Chiral Aspects Research Articles

Analogues of Anticancer Natural Products: Chiral Aspects.

Life is chiral, as its constituents consist, to a large degree, of optically active molecules, be they macromolecules (proteins, nucleic acids) or small biomolecules. Hence, these molecules interact disparately with different enantiomers of chiral compounds, creating a preference for a particular enantiomer. This chiral discrimination is of special importance in medicinal chemistry, since many pharmacologically active compounds are used as racemates-equimolar mixtures of two enantiomers. Each of these enantiomers may express different behaviour in terms of pharmacodynamics, pharmacokinetics, and toxicity. The application of only one enantiomer may improve the bioactivity of a drug, as well as reduce the incidence and intensity of adverse effects. This is of special significance regarding the structure of natural products since the great majority of these compounds contain one or several chiral centres. In the present survey, we discuss the impact of chirality on anticancer chemotherapy and highlight the recent developments in this area. Particular attention has been given to synthetic derivatives of drugs of natural origin, as naturally occurring compounds constitute a major pool of new pharmacological leads. Studies have been selected which report the differential activity of the enantiomers or the activities of a single enantiomer and the racemate.

Chirality: An inescapable concept for the pharmaceutical, bio‐pharmaceutical, food, and cosmetic industries

AbstractChirality resides in diverse fields such as pharmaceuticals, food, bio‐pharmaceuticals, and cosmetics. Drugs used in treating various disease conditions, the majority of the plant secondary metabolites, various chemicals used in cosmetics, and distinct flavoring agents used in food industries exhibit chirality. In this context, there is an obligation to extend the analysis to chiral aspects. Attempts have been made to summarize the systematic, successful approaches for enantiomeric production via both enantio‐selective synthesis and the resolution of enantiomers using various analytical techniques including crystallization, chiral chromatography, capillary electrophoresis, kinetic resolution mediated by enzymes. Efforts have also been made to describe the regulatory guidance regarding bridging studies in the milieu of chiral switching. The majority of the monoclonal antibodies, growth factors, blood components, deoxyribonucleic acids, enzymes, and even vaccines for various diseases like cancer, polio, malaria, tetanus, hepatitis B, cholera, diphtheria bind differently to the receptors because the majority of drug binding and antibody binding receptors are also exhibiting chirality. Recent advancements in the various analytical techniques involved in the chiral analysis of food to preserve the authenticity of distinct flavors and cosmetics to identify safer enantiomers and reduce side effects both to humans and the environment are described.

Perturbative theoretical model of electronic transient circular dichroism spectroscopy of molecular aggregates.

A chiral analog of transient absorption spectroscopy, transient circular dichroism (TCD) spectroscopy is an emerging time-resolved method. Both spectroscopic methods can probe the electronic transitions of a sample, and TCD is additionally sensitive to the dynamic aspects of chirality, such as those induced by molecular excitons. Here, we develop a theoretical description of TCD for electronic multi-level models in which the pump pulse is linearly polarized and probe pulse is alternately left- and right-circularly polarized. We derive effective response functions analogous to those often used to describe other four-wave mixing methods and then simulate and analyze TCD spectra for three representative multi-level electronic model systems. We elaborate on the presence and detection of the spectral signatures of electronic coherences.

Multiple aspects of chirality in coordination polymers formed by the uranyl ion with (1R,3S)-(+)-camphorate ligands

Following previous work on complexes of the anions of (1R,3S)-(+)-camphoric acid (H2cam) with the uranyl cation, three novel species have been synthesized under solvo-hydrothermal conditions. [UO2(Hcam)2(4,4ʹ-bipy)] (1), where 4,4ʹ-bipy is 4,4ʹ-bipyridine, crystallizes as a monoperiodic polymer with bridging 4,4ʹ-bipy molecules and chelating, terminal Hcam– anions, hydrogen bonding between carboxylic and carboxylate groups in adjacent chains giving diperiodic networks. [UO2(cam)(2,2ʹ-bipy)] (2), where 2,2ʹ-bipy is 2,2ʹ-bipyridine, crystallizes also as a monoperiodic polymer, but bis-chelating cam2– anions are here bridging and the chelating 2,2ʹ-bipy ligands induce chirality at the uranium atoms; the chains are helical, left- or right-handed depending on the chirality of the associated uranium centres. [Zn(phen)3][(UO2)2(cam)3] (3), where phen is 1,10-phenanthroline, is an anionic diperiodic network with hcb topology displaying a grooved shape. In all three instances, the enantiomeric purity of the camphorate ligands does not produce significant enantioselectivity in regard to other aspects of the structural chirality.

