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Single Enantiomers (single + enantiomer)

Distribution by Scientific Domains

Chemistry	47%
Medical Sciences	41%

Selected Abstracts

Novel Pirinixic Acids as PPAR, Preferential Dual PPAR,/, Agonists

MOLECULAR INFORMATICS, Issue 5 2009
Heiko Zettl
Abstract Pirinixic 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 ,-alkyl substitution leads to balanced low micromolar-active dual agonists of PPAR, and PPAR,. Taking ,-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 PPAR, activity but further increased PPAR, activity leading to nanomolar activities. Supporting docking studies proposed that the (R)-enantiomer should fit the PPAR, 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. [source]

Chiral HPLC separation and CD spectra of the enantiomers of the alkaloid tacamonine and related compounds

CHIRALITY, Issue 10 2001
Salvatore Caccamese
Abstract The HPLC enantiomeric separation of racemic indole alkaloids tacamonine, 17,-hydroxytacamonine, deethyleburnamonine, and vindeburnol was accomplished using Chiralpak AD and Chiralcel OD as chiral stationary phases. Small structural differences affect the enantioselectivity ability of these phases. Single enantiomers of tacamonine and vindeburnol were isolated by semipreparative HPLC and their CD spectra and optical rotations were measured. Chirality 13:691,693, 2001. © 2001 Wiley-Liss, Inc. [source]

2-Methylisocitrate lyases from the bacterium Escherichia coli and the filamentous fungus Aspergillus nidulans

FEBS JOURNAL, Issue 12 2001
Characterization, comparison of both enzymes
In Escherichia coli and Aspergillus nidulans, propionate is oxidized to pyruvate via the methylcitrate cycle. The last step of this cycle, the cleavage of 2-methylisocitrate to succinate and pyruvate is catalysed by 2-methylisocitrate lyase. The enzymes from both organisms were assayed with chemically synthesized threo -2-methylisocitrate; the erythro -diastereomer was not active. 2-Methylisocitrate lyase from E. coli corresponds to the PrpB protein of the prp operon involved in propionate oxidation. The purified enzyme has a molecular mass of approximately 32 kDa per subunit, which is lower than those of isocitrate lyases from bacterial sources (, 48 kDa). 2-Methylisocitrate lyase from A. nidulans shows an apparent molecular mass of 66 kDa per subunit, almost equal to that of isocitrate lyase of the same organism. Both 2-methylisocitrate lyases have a native homotetrameric structure as identified by size-exclusion chromatography. The enzymes show no measurable activity with isocitrate. Starting from 250 mm pyruvate, 150 mm succinate and 10 µm PrpB, the enzymatically active stereoisomer could be synthesized in 1% yield. As revealed by chiral HPLC, the product consisted of a single enantiomer. This isomer is cleaved by 2-methylisocitrate lyases from A. nidulans and E. coli. The PrpB protein reacted with stoichiometric amounts of 3-bromopyruvate whereby the activity was lost and one amino-acid residue per subunit became modified, most likely a cysteine as shown for isocitrate lyase of E. coli. PrpB exhibits 34% sequence identity with carboxyphosphoenolpyruvate phosphonomutase from Streptomyces hygroscopicus, in which the essential cysteine residue is conserved. [source]

