. Here we present the NMR-determined structure of the cyclic, cationic antimicrobial peptide cyclo(RRWWRF) both free in aqueous solution and bound to detergent micelles. The peptide has a rather flexible but ordered structure in water. A distinct structure is formed when the peptide is bound to a detergent micelle. The structures in neutral and negatively charged micelles are nearly identical but differ from that in aqueous solution. The orientation of the amino acid side chains creates an amphipathic molecule with the peptide backbone forming the hydrophilic part. The orientation of the peptide in the micelle was determined by using NOEs and paramagnetic agents. The peptide is oriented mainly parallel to the micelle surface in both detergents. Substitution of the arginine and tryptophan residues is known to influence the antimicrobial activity. Therefore the structure of the micelle-bound analogues cyclo(RRYYRF), cyclo(KKWWKF) and cyclo(RRNalNalRF) were also determined. They exhibit remarkable similarities in backbone conformation and side-chain orientation. The structure of these peptides allows the side-chain properties to be correlated to biological activity.

Interaction of the antimicrobial peptide cyclo(RRWWRF) with membranes by molecular dynamics simulations.

Antimicrobial peptides have gained a lot of interest in recent years due to their potential use as a new generation of antibiotics. It is believed that this type of relatively short, amphipathic, cationic peptide targets the bacterial membrane, and destroys the chemical gradients over the membrane via formation of stable or transient pores. Here we use the NMR structure of cyclo(RRWWRF) in a series of molecular dynamics simulations in membranes at various peptide/lipid ratios. We observe that the NMR structure of the peptide is still stable after 100 ns simulation. At a peptide/lipid ratio of 2:128, the membrane is only a little affected compared to a pure dipalmitoylphosphatidylcholine lipid membrane, but at a ratio of 12:128, the water-lipid interface becomes more fuzzy, the water molecules can reach deeper into the hydrophobic core, and the water penetration free-energy barrier changes. Moreover, we observe that the area per lipid decreases and the deuterium order parameters increase in the presence of the peptide. We suggest that the changes in the hydrophobic core, together with the changes in the headgroups, result in an imbalance of the membrane and that it is thus not an efficient hydrophobic barrier in the presence of the peptides, independent of pore formation.