Chiral Macromolecules Research Articles

Symmetry versus Asymmetry in the Molecules of Life: Homomeric Protein Assemblies

The essay is dedicated to the relation of symmetry and asymmetry-chirality in Nature. The Introduction defines symmetry and its impact on basic definitions in science and human activities. The following section Chirality of molecules reveals breifly development of notion of chirality and its significance in living organisms and science. Homochirality is a characteristic hallmark of life and its significance is presented in the section Homochirality of Life. Proteins, important constituents of living cells performing versatile functions are chiral macromolecules composed of L-amino acids. In particular, the protein assemblies are of a great importance in functions of a cell. Therefore, they have attracted researches to examine them from different points of view. Among proteins of known three-dimensional structures about 50–80% of them exist as homomeric protein complexes. Protein monomers lack any intrinsic, underlying symmetry, i.e. enantiomorphic protein molecules involve left-handed amino acids but their asymmetry does not appear to extend to the level of quaternary structures (homomeric complexes) as observed by Chothia in 1991. In the section Homomeric assemblies we performed our analysis of very special cases of homomers revealing non-crystallographic symmetry in crystals. Homochiral proteins can crystallize only in enantiomorphic space groups. Among 230 existing space groups 65 are enantiomorphic containing limited symmetry elements that are rotation and screw-rotation axes. Any axis of rotation symmetry of a crystal lattice must be two-fold, three-fold, four-fold, or six-fold. Five-fold, seven-fold, and higher-fold rotation symmetry axes are incompatible with the symmetry under spatial displacement of the three-dimensional crystal lattice.

Chiral conducting polymers

This critical review describes the preparation and properties of a relatively new class of chiral macromolecules, namely chiral conducting polymers. It focuses in particular on examples based on polypyrrole, polythiophene and polyaniline. They possess remarkable properties, combining not only chirality with electrical conductivity but also the ability to undergo facile redox and pH switching. These unique properties have opened up a range of exciting new potential applications, including as chiral sensors, as novel stationary phases for chiral separations, and as chiral electrodes for electrochemical asymmetric synthesis (153 references).

Chiral Polychlorinated Biphenyl Transport, Metabolism, and Distribution: A Review

Chirality can be exploited to gain insight into enantioselective fate processes that may otherwise remain undetected because only biological, but not physical and chemical transport and transformation processes in an achiral environment will change enantiomer compositions. This review provides an in-depth overview of the application of chirality to the study of chiral polychlorinated biphenyls (PCBs), an important group of legacy pollutants. Like other chiral compounds, individual PCB enantiomers may interact enantioselectively (or enantiospecifically) with chiral macromolecules, such as cytochrome P-450 enzymes or ryanodine receptors, leading to differences in their toxicological effects and the enantioselective formation of chiral biotransformation products. Species and congener-specific enantiomer enrichment has been demonstrated in environmental compartments, wildlife, and mammals, including humans, typically due to a complex combination of biotransformation processes and uptake via the diet by passive diffusion. Changes in the enantiomer composition of chiral PCBs in the environment have been used to understand complex aerobic and anaerobic microbial transformation pathways, to delineate and quantify PCB sources and transport in the environment, to gain insight into the biotransformation of PCBs in aquatic food webs, and to investigate the enantioselective disposition of PCBs and their methylsulfonyl PCBs metabolites in rodents. Overall, changes in chiral signatures are powerful, but currently underutilized tools for studies of environmental and biological processes of PCBs.

Stereoselectivity in Drug Metabolism: Molecular Mechanisms and Analytical Methods

About 50% of therapeutic drugs are currently administered as a racemate, a mixture of equal proportions of two enantiomers. In an achiral environment, the enantiomers of a chiral drug show identical chemical and physical properties. However, they can present different chemical and pharmacological behavior in a chiral environment such as in the body. The interaction of two enantiomers with a chiral macromolecule, such as an enzyme or receptor, is three dimensional in nature, forming diastereomeric complexes resulting in a chiral recognition process. Moreover, when administered as a racemate, two enantiomers can display the pharmacokinetic processes (absorption, distribution, metabolism and excretion) in a stereoselective manner. Among these processes, stereoselectivity plays a central role in the metabolism due to the involvement of the enzymatic system. Thus, the purpose of the current review is to present important aspects related to stereochemistry of drug metabolism, with emphasis on molecular mechanisms involved in enzyme mediated reactions, such as those catalyzed by cytochrome P450, uridine 5'-diphospho (UDP)-glucuronosyltransferases and sulfotransferases. Additionally, recent advances regarding the analysis of chiral drugs and their metabolites employing different analytical techniques (high-performance liquid chromatography-HPLC and capillary electrophoresis-CE) will also be outlined.

