III. Foldamer Research 3910 A. Overview 3910 B. Motivation 3910 C. Methods 3910 D. General Scope 3912 IV. Peptidomimetic Foldamers 3912 A. The R-Peptide Family 3913 1. Peptoids 3913 2. N,N-Linked Oligoureas 3914 3. Oligopyrrolinones 3915 4. Oxazolidin-2-ones 3916 5. Azatides and Azapeptides 3916 B. The â-Peptide Family 3917 1. â-Peptide Foldamers 3917 2. R-Aminoxy Acids 3937 3. Sulfur-Containing â-Peptide Analogues 3937 4. Hydrazino Peptides 3938 C. The γ-Peptide Family 3938 1. γ-Peptide Foldamers 3938 2. Other Members of the γ-Peptide Family 3941 D. The δ-Peptide Family 3941 1. Alkene-Based δ-Amino Acids 3941 2. Carbopeptoids 3941 V. Single-Stranded Abiotic Foldamers 3944 A. Overview 3944 B. Backbones Utilizing Bipyridine Segments 3944 1. Pyridine−Pyrimidines 3944 2. Pyridine−Pyrimidines with Hydrazal Linkers 3945

A field guide to foldamers.

Chirality-Sensing Supramolecular Systems

In chemical terms, the regio- and stereoselective hydroxylation of hydrocarbon C-H bonds is a very difficult transformation. Nevertheless, these reactions are deftly catalyzed by a variety of metalloenzymes, among which the most diverse are the many members of the cytochrome P450 family. Cytochrome P450 enzymes are found in most classes of organisms, including bacteria, fungi, plants, insects, and mammals. Thousands of such proteins are now known (http://drnelson.utmem.edu/cytochromeP450.html), including 57 in the human genome (1), 20 in Mycobacterium tuberculosis (2), 272 in Arabidopsis (3), and the amazing number of 457 in rice (4). The nomenclature for these enzymes is based on their sequence similarity when appropriately aligned, a somewhat arbitrary similarity cutoff (approximately >40% identity) being used to define members of a family and a higher cutoff (approximately >55% identity) members of a subfamily (5). Thus CYP3A4 corresponds to the fourth enzyme in family 3, subfamily A. This nomenclature allows the naming of enzymes without regard to their origin or specific properties.

The mammalian, plant, and fungal proteins are commonly membrane bound and are relatively difficult to manipulate, but the bacterial proteins are usually soluble, monomeric proteins. For that reason, much of the early research on mechanisms of cytochrome P450 enzymes was carried out with bacterial enzymes, particularly with the prototypical enzyme CYP101 (P450cam) from Pseudomonas putida (6, 7). From a chemist's point of view, there is a particular interest in the thermophilic enzymes, which currently include CYP119 (8-10), P450st (11), CYP174A1 (12), and CYP231A2 (13). The thermal stability of these enzymes makes them attractive starting points for the development of industrially useful catalysts. In this context, particular attention has also focused on CYP102 (P450BM3), a self-sufficient enzyme from Bacillus megaterium in which the flavoprotein protein required for transfer of electrons from NADPH is fused to the hemoprotein (14). The resulting simplicity and high catalytic rate have led to extensive efforts to engineer this protein for practical catalytic purposes (15-19). Although these proteins have properties that make them particularly attractive for engineering purposes, the large reservoir of P450 enzymes that collectively catalyze an astounding diversity of reactions suggests that P450 catalysis will develop into a highly useful technology.

The cytochrome P450 enzymes are defined by the presence in the proteins of a heme (iron protoporphyrin IX) prosthetic group coordinated on the proximal side by a thiolate ion (20, 21). This feature gives rise to the spectroscopic signature that defines these enzymes, as the thiolate-ligated ferrous-CO complex is characterized by a Soret absorption maximum at ∼450 nm (21). A thiolate-coordinated heme group is present in all P450 enzymes, although not all proteins with such coordination are members of this superfamily. One obvious exception, for example, is chloroperoxidase, which has a thiolate-coordinated heme group but normally catalyzes a very different reaction than the P450 enzymes (21-23).

Although there are unusual P450 enzymes, such as the thromboxane and prostacyclin synthases (24), or CYP152 from Sphingomonas paucimobilis or Bacillus subtilis (25, 26), that normally utilize peroxides as substrates, the defining reaction for P450 enzymes is the reductive activation of molecular oxygen. In this reaction, one of the oxygen atoms of molecular oxygen is inserted into the substrate and the other oxygen atom is reduced to a molecule of water. With one exception to date (27, 28), the electrons required for this reduction of molecular oxygen derive from reduced pyridine nucleotides (NADH or NADPH). The overall equation for the reaction thus adheres to the formula: RH + NAD(P)H + O2 + H+ -> ROH + NAD(P)+ + H2O, where RH stands for a substrate with a hydroxylatable site. P450 enzymes therefore belong to the monooxygenase class of enzymes that only insert one of the oxygen atoms of molecular oxygen into their substrates. However, under appropriate circumstances or with specific substrates, other P450-catalyzed reactions can be observed, including desaturation, carbon-carbon bond scission, and carbon-carbon bond formation (29, 30). This review specifically focuses on P450-catalyzed hydrocarbon hydroxylation, the reaction that is most characteristic of P450 enzymes and that has been most extensively investigated. However, the principles that apply in these reactions also apply to other hydroxylation reactions, including those that occur on carbons adjacent to nitrogen, sulfur, or oxygen.

