Distinct Enantiomers Research Articles

Dual Signature of Chirality Induced Spin Selectivity through Spontaneous Resolution of 2D Metal‐Organic Frameworks

The Chiral‐Induced Spin Selectivity (CISS) effect has emerged as a fascinating phenomenon within the realm of electron’s spin manipulation, showcasing a unique interplay between electron’s spin and molecular chirality. Subsequent to its discovery, researchers have been actively involved in exploring the new chiral molecules as effective spin filters. In the realm of observing the CISS effect, the conventional approach has mandated the utilization of two distinct enantiomers of chiral molecules. However, this present study represents a significant advancement by demonstrating the ability to control both spin states of electrons in a single system. In this work, we have demonstrated the preparation of chiral metal‐organic frameworks (MOFs) via a "spontaneous resolution" process, obviating the requirement for chiral sources. Remarkably, this work signifies the first instance of achieving dual signature of spin selectivity from a single and exclusively achiral system through a spontaneous resolution process. This holds immense potential as it facilitates the production of two distinct spin‐filtering materials from a unified system. In overall, the significant findings achieved using these robust and easily synthesized MOF crystals without the requirement for chiral medium represent a crucial advancement in enhancing the effectiveness of spin filtering materials to produce spintronic devices.

Dual Signature of Chirality Induced Spin Selectivity through Spontaneous Resolution of 2D Metal-Organic Frameworks.

The Chiral-Induced Spin Selectivity (CISS) effect has emerged as a fascinating phenomenon within the realm of electron's spin manipulation, showcasing a unique interplay between electron's spin and molecular chirality. Subsequent to its discovery, researchers have been actively involved in exploring the new chiral molecules as effective spin filters. In the realm of observing the CISS effect, the conventional approach has mandated the utilization of two distinct enantiomers of chiral molecules. However, this present study represents a significant advancement by demonstrating the ability to control both spin states of electrons in a single system. In this work, we have demonstrated the preparation of chiral metal-organic frameworks (MOFs) via a "spontaneous resolution" process, obviating the requirement for chiral sources. Remarkably, this work signifies the first instance of achieving dual signature of spin selectivity from a single and exclusively achiral system through a spontaneous resolution process. This holds immense potential as it facilitates the production of two distinct spin-filtering materials from a unified system. In overall, the significant findings achieved using these robust and easily synthesized MOF crystals without the requirement for chiral medium represent a crucial advancement in enhancing the effectiveness of spin filtering materials to produce spintronic devices.

Enantiomeric contributions to methamphetamine's bidirectional effects on basal and fentanyl-depressed respiration in mice

RationaleFentanyl remains the primary cause of fatal overdoses, and its co-use with methamphetamine (METH) is a growing concern. We previously demonstrated that racemic METH can either enhance or mitigate opioid-induced respiratory depression (OIRD) dependent upon whether a low or high dose is administered. The optical isomers of METH, dextromethamphetamine (d-METH) and levomethamphetamine (l-METH), differ substantially in their selectivity and potency to activate various monoamine (MA) receptors, and these pharmacological differences may underlie the bidirectional effects of the racemate. Since it is unknown which of METH's MA receptor mechanisms mediate these respiratory effects, examination of METH's pharmacologically distinct enantiomers may provide insight into treatment targets for OIRD. MethodsThe two optical isomers of METH, d-METH and l-METH, were tested in adult male mice to determine their effects on basal and fentanyl-depressed respiratory frequency, tidal volume, and minute ventilation (MVb; i.e., respiratory frequency x tidal volume) using whole-body plethysmography. ResultsWhen tested at dose ranges of 1.0–10 mg/kg, d-METH elevated MVb and l-METH decreased basal MVb. A dose of 30 mg/kg l-METH increased basal MVb. Under fentanyl-depressed conditions, the bidirectional effects of racemic METH were observed with d-METH treatment while l-METH significantly exacerbated OIRD at 1.0 and 3.0 mg/kg. Conclusionsd-METH and l-METH differentially contribute to the bidirectional respiratory modulation observed by the racemate, with d-METH exhibiting predominantly stimulatory effects and l-METH exhibiting primarily depressant effects depending on dose.