An introduction to enantiomers in psychopharmacology

HUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue S2 2001
Brian E. Leonard
Abstract There is growing scientific, clinical, commercial and regulatory recognition that enantiomers offer benefits over racemates in the management of psychiatric diseases as well as in clinical medicine generally. However, relatively few studies consider enantiomers' individual characteristics. This review considers some of the clinical benefits associated with using stereochemically pure drugs in psychiatric conditions other than depression. A review of the evidence shows that enantiomers offer four main benefits. Firstly, using a single enantiomer may allow a reduction in total dose, while maintaining or improving outcomes. For example, (+)-nefopam's antinociceptive activity is greater than that produced by both the racemate and (,)-nefopam, but with the same level of acute toxicity. Thus, a single enantiomer may offer greater efficacy, dose for dose, than the racemate. Secondly, assessing dose,response relationships is simpler. There is no reason to suppose that a racemate will necessarily contain the isomers' optimum therapeutic ratio, that one of the isomers will be inactive or that the enantiomers' dose,response curves will coincide. For example, the dose,response relationship for the induction of catalepsy in the rat by thioridazine suggested that the racemate was around 12 times more potent than (+)-thioridazine and three times more potent than (,)-thioridazine, when considering the actual concentrations in the striatum. Thirdly, using a single enantiomer may reduce pharmacokinetic and pharmacodynamic variability between patients. For example, the coefficients of variation for some of methadone's pharmacokinetic parameters may reach 70%, which might have clinical consequences. Finally, using a single enantiomer may reduce toxicity arising from the therapeutically inactive stereoisomer. For example, the single enantiomers of bupivacaine and ropivacaine are significantly less cardiotoxic than their respective racemates. This review illustrates why stereochemistry should be considered when assessing the toxicology, pharmacokinetics, metabolism and efficacy of a racemate. Indeed, the differences may be so marked that achiral analyses may be misleading, and clinicians should consider prescribing an enantiomer whenever possible. In many cases, prescribing a single enantiomer improves the benefit:risk ratio. Finally, there is no reason to suppose that a racemate's characteristics will apply to the constituent enantiomers. Copyright © 2001 John Wiley & Sons, Ltd. [source]

Enantiomeric antidepressant drugs should be considered on individual merit

HUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue S2 2001
Pierre Baumann
Abstract Many antidepressants have been introduced as racemic drugs, the enantiomers of which may differ in some of their pharmacodynamic and pharmacokinetic properties. This review argues that each enantiomer of a chiral antidepressant should be evaluated according to its individual characteristics rather than by extrapolation from the racemate, or by assumptions based on the stereoselective characteristics of other enantiomeric drugs. For example, in some cases the enantiomers' pharmacodynamic and therapeutic properties can be complementary, which suggests that the racemate should be used clinically. In other cases where enantiomers show qualitatively similar but quantitatively different properties to the racemate, using a single enantiomer might be more appropriate. In yet further cases, a distomer may induce the metabolism of the eutomer, enantiomers may be metabolised by different enzymes, there may be a different profile of drug,drug interactions, and therapeutic drug monitoring may be simpler. Therefore, this review exemplifies the principle that each enantiomer of a chiral antidepressant should be evaluated according to its individual pharmacological, pharmacokinetic and pharmacogenetic characteristics. These factors are discussed in relation to five chiral antidepressants: trimipramine, mianserin, mirtazapine, fluoxetine and citalopram. It is hoped that an appreciation of the stereoselective differences between enantiomers will facilitate improvements in the benefit:risk ratio of drugs used in the management of depression. Copyright © 2001 John Wiley & Sons, Ltd. [source]

Lower critical solution temperatures of thermo-responsive poly(N -isopropylacrylamide) copolymers with racemate or single enantiomer groups

POLYMER INTERNATIONAL, Issue 2 2009
Peng-Fei Li
Abstract BACKGROUND: Thermo-responsive copolymers with racemate or single enantiomer groups are attracting increasing attention due to their fascinating functional properties and potential applications. However, there is a lack of systematic information about the lower critical solution temperature (LCST) of poly(N -isopropylacrylamide)-based thermo-responsive chiral recognition systems. In this study, a series of thermo-responsive chiral recognition copolymers, poly[(N -isopropylacrylamide)- co -(N -(S)- sec -butylacrylamide)] (PN- S -B) and poly[(N -isopropylacrylamide)- co -(N -(R,S)- sec -butylacrylamide)] (PN- R,S -B), with different molar compositions, were prepared. The effects of heating and cooling processes, optical activity and amount of chiral recognition groups in the copolymers on the LCSTs of the prepared copolymers were systematically studied. RESULTS: LCST hysteresis phenomena are found in the phase transition processes of PN- S -B and PN- R,S -B copolymers in a heating and cooling cycle. The LCSTs of PN- S -B and PN- R,S -B during the heating process are higher than those during the cooling process. With similar molar ratios of N -isopropylacrylamide groups in the copolymers, the LCST of the copolymer containing a single enantiomer (PN- S -B) is lower than that of the copolymer containing racemate (PN- R,S -B) due to the steric structural difference. The LCSTs of PN- R,S -B copolymers are in inverse proportion to the molar contents of the hydrophobic R,S -B moieties in these copolymers. CONCLUSION: The results provide valuable guidance for designing and fabricating thermo-responsive chiral recognition systems with desired LCSTs. Copyright © 2008 Society of Chemical Industry [source]