Withdrawal Notice: New Aspect of Chirality or Mirror Symmetry Effect in Organic Chemistry, Physics, and Two-Component Biostructures

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Celkové inhalačné anestetiká – farmakodynamika, farmakokinetika a chirálne vlastnosti

Since the advent of nitric oxide, diethyl ether, chloroform and cyclopropane, the greatest advancement in the area of general inhalational anesthetics has been achieved by the introduction of fluorinated anesthetics and the relevant chiral techniques. This progress led to marked decrease in mortality rates in anesthesia. In the group of chiral fluorinated compounds, halothane (Fluotan®), isoflurane (Foran®), desflurane (Supran®) and enflurane (Ehran®) are deployed as volatile anesthetics. Chiral anesthetics possess a stereogenic center in their molecules and thus exist as two enantiomers (S)-(+) and (R)-(–). Although these chiral anesthetics are used as racemates, it is crucial to study besides the bioactivities of the racemic compounds also the biological activity and other properties of the particular enantiomers. The present survey discusses the drug category known as inhalational anesthetics in regard to their chiral aspects. These compounds exhibit marked differences between the (R) and (S)-enantiomers in their pharmacodynamics, pharmacokinetics and toxicity. The main analytical technique employed in the enantioseparation of these compounds is gas chromatography (GC). This review lists the individual chiral phases (chiral selectors) used in the enantioseparation as well as in pharmacokinetic studies. The possibilities of preparation of these compounds in their enantiomerically pure form by means of stereoselective synthesis are also mentioned.

Chiral Aspects of Local Anesthetics.

Thanks to the progress made in chemical technology (particularly in the methodologies of stereoselective syntheses and analyses) along with regulatory measures, the number of new chiral drugs registered in the form of pure enantiomers has increased over the past decade. In addition, the pharmacological and pharmacokinetic properties of the individual enantiomers of already-introduced racemic drugs are being re-examined. The use of the pure enantiomer of a drug that has been used to date in the form of a racemate is called a “chiral switch”. A re-examination of the properties of the pure enantiomers of racemates has taken place for local anesthetics, which represent a group of drugs which have long been used. Differences in (R) and (S)-enantiomers were found in terms of pharmacodynamic and pharmacokinetic activity as well as in toxicity. Levobupivacaine and robivacaine were introduced into practice as pure (S)-(−)-enantiomers, exhibiting more favorable properties than their (R)-(+)-stereoisomers or racemates. This overview focuses on the influence of chirality on the pharmacological and toxicological activity of local anesthetics as well as on individual HPLC and capillary electrophoresis (CE) methods used for enantioseparation and the pharmacokinetic study of individual local anesthetics with a chiral center.

Chirality breakdown in the presence of multiple exceptional points and specific mode excitation.

The dynamical parametric encirclement around a second-order exceptional point (EP) enables the time-asymmetric nonadiabatic evolution of light, which follows the chirality of the underlying system. Such light dynamics in the presence of multiple EPs and the corresponding chiral aspect is yet to be explored. In this Letter, we report a gain-loss assisted four-mode-supported optical waveguide that hosts a parameter space to dynamically encircle multiple EPs. In the presence of multiple EPs, we establish a unique nonadiabatic behavior of light, where beyond the chiral aspect of the system, light is switched to a particular mode, irrespective of the choice of the input mode. Proposed scheme certainly opens a step-forward approach in light manipulation to facilitate next-generation integrated photonic systems.

Enantiomeric Control of Intrinsically Chiral Nanocrystals.