Distinct Effects of Methamphetamine Isomers on Limbic Norepinephrine and Dopamine Transmission in the Rat Brain.

Methamphetamine (METH) is a psychostimulant that primarily exerts its effects on the catecholamine (dopamine (DA) and norepinephrine (NE)) systems, which are implicated in drug addiction. METH exists as two distinct enantiomers, dextrorotatory (d) and levorotatory (l). In contrast to d-METH, the major component of illicit METH used to induce states of euphoria and alertness, l-METH is available without prescription as a nasal decongestant and has been highlighted as a potential agonist replacement therapy to treat stimulant use disorder. However, little is known regarding l-METH's effects on central catecholamine transmission and behavior. In this study, we used fast-scan cyclic voltammetry to elucidate how METH isomers impact NE and DA transmission in two limbic structures, the ventral bed nucleus of the stria terminalis (vBNST) and nucleus accumbens (NAc), respectively, of anesthetized rats. In addition, the dose-dependent effects of METH isomers on locomotion were characterized. d-METH (0.5, 2.0, 5.0 mg/kg) enhanced both electrically evoked vBNST-NE and NAc-DA concentrations and locomotion. Alternatively, l-METH increased electrically evoked NE concentration with minimal effects on DA regulation (release and clearance) and locomotion at lower doses (0.5 and 2.0 mg/kg). Furthermore, a high dose (5.0 mg/kg) of d-METH but not l-METH elevated baseline NE and DA concentrations. These results suggest mechanistic differences between NE and DA regulation by the METH isomers. Moreover, l-METH's asymmetric regulation of NE relative to DA may have distinct implications in behaviors and addiction, which will set the neurochemical framework for future studies examining l-METH as a potential treatment for stimulant use disorders.

Technical Advances in the Chiral Separation of Anti-diabetic Drugs Using Analytical and Bio-analytical Methods: A Comprehensive Review

Abstract:Chirality seems to be a pivotal technique in the field of science. Research teams are quite well versed in empirical separation, however, at the same time, they are clueless about the evolution of chiral separation. As per the guidelines of the United States Food and Drug Administration (US FDA), chiral drugs must be untangled before they are sold to the public. Stereogenic separation has gained prominence during the last 10 decades due to the disparate biological function of enantiomers in the stereogenic environment. Chiral drugs exhibit a wide range of bioavailability, distribution, and pharmacodynamic properties concomitantly they exert divergent pharmacological and toxicological properties. Enantiomeric chiral products could be considered safe and potent in combating various diseases including metabolic diseases like diabetes. Several studies have delineated the development of a novel analytical and bioanalytical method to detect/segregate/quantify chiral chemical components in medicinal chemistry. The same physicochemical characteristics of enantiomers have been proven to be beneficial to the estrangement of stereogenic compounds. Furthermore, the advancement of bioanalytical methods is also critical to shedding light on the destiny of distinct enantiomers in the biological environment. HPLC (High-Performance Liquid Chromatography) and CE (Capillary Electrophoresis) have been the most commonly employed separation techniques. But the technical advances are required to enhance the efficiency of detection and quantification of chiral molecules on a large scale. The current review delineates the need for the chiral separation of stereogenic antidiabetic drug compounds with technical advances. Furthermore, this research is focused on the enantioseparation of chiral antidiabetic drugs and a brief overview of the analytical and bioanalytical methods conducted on distant chiral antidiabetic drugs to improve the efficiency of chiral separation.

Enhanced chiroptical activity with slotted high refractive index dielectric nanodisks

In this paper we employ finite difference time-domain (FDTD) calculations to demonstrate the enhancement of chiroptical activity in high refractive index dielectric slotted nanodisks. The chiral enhancement mechanism consists of pairing the electric and magnetic modes of the slit cavity with the resonances of the rest of the disk, i.e., the weak chiroptical activity ($\ensuremath{\sim}{10}^{\ensuremath{-}1}$) inside the chiral gap region (which is chiral itself) is enhanced through the interaction with the electric and magnetic resonances in the nanodisk. These results are extended to a two-dimensional periodic arrangement of slotted nanosdisks forming a metasurface. The chiral electromagnetic near field at the slotted region can be harnessed for increasing the asymmetry in energy absorption of circularly polarized light (CPL). This chiral enhancement makes this novel metasurface useful for sensing or to control the optical forces that can be exerted on chiral molecules placed in those slotted regions. The latter can be relevant to the pharmaceutical industry since distinct enantiomers of racemic drugs frequently exhibit different biological activities.