Hydrocarbon hydroxylation by cytochrome P450 enzymes.

The CH/π hydrogen bond is an attractive molecular force occurring between a soft acid and a soft base. Contribution from the dispersion energy is important in typical cases where aliphatic or aromatic CH groups are involved. Coulombic energy is of minor importance as compared to the other weak hydrogen bonds. The hydrogen bond nature of this force, however, has been confirmed by AIM analyses. The dual characteristic of the CH/π hydrogen bond is the basis for ubiquitous existence of this force in various fields of chemistry. A salient feature is that the CH/π hydrogen bond works cooperatively. Another significant point is that it works in nonpolar as well as polar, protic solvents such as water. The interaction energy depends on the nature of the molecular fragments, CH as well as π-groups: the stronger the proton donating ability of the CH group, the larger the stabilizing effect. This Perspective focuses on the consequence of this molecular force in the conformation of organic compounds and supramolecular chemistry. Implication of the CH/π hydrogen bond extends to the specificity of molecular recognition or selectivity in organic reactions, polymer science, surface phenomena and interactions involving proteins. Many problems, unsettled to date, will become clearer in the light of the CH/π paradigm.

The CH/π hydrogen bond in chemistry. Conformation, supramolecules, optical resolution and interactions involving carbohydrates

Organic chemists tend to consider the conformation of compounds as a consequence of repulsive steric interactions. In other words, “the steric effect” means “repulsive” in many cases. Thus, folded conformations observed in organic molecules have been often regarded as unusual, while the reason remained undecided. However, accurate determinations by modern spectroscopic methods, recent crystallographic data, and high-level ab initio MO calculations have demonstrated that the folded conformation is by no means exceptional. We will show that the gauche or folded conformation prevails in organic compounds bearing at least an electronegative or π-group in the molecule. We consider that the above phenomenon finds its origin, in most cases, in nonconventional hydrogen bonds such as the CH/X (X ) O, halogen, etc.) and the XH/π (X ) O, N, C, etc.) hydrogen bonds. * To whom correspondence should be addressed. E-mail: shu@ hiroshima-u.ac.jp. ‡ Hiroshima University. § Yokohama National University. ⊥ The CHPI Institute. Chem. Rev. 2010, 110, 6049–6076 6049

Relevance of Weak Hydrogen Bonds in the Conformation of Organic Compounds and Bioconjugates: Evidence from Recent Experimental Data and High-Level ab Initio MO Calculations

The synthesis and binding properties for carbohydrates of several artificial, acyclic receptors containing two or three heterocyclic recognition units covalently attached to a phenyl spacer is described. These host molecules having uncharged hydrogen-bonding sites were used in a systematic study towards the evaluation of recognition motifs for carbohydrates. A novel effective, acyclic hydrogen-bonding receptor possessing naphthyridine–amide moieties as heterocyclic recognition units has been developed.



Es werden die Synthesen von kunstlichen, acyclischen Rezeptoren 4–8 und ihre Bindungseigenschaften gegenuber Kohlenhydraten beschrieben. Diese Rezeptorverbindungen enthalten zwei oder drei heterocyclische Erkennungseinheiten, die kovalent uber einen Phenyl-Spacer verbunden sind. Diese Wirtmolekule, die nicht ionische Wasserstoffbruckenbindungs-Gruppen besitzen, wurden fur systematische Studien zur Bestimmung von Erkennungsmotiven fur Kohlenhydrate verwendet. Der neue, effektive, uber Wasserstoffbrucken bindende Rezeptor 4, der Naphthyridin-Amid-Einheiten als heterocyclische Erkennungsstrukturen enthalt, wurde entwickelt.

Molecular recognition of carbohydrates by artificial receptors: systematic studies towards recognition motifs for carbohydrates.

Despite their acyclic structure, the simple host molecules 1 and 2 can effectively hydrogen bond to monosaccharides. They show marked binding affinities to glucopyranosides in chloroform, and they are able to participate in three-dimensional recognition of monosaccharides.

Willi Sicking

Papers

Molecular recognition of carbohydrates by artificial receptors: systematic studies towards recognition motifs for carbohydrates.

Molecular Recognition of Carbohydrates by Artificial Polypyridine and Polypyrimidine Receptors

The High Reactivity of the CS Double Bond in 1,3-Dipolar Cycloadditions of Nitrones: A Molecular Orbital Theoretical Analysis

High alpha/beta-anomer selectivity in molecular recognition of carbohydrates by artificial receptors.

Crown Ethers as Building Blocks for Carbohydrate Receptors