Chiral Oligomers by Iterative Tandem Catalysis

Iterative tandem catalysis is presented as a flexible tool for obtaining chiral macromolecules from racemic or prochiral monomers. Here, we combine lipase-catalyzed ring-opening of omega-substituted lactones with ruthenium-catalyzed racemization. In a two-pot system, enantioenriched oligomers of 6-methyl-epsilon-caprolactone were synthesized, which could not have been obtained by enzymatic ring-opening alone. A one-pot experiment proved highly promising in developing a novel route toward enantiopure polyesters.

Conclusion: the future of single-isomer pharmacology.

Taken together, the articles gathered in this supplement underscore the major role in drug development that single-isomer science can play—a role that will undoubtedly take on a greater importance in the future. While the chirality of certain pharmacologically active molecules has been recognized for almost a century, it is only in recent years that drug synthesis and chiral separation techniques have advanced far enough to allow meaningful comparisons among enantiomers. Now that these methods are broadly available, the potential applications of single isomer drug development are considerable.Numerous examples from a range of therapeutic areas confirm that single enantiomers can enhance clinical efficacy, reduce adverse effects, cause fewer interactions with other drugs, and minimize response variations among patients by offering more predictable pharmacokinetics and greater selectivity. In some cases, these advantages are simply due to the removal of an inactive enantiomer, but in other cases, a given dose of a single isomer offers greater benefits when administered alone than when administered as the racemic mixture, suggesting that the opposite enantiomer (the distomer) actually has detracting effects. As the papers by Drs. Gal and Hurt explain, the different activities of a pair of enantiomers are usually traceable to stereochemical differences in the way they interact with chiral macromolecules such as enzymes, transport systems, and receptors.

Effects of ultraviolet radiation on the type-I collagen protein triple helical structure: a method for measuring structural changes through optical activity.

A detailed study of the effects of ultraviolet radiation on type-I collagen has been conducted. We have confirmed that exposure to ultraviolet radiation lowers the denaturation temperature of type-I collagen and that the triple helical state is destroyed provided that the radiation dose exceeds a threshold level, which is defined as the incident radiation dose that raises the sample temperature above the (lower) denaturation temperature. For incident radiation doses below threshold, the collagen molecule remains in a triple helical state. Denaturation is determined by changes in the optical activity of the collagen solution. Furthermore, a new instrument has been developed and tested to measure the optical rotatory dispersion properties of chiral molecules. The advantage of this instrument is that it enables a real-time measurement of the optical activity of chiral macromolecules while exposing samples to ultraviolet radiation and requiring no special sample preparation techniques. Using a differential measurement scheme, system errors have been minimized.

Glassy State and Secondary Structures of Chiral Macromolecules: Polyisocyanates and Polyketones

The temperature dependence of the optical activity in the amorphous and therefore nonbirefringent solid state is used here to study the conformational properties of polyisocyanates and isotactic polyketones. Optically active polyisocyanates, which are not entirely amorphous in the solid state, were rendered amorphous by blending, while the glass transition temperature of the inherently amorphous polyketones was varied from 145 to 1 °C by terpolymerization of alternating styrenic/CO units with alternating 1-alkene/CO units. In both polymer systems, the optical activity changed significantly at temperatures only above Tg. This result, which was controlled for the contribution of degradation and epimerization of stereocenters in the polyketones, requires that the chiral optical properties of these polymers arise from long-range conformational properties of the chain that are impeded from changing with temperature only in the glassy state. This is consistent with the known character of the polyisocyanates but...

Dendrimers and chirality

The preparation, chiroptical properties and potential application of chiral dendritic polymers are reviewed. Mislow's analysis of the manifestation of chirality, cryptochirality and fuzzy chirality is useful in studying these unique chiral macromolecules. Chirality 10:53–59, 1998. © 1998 Wiley-Liss,Inc.