Acute Aerobic Exercise Leads to Increased Plasma Levels of R- and S-β-Aminoisobutyric Acid in Humans.

Recently, it was suggested that β-aminoisobutyric acid (BAIBA) is a myokine involved in browning of fat. However, there is no evidence for an acute effect of exercise supporting this statement and the metabolic distinct enantiomers of BAIBA were not taken into account. Concerning these enantiomers, there is at this point no consensus about resting concentrations of plasma R- and S-BAIBA. Additionally, a polymorphism of the alanine - glyoxylate aminotransferase 2 (AGXT2) gene (rs37369) is known to have a high impact on baseline levels of total BAIBA, but the effect on the enantiomers is unknown. Fifteen healthy recreationally active subjects, with different genotypes of rs37369, participated in a randomized crossover trial where they exercised for 1 h at 40% of Ppeak or remained at rest. Plasma samples were analyzed for R- and S-BAIBA using dual column HPLC-fluorescence. The plasma concentration of baseline R-BAIBA was 67 times higher compared to S-BAIBA (1734 ± 821 vs. 29.3 ± 7.8 nM). Exercise induced a 13 and 20% increase in R-BAIBA and S-BAIBA, respectively. The AGXT2 rs37369 genotype strongly affected baseline levels of R-BAIBA, but did not have an impact on baseline S-BAIBA. We demonstrate that BAIBA should not be treated as one molecule, given (1) the markedly uneven distribution of its enantiomers in human plasma favoring R-BAIBA, and (2) their different metabolic source, as evidenced by the AGXT2 polymorphism only affecting R-BAIBA. The proposed function in organ cross talk is supported by the current data and may apply to both enantiomers, but the tissue of origin remains unclear.

Structural and Functional Insights into Cytochromes P450 11B1 and 11B2 Interaction with Ligands and Redox Partner Proteins

Human steroidogenic cytochrome P450 enzymes 11B1 (CYP11B1) and 11B2 (CYP11B2) generate cortisol and aldosterone, controlling stress/immune responses and blood pressure, respectively. Excessive cortisol production by CYP11B1 results in Cushing's disease, while aldosterone overproduction by CYP11B2 causes hypertension and cardiac disease. Treatment of each disease with drugs inhibiting the respective enzyme is impeded because CYP11B1 and CYP11B2 have 93% identical amino acid sequences and no structures of CYP11B1 are available to identify structural differences that could be exploited clinically. A two‐fold strategy is employed herein to support the development of more selective treatment options for Cushing's and hypertension. First, structural differences between human CYP11B1 and CYP11B2 were identified. The first X‐ray structure of human CYP11B1 was solved, doing so in complex with the non‐selective inhibitor fadrozole. Comparison with a previous CYP11B2 structure also binding fadrozole revealed large differences in inhibitor orientation in the respective active sites. The two CYP11B enzymes bind distinct enantiomers of fadrozole, with CYP11B1 binding (S)‐fadrozole and CYP11B2 binding (R)‐fadrozole. Knowledge of the distinct active site architectures will facilitate structure‐based drug design for the treatment of Cushing's and hypertension. A second strategy explores the concept of selective inhibition of CYP11B enzymes interactions with their redox partner protein adrenodoxin (Adx). Binding assays revealed that adrenodoxin binding on the CYP11B2 surface significantly increases CYP11B2 affinity for its substrate in the distant active site, with much less effect on CYP11B1. Any differences in the protein/protein interaction might be exploited to provide an orthogonal approach for selective inhibition of CYP11B enzymes. A combination of structural and functional studies is thus used to identify similarities and differences in CYP11B interactions with Adx and with ligands to facilitate the design of compounds useful in the treatment of Cushing's disease and hypertension.Support or Funding InformationX‐ray data were collected at the Stanford Synchrotron Radiation Lightsource (SSRL). The SSRL Structural Molecular Biology Program is supported by the US Department of Energy Office of Biological and Environmental Research and by the US National Institutes of Health (NIH), National Center for Research Resources, Biomedical Technology Program and the National Institute of General Medical Sciences. This research was funded by R37 GM 076343 and startup funds from the University of MichiganThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Structural and stereochemical diversity in prenylated indole alkaloids containing the bicyclo[2.2.2]diazaoctane ring system from marine and terrestrial fungi.