The chiral aspect of inorganic crystals that crystallize in chiral space groups has been largely ignored until recently, partly due to difficulties in characterizing the chiroptical properties of bulk crystals, and also due to the difficulty in separating (sub)micrometer-scale chiral crystal enantiomers. In recent years, the colloidal synthesis of intrinsically chiral nanocrystals (NCs) of several chiral inorganic compounds with significant enantiomeric excess has been demonstrated. This is achieved through the use of chiral molecular ligands, which bind to the atomic/ionic components of the crystals, preferentially forming one crystal enantiomorph. Here, recent progress on several aspects of these NCs is described, including the connection between ligand structure and its ability to direct NC handedness, chiral amplification in the synthesis leading to enantiopure NC samples, spontaneous symmetry breaking, the formation of NCs with chiral shapes, the connection between lattice and shape chirality and mixed contributions of atomic-scale and shape chirality to the chiroptical properties.

Enantioselective Drug Recognition by Drug Transporters.

Drug transporters mediate the absorption, tissue distribution, and excretion of drugs. The cDNAs of P-glycoprotein, multidrug resistance proteins (MRPs/ABCC), breast cancer resistance protein (BCRP/ABCG2), peptide transporters (PEPTs/SLC15), proton-coupled folate transporters (PCFT/SLC46A1), organic anion transporting polypeptides (OATPs/SLCO), organic anion transporters (OATs/SLC22), organic cation transporters (OCTs/SLC22), and multidrug and toxin extrusions (MATEs/SLC47) have been isolated, and their functions have been elucidated. Enantioselectivity has been demonstrated in the pharmacokinetics and efficacy of drugs, and is important for elucidating the relationship with recognition of drugs by drug transporters from a chiral aspect. Enantioselectivity in the transport of drugs by drug transporters and the inhibitory effects of drugs on drug transporters has been summarized in this review.

Temperature Dependence of Anomalous Hall Conductivity in Rashba-type Ferromagnets

The applicability and usefulness of Rashba model have been extended by recent observations in the field of spintronics, such as the spin-orbit torque at the junction interfaces between ferromagnetic (FM) metals and non-magnetic (NM) metals and the perpendicular anomalous magnetoresistance (AMR) in heterostructures such as FI/NM or FM/NI (I denotes an insulator). In particular, the observations of the perpendicular AMR effect stimulate further interest in the Rashba-type spin-orbit interaction (SOI) at interfaces. Thus, the Rashba model with exchange splitting (EXS) is considered not only to play as an effective model for the physical understanding but also to reflect actual bi-layer systems in current spintronics devices. In the present work, we have first investigated the temperature dependence of anomalous Hall conductivity (AHC) of Rashba-type ferromagnets considered effects of spin fluctuations within the disordered local moment (DLM) scheme. The most distinctive feature that we observed is that intrinsic AHC increases with increasing temperature. This can be understood from the aspect of spin chirality, which indicates that the AHC increases with decreasing EXS when the SOI is much smaller than the EXS. The extrinsic part of the Fermi surface term also increases with increasing temperature and has a large contribution, comparable to that of the intrinsic part. Although, such a behaviour has not yet been observed experimentally, we suggest that the physical picture found in this work might lurk in an anomalous Hall effects in Rashbe-type ferromagnets.

Investigation of Two Seized Crystal Meth Labs in Austria – Parameters and Chirality Aspects of Methamphetamine Low Scale Synthesis

Investigation of Two Seized Crystal Meth Labs in Austria – Parameters and Chirality Aspects of Methamphetamine Low Scale Synthesis

Inherently Chiral Calixarenes: Synthesis and Applications.

This article looks at the chemistry surrounding the concept of inherently chiral calixarenes (ICCs), whose synthesis and application have only recently being realised. One challenge in the area of ICC chemistry is the sheer breadth and scope for installing different aspects of inherent chirality. The aim of this article is not to cover every known method, but rather to give the reader an overview of the main themes that have emerged in this area, including more recent additions to the literature. This overview will also touch on the very limited reports on the applications of ICCs which give a glimpse into the potential these compounds may have in future studies.