Materials chemistry of chiral macromolecules. 1. Synthesis and phase transitions

This paper describes work on synthesis of chiral macromolecules as part of a materials chemistry study which seeks to establish links in these systems among molecular structure, three-dimensional molecular organization, and properties. The basic materials chemistry hypothesis driving this work is that chiral forces among stereogenic centers may serve as guiding fields to organize polymers in two or three dimensions. It follows that physical properties could be directly or indirectly controlled by chirality. In order to promote strong forces among chiral centers the chains were designed to have stereogenic carbons substituted by the strongly dipolar cyano group and spaced by 16 atoms along the backbone. The preparative chemistry of chiral macromolecules is challenging given the limited number of polymerization methodologies and the inherent translational periodicity of synthetic polymers. The authors have synthesized here low symmetry chiral macromolecules in which the only symmetry element retained is polar translation; achiral homogues lacking the nitril function, the configurationally disordered polymer, and dimeric model compounds were prepared as well. 25 refs., 15 figs., 4 tabs.

Synthesis of Materials with Self-Ordering Chiral Macromolecules

Abstract The present work focuses on chirality, functionalization, and molecular shape to establish links between molecular architecture and the spatial organization of polymer chains in organic materials. The approach used was to synthesize chiral and racemic homologous polymers exhibiting a preference for extended chain conformations and having the strongly dipolar cyano group as a substituent of the stereogenic center. The strong dipole moment at the chiral center offered potential to combine strong long-range forces with chiral recognition. Electron and optical microscopies were our selected tools to probe three-dimensional structures, and nonlinear optics was used to measure the properties of the materials obtained. We found that the relative stereochemistry of the repeat unit dipole impacts significantly on global chain symmetry and its packing mode. Enantiomeric enrichment of chains changed hexagonally packed cylindrical molecules to board-like molecules which pack edge-to-edge in an orthorhombic l...

Cholesteric ordering of synthetic polypeptides in a chiral solvent

With the general theory of chiral dispersion interaction of macromolecules the author considers the influence of the chirality of the solvent. An expression is obtained for the effective optical activity of the macromolecule in a chiral medium. In the polymer liquid crystal formed by rod-shaped macromolecules in solution the pitch of the cholesteric helix depends on the chirality of the solvent in line with the experimental data for poly- γ-benzyl- L-glutamate. Cholesteric ordering in the LC polymer formed by the rigid chain or semiflexible macromolecules in a chiral solvent is predicted. Cholesteric ordering in a system of chiral macromolecules in a non-chiral solvent is also considered.

Molecular theory of solvent effect on cholesteric ordering in lyotropic polypeptide liquid crystals

An expression for the energy of chiral interaction between polypeptide molecules in a solution is obtained using the general theory of van der Waals-Lifshitz forces between macromolecules. The resulting chiral interaction potential is a function of the anisotropic permittivity and optical activity of the polypeptide molecule and of the solvent dielectric constant. An expression for the effective optical activity of a chiral macromolecule embedded in dielectric media is also obtained. A statistical theory of cholesteric polypeptide liquid crystals is presented taking into account both steric and chiral dispersion interactions between polypeptide molecules. The theory accounts for the helix inversion in polypeptide liquid crystals, induced by a change in temperature and a change in the solvent dielectric constant. In particular the results of the theory allow the explanation of the twofold cholesteric sense inversion observed recently in the lyotropic liquid crystal formed by poly-γ-benzyl-L-glutamate in mixed solvents.

Use of circularly polarized light to study biological macromolecules

Abstract

The optical activity of nucleic acids and their aggregates.

This review includes experimental and theoretical work on absorption and scattering of light by chiral macromolecules. All molecules absorb light, but only chiral (handed) molecules show a preferential absorption for right or left circularly polarized light. This phenomenon of circular dichroism (CD) has been very useful in characterizing any chiral aggre­ gate of chromophores-including proteins, nucleic acids, and their complexes. We discuss theoretical methods that relate the absorption and circular dichroism of a polymer or aggregate to the optical proper­ ties of its constituent parts. The experimental data reviewed is limited essentially to nucleic acids, for lack of space. Two new experimental methods that are particularly useful for mac­ romolecules or for systems that scatter a significant fraction of the incident light are fluorescence-detected circular dichroism and circular intensity differential scattered light. Fluorescence-detected circular di­ chroism (FDCD), as the name implies, used the intensity of the fluores­ cence emitted to monitor the intensity of the light absorbed (167). This method provides two main advantages: (a) The spectrum of a complex system containing many chromophores, but only a few fluorophores is greatly simplified, and (b) scattering artifacts, which plague circular dichroism studies using transmitted light measurements, are partly avoided by use of fluorescence detection. The theory (159, 160) and