Covering: up to February 2017 Various fungi of the genera Aspergillus, Penicillium, and Malbranchea produce prenylated indole alkaloids possessing a bicyclo[2.2.2]diazaoctane ring system. After the discovery of distinct enantiomers of the natural alkaloids stephacidin A and notoamide B, from A. protuberus MF297-2 and A. amoenus NRRL 35660, another fungi, A. taichungensis, was found to produce their diastereomers, 6-epi-stephacidin A and versicolamide B, as major metabolites. Distinct enantiomers of stephacidin A and 6-epi-stephacidin A may be derived from a common precursor, notoamide S, by enzymes that form a bicyclo[2.2.2]diazaoctane core via a putative intramolecular hetero-Diels-Alder cycloaddition. This review provides our current understanding of the structural and stereochemical homologies and disparities of these alkaloids. Through the deployment of biomimetic syntheses, whole-genome sequencing, and biochemical studies, a unified biogenesis of both the dioxopiperazine and the monooxopiperazine families of prenylated indole alkaloids constituted of bicyclo[2.2.2]diazaoctane ring systems is presented.

R(-)-O-desmethylangolensin is the main enantiomeric form of daidzein metabolite produced by human in vitro and in vivo

After ingestion, human intestinal bacteria transform daidzein into dihydrodaidzein, which can be further metabolised to O-desmethylangolensin. This metabolite, unlike daidzein, has a chiral centre and can therefore occur as two distinct enantiomers; however, it is unclear which enantiomer is present in humans. The aim of this study was to define in vitro and in vivo the structure of O-desmethylangolensin and then to evaluate its pharmacokinetic parameters. Daidzein metabolism was preliminarily investigated in anaerobic batch cultures inoculated with mixed faecal bacteria from O-desmethylangolensin producer volunteers. The transformation was monitored by liquid chromatography-mass spectrometry and a chiral column was used to distinguish dihydrodaidzein and O-desmethylangolensin enantiomers. These were purified, analysed by circular dichroism and the results established R(-)-O-desmethylangolensin as the main product (enantiomer excess 91%). However, both dihydrodaidzein enantiomers were detected. Similar results were obtained by in vivo trials. The in vitro formation of O-desmethylangolensin seems to be directly correlated with the number of transforming microorganisms. This correlation was found in vivo for tmax but not for other pharmacokinetic indexes. The pharmacokinetics of daidzein, dihydrodaidzein and O-desmethylangolensin were then evaluated in 11 healthy adult O-desmethylangolensin producers after the single administration of soy milk containing 100mg daidzein. The conjugated forms of daidzein, dihydrodaidzein and O-desmethylangolensin represent more than 90 and 95% of the plasmatic and urinary forms, respectively. The Cmax, tmax and half-life of O-desmethylangolensin in plasma were 62±53nM, 28±11 and 15±6h, respectively. Relevant inter-individual variations were observed as indicated by the high standard deviations.

A Fragment-Based Approach toward Substituted Trioxa[7]helicenes

A series of novel substituted trioxa[7]helicenes have been successfully prepared by a one-pot palladium catalyzed C-H arylation reaction starting from readily prepared dibenzofuran fragments. The dinitro-substituted helicene was analyzed by X-ray crystallography revealing the occurrence of two distinct enantiomers in the asymmetric unit, which forms interesting supramolecular motifs in the crystal, based on weak H-bonding interactions.