Magnetochiral nonreciprocity of volume spin wave propagation in chiral-lattice ferromagnets

Spin current, i.e. the flow of spin angular momentum or magnetic moment, has recently attracted much attention as the promising alternative for charge current with better energy efficiency. Genuine spin current is generally carried by the spin wave (propagating spin precession) in insulating ferromagnets, and should hold the chiral symmetry when it propagates along the spin direction. Here, we experimentally demonstrate that such a spin wave spin current (SWSC) shows nonreciprocal propagation characters in a chiral-lattice ferromagnet. This phenomenon originates from the interference of chirality between the SWSC and crystal-lattice, which is mediated by the relativistic spin-orbit interaction. The present finding enables the design of perfect spin current diode, and highlights the importance of the chiral aspect in SWSC.

Carbonyl reduction of warfarin: Identification and characterization of human warfarin reductases

Warfarin is a widely used anticoagulant and, unfortunately, is a drug that is commonly implicated in serious adverse events including fatalities. Although several factors, including the metabolism of warfarin via CYP450, have been reported to affect the safety and efficacy of warfarin therapy, the wide variance in the warfarin dosage in patients has not been completely clarified. In addition to the oxidative metabolism of warfarin mediated by CYP450, reductive metabolism is involved in warfarin biotransformation. However, the reductive metabolism of warfarin has been largely unexplored and deserves further investigation. We studied warfarin reduction by human liver fractions and found a 9-fold higher velocity of warfarin reduction in the cytosol than in microsomes (Vmax=77.2 vs. 8.7pmol/mgprotein/min, respectively). Furthermore, of nine recombinant cytosolic carbonyl reducing enzymes tested for their ability to reduce warfarin, AKR1C3 and CBR1 were identified as warfarin reductases and their kinetic parameters were determined. The internal clearance of warfarin was 3 orders of magnitude higher with AKR1C3 than with CBR1 (CLint=65.922 vs. 0.070μl/mgprotein/min, respectively). This is the first time that warfarin reducing enzymes in human liver subcellular fraction have been identified. Moreover, we have described the chiral aspects of warfarin reduction using an HPLC method that enabled the detection of individual warfarin alcohol stereoisomers. Cytosol and AKR1C3 exhibit the stereoselective metabolism of (R)-warfarin to preferentially form (SR)-warfarin alcohol as the primary in vivo metabolite of warfarin. On the other hand, microsomes and CBR1 preferentially reduce (S)-warfarin to form (RS)-warfarin alcohol and (SS)-warfarin alcohol, respectively.

Historical aspects of chirality of drugs

Currently only about 15% of all pharmaceutical products synthesized are presented by pure enantiomers.Many medicines exist as a mixture of two, and often a larger number of spatial isomers with a different biological activity. Optical isomers have different biological, pharmacological and technological properties. The optical activity, odor, toxicity, pharmacodynamic, pharmacokinetic and technological properties depend on chirality of the same substance. This led to the study of important aspects of the theory of chirality when creating medicines. The article considers historical aspects of chirality of drugs. Based on the library analysis the mandatory consideration of the chemical nature of chirality of drugs in production of pharmaceuticals, as well as the necessity of the preclinical and clinical trials of drugs have been substantiated. It has been found that creation of pure chiral drugs is a promising research direction. Its introduction into clinical practice allows, firstly, to use lowerdoses of drugs without the loss of efficiency, and secondly, to improve the safety and reduce the risk of adverse reactions during therapy.

ChemInform Abstract: Molecular Chirality: Language, History, and Significance

AbstractReview: 60 refs.