Four differently substituted 2-aryl-2,3,4,5-tetrahydro-1H -1,4-epoxy-1-benzazepines: hydrogen-bonded structures in one, two and three dimensions

ACTA CRYSTALLOGRAPHICA SECTION C, Issue 9 2009
Sandra L. Gómez
In (2RS,4SR)-7-chloro-2- exo -(2-chloro-6-fluorophenyl)-2,3,4,5-tetrahydro-1H -1,4-epoxy-1-benzazepine, C16H12Cl2FNO, (I), molecules are linked into chains by a single C,H...,(arene) hydrogen bond. (2RS,4SR)-2- exo -(2-Chloro-6-fluorophenyl)-2,3,4,5-tetrahydro-1H -1,4-epoxy-1-benzazepine, C16H13ClFNO, (II), is isomorphous with compound (I) but not strictly isostructural with it, as the hydrogen-bonded chains in (II) are linked into sheets by an aromatic ,,, stacking interaction. The molecules of (2RS,4SR)-7-methyl-2- exo -(4-methylphenyl)-2,3,4,5-tetrahydro-1H -1,4-epoxy-1-benzazepine, C18H19NO, (III), are linked into sheets by a combination of C,H...N and C,H...,(arene) hydrogen bonds. (2S,4R)-2- exo -(2-Chlorophenyl)-2,3,4,5-tetrahydro-1H -1,4-epoxy-1-benzazepine, C16H14ClNO, (IV), crystallizes as a single enantiomer and the molecules are linked into a three-dimensional framework structure by a combination of one C,H...O hydrogen bond and three C,H...,(arene) hydrogen bonds. [source]

A consideration of the patentability of enantiomers in the pharmaceutical industry in the United States,

CHIRALITY, Issue 6 2008
Chris P. Miller
Abstract During the last thirty years, concern over stereoselectivity of drug action has drawn a great deal of interest within the pharmaceutical field due to an improved understanding of the pharmacology and pharmacokinetics of enantiomers. Developing single enantiomers versus racemates or introducing a single enantiomer following the development of the racemic mixture appears to be the new trend. The intellectual property status of single enantiomers from racemates may be unclear. Drug discoverers and patent attorneys must examine the examples of the past to establish an appropriate pathway towards the development and intellectual property protection of chiral drugs. The review will focus on the patenting of an enantiomer in view of the prior art disclosure for the racemic mixture. Chirality, 2008. © 2008 Wiley-Liss, Inc. [source]

Advances in the enantioseparation of second-generation antidepressant drugs by electrodriven methods

ELECTROPHORESIS, Issue 1 2006
Roberto Mandrioli
Abstract Stereochemistry is steadily increasing in importance in the development of new drugs, and the availability of pure enantiomer drugs can make therapy safer and more efficacious. In particular, almost all second-generation antidepressant drugs possess one or more chiral centres; however, only some of them are administered as single enantiomers. A fundamental part of the quality control of pharmaceutical formulations is the determination of enantiomeric excess and enantiomeric purity; this is also important for the therapeutic drug monitoring of depressed patients. For this purpose, efficient and reliable analytical methods are needed and electrodriven techniques (most of all CE, CEC and MEKC) are very efficient and inexpensive candidates for the role. In this review, the enantioselective electrodriven methods available for the analysis of second-generation antidepressant are presented and discussed. In particular, the following pharmacological classes of antidepressants will be considered: selective serotonin reuptake inhibitors (fluoxetine, citalopram, paroxetine, sertraline); norepinephrine reuptake inhibitors (reboxetine); serotonin and norepinephrine reuptake inhibitors (venlafaxine, milnacipran, duloxetine); and noradrenergic and specific serotonergic antidepressants (mirtazapine). [source]

The therapeutic promise of single enantiomers: introduction

HUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue S2 2001
Irving W. Wainer
Abstract This review uses several examples drawn from the literature to show how using active enantiomers as therapeutic agents may yield several benefits, including more predictable pharmacokinetics, more accurate drug monitoring and enhanced tolerability. As a result of these benefits, the therapeutic use of single enantiomers will become increasingly important not only in psychopharmacology, but in medicine generally. Indeed, over the early years of the new millennium, the therapeutic use of single active enantiomers is set to redefine the benefit,risk ratio in the management of many common conditions. Copyright © 2001 John Wiley & Sons, Ltd. [source]