Revealing Atropisomer Axial Chirality in Drug Discovery

An often overlooked source of chirality is atropisomerism, which results from slow rotation along a bond axis due to steric hindrance and/or electronic factors. If undetected or not managed properly, this time-dependent chirality has the potential to lead to serious consequences, because atropisomers can be present as distinct enantiomers or diastereoisomers with their attendant different properties. Herein we introduce a strategy to reveal and classify compounds that have atropisomeric chirality. Energy barriers to axial rotation were calculated using quantum mechanics, from which predicted high barriers could be experimentally validated. A calculated rotational energy barrier of 20 kcal mol(-1) was established as a suitable threshold to distinguish between atropisomers and non-atropisomers with a prediction accuracy of 86%. This methodology was applied to subsets of drug databases in the course of which atropisomeric drugs were identified. In addition, some drugs were exposed that were not yet known to have this chiral attribute. The most valuable utility of this tool will be to predict atropisomerism along the drug discovery pathway. When used in concert with our compound classification scheme, decisions can be made during early discovery stages such as "hit-to-lead" and "lead optimization," to foresee and validate the presence of atropisomers and to exercise options of removing, further stabilizing, or rendering the chiral axis of interest more freely rotatable via SAR design, thereby decreasing this potential liability within a compound series. The strategy can also improve drug development plans, such as determining whether a drug or series should be developed as a racemic mixture or as an isolated single compound. Moreover, the work described herein can be extended to other chemical fields that require the assessment of potential chiral axes.

Novel Pirinixic Acids as PPARα Preferential Dual PPARα/γ Agonists

AbstractPirinixic acid is a moderate agonist of both the alpha and the gamma subtype of the peroxisome proliferator activated receptor (PPAR). Previously, we have shown that α‐alkyl substitution leads to balanced low micromolar‐active dual agonists of PPARα and PPARγ. Taking α‐hexyl pirinixic acid as a new scaffold, we further optimized PPAR activity by enlargement of the lipophilic backbone by substituting the 2,3‐dimethylphenyl with biphenylic moieties. Such a substitution pattern had only minor impact on PPARγ activity but further increased PPARα activity leading to nanomolar activities. Supporting docking studies proposed that the (R)‐enantiomer should fit the PPARα ligand‐binding pocket better and thus be more active than the (S)‐enantiomer. Single enantiomers of selected active analogues were then prepared by enantio‐selective synthesis and enantio‐selective preparative HPLC, respectively. Biological data for the distinct enantiomers fully corroborated the docking experiments and substantiate a stereochemical impact on PPAR activation.

ChemInform Abstract: An Analogue of the Antioestrogen Tamoxifen of Sufficient Rigidity to Exist as Distinct Enantiomers: Synthesis and Conformational Dynamics Studies.

AbstractThe key step in the synthesis of the conformationally constrained analogue (X) of the drug tamixofen (I) is a novel method for introduction of a methyl group into the aromatic ring of benzosuberone by enolate oxygen directed lithiation ((II) → (IV)).

An analogue of the antioestrogen tamoxifen of sufficient rigidity to exist as distinct enantiomers: synthesis and conformational dynamics studies

The conformationally constrained tamoxifen analogue 1-methyl-8-phenyl-4-[4-[2-(dimethylamino)ethoxy]phenyl-6,7-dihydro-5- H -benzocycloheptane has been synthesised. A key synthetic step is a novel method for introduction of a methyl group into the aromatic ring of bnenzosuberone by enolate oxygen directed lithiation. Conformational studies were carried out on the methoxy of the above compound. Dynamic 1H NMR revealed a free energy barrier to racemisation of enantiomeric atropisomers, ΔG ‡ - 20 (±1) kcal mol −1. It could be separated by chromatography at −5°C on (+)-poly(triphenylmethylmethacryate) into enantiomers which racemised with t 1 2 1.8 h at −5.2°C corresponding to ΔG ‡-20.9 20.9 kcal mol −1. The difficulties in designing analogues having a greater degree of conformational constraint are discussed.