DMSO Induced Breaking up of Insulin Fibrils Monitored by Vibrational Circular Dichroism

Bovine insulin can form stable β-sheet-rich amyloid aggregations composing of several protofibrils and adopt variable morphologies based on the fibrillation condition. Vibrational circular dichroism (VCD) was reported as a very useful probe for charactering the chirality of amyloid aggregates and detecting formation of extended, twisted fibrils.(1) We studied the effect of adding dimethyl sulfoxide (DMSO) to aqueous insulin fibrils and monitored their destabilization by VCD. We compared two types of insulin fibrils depending on sample preparation protocol, one type can have oppositely signed induced circular dichroism for amyloid-bound THT,(2) and the other type has oppositely signed VCD.(1) Transmission electron microscopy (TEM) was used to correlate the morphology with VCD spectrum to show both the molecular morphology and supramolecular chirality aspects of the DMSO induced insulin fibril breaking-up process. The two types of insulin fibrils behaved differently on addition of DMSO, but both of them were eventually denatured by high concentrated DMSO.1. Kurouski, D., Dukor, R. K., Lu, X. F., Nafie, L. A. and Lednev, I. K. (2012) Normal and reversed supramolecular chirality of insulin fibrils probed by vibrational circular dichroism at the protofilament level of fibril structure. Biophys. J. 103, 522-531.2. Loksztejn, A. and Dzwolak, W. (2008) Chiral bifurcation in aggregating insulin: an induced circular dichroism study. J. Mol. Biol. 379, 9-16.

Stereoisograms for three-membered heterocycles: III. R/S-stereodescriptors for characterizing the RS-stereogenic aspect of absolute configuration

The stereoisogram approach presumes the presence of three pairs of attributes, i.e., chirality/achirality, RS-stereogenicity/RS-astereogenicity, and sclerality/asclerality, in contrast to the modern stereochemistry which presumes the presence of a single pair of chirality/achirality. From this viewpoint of the stereoisogram approach, the scope and limitations of R/S-stereodescriptors of the Cahn–Ingold–Prelog (CIP) system are discussed, where oxirane derivatives are used as probes. In particular, correlation diagrams of stereoisograms are used to comprehend the global and local symmetries of oxirane derivatives. Thereby, R/S-stereodescriptors of the CIP system are found to specify local symmetries at each positions of an oxirane derivative, so that the global symmetry of the oxirane derivative requires the other types of descriptors proposed in Part II of this series ( $$\textit{R}_{\mathrm{a}}/\textit{S}_{\mathrm{a}}$$ -descriptors and Z/E-descriptors). A correlation diagram of each position clarifies that R/S-stereodescriptors characterize the RS-stereogenic aspect of absolute configuration in the specification of local symmetries, but by no means the chiral aspect of absolute configuration. In other words, a pair of R/S-stereodescriptors is assigned to a pair of RS-diastereomers, not to a pair of enantiomers. This fact stems from the misleading foundation of the modern stereochemistry that it presumes a pair of chirality/achirality as a single pair of attributes. The pair of R/S-stereodescriptors originally assigned to a pair of RS-diastereomers should be interpreted subsidiarily to characterize the corresponding pair of enantiomers, where the concept of chirality faithfulness is necessary. Chirality-unfaithful cases are discussed by means of stereoisograms. Exceptional cases in the practices of the modern stereochemistry, e.g., pseudoasymmetry and ‘geometric enantiomers’, are discussed in a rational fashion according to the stereoisogram approach.

Chlorophylls, Symmetry, Chirality, and Photosynthesis

Chlorophylls are a fundamental class of tetrapyrroles and function as the central reaction center, accessory and photoprotective pigments in photosynthesis. Their unique individual photochemical properties are a consequence of the tetrapyrrole macrocycle, the structural chemistry and coordination behavior of the phytochlorin system, and specific substituent pattern. They achieve their full potential in solar energy conversion by working in concert in highly complex, supramolecular structures such as the reaction centers and light-harvesting complexes of photobiology. The biochemical function of these structures depends on the controlled interplay of structural and functional principles of the apoprotein and pigment cofactors. Chlorophylls and bacteriochlorophylls are optically active molecules with several chiral centers, which are necessary for their natural biological function and the assembly of their supramolecular complexes. However, in many cases the exact role of chromophore stereochemistry in the biological context is unknown. This review gives an overview of chlorophyll research in terms of basic function, biosynthesis and their functional and structural role in photosynthesis. It highlights aspects of chirality and symmetry of chlorophylls to elicit further interest in their role in nature.