An introduction to enantiomers in psychopharmacology

Asymmetric Lithiation of Boron Trifluoride-Activated Aminoferrocenes: An Experimental and Computational Investigation

ADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 11-12 2010
Costa Metallinos
Abstract Tertiary aminoferrocenes complexed to boron trifluoride (BF3) are shown to undergo asymmetric lithiation with alkyllithiums in the presence of bulky chiral 1,2-diaminocyclohexane ligands. This reaction represents the first BF3 -activated asymmetric lithiation of a prochiral aromatic amine and the first such transformation to be mediated by a chiral diamine other than (,)-sparteine. The process provides rapid access to a broad range of enantiomerically enriched 2-substituted-1-aminoferrocenes, including derivatives with uncommon substitution patterns that are of interest in catalysis. The enantioselectivity of the process is high enough (87:13 to 91:9 er) to allow for isolation of single enantiomers of several products after simple recrystallization as either the free aminoferrocenes or their ammonium fluoroborate salts. Both antipodes of the planar chiral 2-substituted-1-aminoferrocene products are accessible, as confirmed by single crystal X-ray diffraction analysis of two compounds with opposite relative stereochemistry. Single-point calculation of thirty-two different transition states of the reaction at the M06-2X/6-311+g(2d,2p) level produced a computational model that correctly predicted both the sense and extent of chiral induction. Three factors appeared to play important roles in determining enantioinduction during lithiation of BF3 -complexed tertiary aminoferrocenes: (i) the maintenance of a highly organized eight-membered ring transition state; (ii) the existence of a strong Li,,,F contact which placed the chiral diamine ligand in close proximity to the ferrocene substrate; (iii) the orientation of the sterically demanding N -alkyl groups of the chiral diamine additives, either away or towards, the aminoferrocene and the alkyllithium. The model may serve as a predictive tool for the rational design of new ligands for this and related asymmetric lithiations. [source]

Three-Dimensional Pharmacology, a Subject Ranging from Ignorance to Overstatements

BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 5 2003
Bertil Waldeck
Nevertheless, chiral drugs have been developed and used as racemates, neglecting the fact that they comprise mixtures of two or more compounds which may have quite different pharmacological properties. A very limited access to pure enantiomers in the past has been responsible for this unsatisfactory state of affairs. During the last 20 years, significant achievements have made it possible to perform stereoselective synthesis and analysis. Today, novel chiral drugs are as a rule developed as single enantiomers. Yet, studies of old racaemic drugs are still designed, performed and published without mention of the fact that two or more compounds are involved. In recent years, a number of old racaemic drugs have been re-evaluated and re-introduced into the clinical area as the pure, active enantiomer (the eutomer). While in principle correct, the clinical benefit of this shift from a well established racaemate to a pure enantiomer often seems to be limited and sometimes exaggerated. Racaemic drugs with a deleterious enantiomer that does not contribute to the therapeutic effect (the distomer), may have been sorted out in the safety evaluation process. However, in the future any pharmacological study of racaemic drugs must include the pure enantiomers. This will generate new, valuable information on stereoselectivity in drug action and interaction. [source]

Molecular impact of MinK on the enantiospecific block of IKs by chromanols

BRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2000
C Lerche
Slowly activating IKs (KCNQ1/MinK) channels were expressed in Xenopous oocytes and their sensitivity to chromanols was compared to homomeric KCNQ1 channels. To elucidate the contribution of the ,-subunit MinK on chromanol block, a formerly described chromanol HMR 1556 and its enantiomer S5557 were tested for enantio-specificity in blocking IKs and KCNQ1 as shown for the single enantiomers of chromanol 293B. Both enantiomers blocked homomeric KCNQ1 channels to a lesser extent than heteromeric IKs channels. Furthermore, we expressed both WT and mutant MinK subunits to examine the involvement of particular MinK protein regions in channel block by chromanols. Through a broad variety of MinK deletion and point mutants, we could not identify amino acids or regions where sensitivity was abolished or strikingly diminished (>2.5 fold). This could indicate that MinK does not directly take part in chromanol binding but acts allosterically to facilitate drug binding to the principal subunit KCNQ1. British Journal of Pharmacology (2000) 131, 1503,1506; doi:10.1038/sj.bjp.0703734 [source]