Current Organic Chemistry - Volume 9, Issue 12, 2005

In this review the idea of a “Peptide/Protein World” preceding the widely rooted idea of the “RNA world” is presented and elaborated. To support this idea, the formation of the building blocks of nucleic acids and peptides and their assembly to biopolymers in a primordial earth scenario is discussed. Furthermore, chemical stability problems of the building blocks and the assembled biomolecules are presented, and finally their ability to efficiently replicate and chemically evolve is argued. Taking into account various problems in all these areas for nucleic acids and nucleotides, the idea of the “Peptide/Protein World” is brought up, stating that peptides and proteins would have come first in chemical evolution with an “RNA world” appearing only later with the protective help of protein shells.

The progress in both peptide and polymer chemistry has led to the preparation of “hybrids” to yield compounds with properties not achievable with the separate components. In this review we aim at describing the current synthetic methodologies for the preparation of peptide containing block copolymers, either being completely peptidic or as hybrids with synthetic polymer blocks. The different techniques to prepare these polymers are ordered by level of control over peptide sequence and hence their molecular structure. First, recent developments in NCA polymerization will be discussed, which enable the construction of well-defined high molecular weight peptide based block copolymers, albeit with no absolute control over amino acid composition. Solution phase peptide synthesis allows the preparation of small peptide sequences, which can be incorporated into the side chain or the main chain of hybrid polymer architectures. Application of solid phase peptide synthesis and the newly developed peptide ligation methods has resulted in an extension of the length of the peptide fragments that can be conveniently incorporated into hybrid polymer structures. Finally absolute control over amino acid sequence, combined with the ability to create high molecular weight species is accomplished with the application of protein engineering to the field of polymer science.

Over the years, γ and δamino acids have gathered much interest in drug discovery, especially in the peptidomimetic area. Much work on γamino acids has been focused towards the generation of γamino butyric acid (GABA) analogues, and the development of asymmetric approaches starting from unsaturated compounds, while few examples have been reported about carbohydrate-derived scaffolds as γamino acids. δAmino acids became of great importance as they have been selected as building blocks for backbone generation of peptide nucleic acid (PNA) structures. As further applications of δamino acids, carbohydrate research produced interesting examples of new δamino acids as building blocks for peptidomimetic design, and several reverse turn mimetics have been reported, too. Moreover, many studies have been concentrated on the conformational analysis of oligomeric sequences in analogy with β-peptides. This report is a description of relevant synthetic approaches to new γamino acids through the use of sugar chemistry and asymmetric synthesis, and to synthetic strategies for δamino acids, covering the area of carbohydrate chemistry, alkenebased chemistry, and asymmetric synthesis.

ortho-Phthalaldehyde (OPA) has become the preferred choice over glutaraldehyde for use as a high-level disinfectant for hospital instrument processing. Its superior antimicrobial performance is not well understood. To explain the exceptional microbicidal activity, a multi-step mechanism combining medium or solvent-induced molecular switching between the lipophilic dialdehyde OPA and the amphiphilic non-aldehyde form, 1,3-phthalandiol, is proposed based on chemical and spectral studies. In this model, OPA is a hydrophobe (the dialdehyde in “open” position) and 1,3- phthalandiol (in “locked” position), is a hydrophile. The amount of each which is present depends on the medium (or solvent) being employed. OPA exists as the dialdehyde in lipophilic media (or solvents) and becomes 1,3-phthalandiol in hydrophilic media (or solvents). These two forms can switch back and forth depending on the medium or solvent being used. The following mechanistic aspects of this model are discussed: (1) the medium-induced molecular switching between OPA and 1,3-phthalandiol and cell-wall penetration via this mechanism; (2) an OPA equilibrium moving in-andout of the bacterial cell aided by a gradient driving force in combination with the molecular switching mechanism which assists significant penetration of OPA into the bacteria cells; (3) the formation of significant amounts of amphiphilic 1,3- phthalandiol from OPA explains the moderate water solubility of OPA, low volatility, and suggests that a different biocidal mechanism operates versus that of glutaraldehyde, and (4) the SAM (self-assembled monolayer) hypothesis, which explains the first-step-attack of OPA on bacteria cell-walls via 1,3-phthalandiol. These observations may explain the superior bactericidal efficacy of OPA against glutaraldehyde-resistant mycobacteria.

The continuous search for new qualities and the desirability of controlling the size, shape and the chemical features had led to the successful synthesis of various molecular containers and their complexes starting from resorcarene skeleton. The rigidified cavitands have been extended to capture in their round hug bigger and bigger molecules. By covalent synthesis many kinds of new hosts have been built, that maintain guests in their prison for more and more long time. Self assembly, driven by metal-ligand interaction, van der Waals forces, hydrophobicity and, mainly, hydrogen bonds, is at the base of capsules, a novel type of compounds with a peculiar inner phase, stereochemistry and reactivity. The amazing variety of hollow buildings with a resorcarene-based framework and often unique properties is reviewed.