Stereochemical Factors Research Articles

Spiropyrans: Structural Features and Photochemical Properties

Abstract It has been shown, that in the ground state the Cspiro−O bond, which is broken upon photoexcitation, is weakened and elongated because of specific orbital n-s* interactions. They become stronger in excited photochemically active state, thus facilitating the rupture of this bond. The nature of products of spiropyran photoconversion and stereochemical factors of its stabilization have been investigated.

Synthesis, structural, conformational and pharmacological study of new fentanyl derivatives of the camphidine system

AbstractA series of N‐phenethyl‐8‐β‐amidocamphidines 4a‐f (3‐phenethyl‐8‐β‐(N‐arylamido)‐3‐azabicyclo‐[3.2.1]octane) has been designed, synthesized and stereochemically characterized as semirigid analogous of the 4‐anilidopiperidine analgesics in an attempt to study the influence of certain stereochemical factors on analgesia in this class of compounds. In deuteriochloroform and deuteriobenzene solution, compounds 4a‐f display the same preferred conformation. The cyclopentane and piperidine rings adopt an envelope and distorted chair conformation respectively flattened at N‐3, with the N and C‐8 substituents in equatorial and axial positions with respect to the piperidine ring.In vivo pharmacological testing demonstrated that compounds 4a‐f were inactive in the analgesic test, with the exception of compound 4f which showed an ED50 of 250 mg/kg p.o.

Contribution of H‐Bonding to the Preference of PlatinumAnti‐Tumour Drugs for Particular Bases and Particular Cross‐Links

The stereochemical factors that influence the tendencies for sequence specific binding of platinum antitumour drugs to DNA are examined. The NHs of the platinum-amine moiety can form hydrogen bonds to the O6 of guanine or to a phosphate oxygen of DNA. Modelling the stereochemistry of the NH atoms can lead to compounds with a strong preference for forming one type of adduct with DNA.

Quantitative structure-activity relationships (QSAR) and odour

An introduction to QSAR is given, in which the three main classes of molecular descriptors—hydrophobic, electronic and steric—are discussed. These can be applied to continuous biological data through the use of multiple regression analysis, or to discontinuous data by pattern recognition techniques. A review is given of published QSAR work in the field of olfaction. These cover studies of the character, threshold and intensity of odour, and include both multiple regression analysis and pattern recognition methods, as well as some molecular modelling. A new QSAR study is reported of the benzaldehydelikeness of odour of 25 alkyl-substituted benzaldehydes and nitobenzenes, and benzonitrile. An excellent correlation was found with two molecular connectivity parameters, indicating that in these compounds odour similarity is governed primarily by stereochemical factors.

Molecular recognition in biological systems: from activation to inhibition.

A fine-tuned system of molecular recognition is a fundamental feature of all biological processes. Although the basic principles of how molecular surfaces fit together in a complementary fashion have been established to a first approximation, the details of the interplay between electrostatic, steric, entropic and solvation effects are not well understood. To provide insight into the stereochemical factors that govern recognition and packing at protein interfaces, a host of biochemical and biophysical techniques have been applied. Perhaps the most widely used of these techniques are mutagenesis and crystallography, and when used together they have proved to be extremely powerful in defining the functional elements that are important in protein interactions. Using these protein-engineering techniques we have focused our studies on the role of molecular recognition in two important, but distinctly different, biological processes: ( 1) the role of molecular recognition in receptor activation, and (2) the stereochemical factors that define specificity and provide binding energy to inhibitors that are associated with their target proteinases. Our findings, discussed below, suggest that the conventional wisdom about specificity and binding needs to be rethought.

Stereochemical factors in the transport and binding of photosensitizers in biological systems and in photodynamic therapy

The uptake and biological activity of porphyrins and phthalocyanines in tumours were correlated with the geometrical features of the photosensitizer molecules. The data suggest that a critical distance of approximately 1.2 nm between oxygen atoms (originating in SO 3 −, COO − or OH substituents) characterizes a biologically active photosensitizer for photodynamic therapy. We propose that tubulin, which is available in large amounts during mitosis, is the main receptor molecule which binds these photosensitizers. Basic amino acid residues or tightly bound cations in tubulin or homologous proteins may act as binding sites on the receptor molecule.

Identification with liquid chromatography-ionspray mass spectrometry of the metabolites of the enantiomers N-methyl dextrorphan and N-methyl levorphanol after rat liver perfusion.

To gather more information on stereochemical factors in the hepatic disposition of organic cations, mass spectrometry coupled to liquid chromatography was used to determine the identity of the metabolites excreted in bile after isolated rat liver perfusions with the quaternary ammonium derivatives of the enantiomeric drugs dextrorphan and levorphanol. Ionspray mass spectrometry was chosen for its soft ionization and absence of thermal degradation of labile compounds. The drugs were labelled with a stable (2H) isotope and mixed with unlabelled drugs to create an artificial isotope pattern in the mass spectrum and facilitate the recognition of unknown metabolites. In mass spectra that were recorded under normal conditions, fragmentation was absent and metabolites of N-methyl dextrorphan and N-methyl levorphanol were visible as parent-ion 'doublets'. Collision-induced fragmentation studies were performed to support the identification of the metabolites. For N-methyl dextrorphan the glucuronide, the glutathione conjugate and the glucuronide of the N-demethylated metabolite were found in bile. For N-methyl levorphanol the glucuronide, the glutathione conjugate, the sulphate conjugate and the glucuronide of a hydroxylated N-methyl levorphanol were excreted in bile. Thus a remarkable stereoselectivity occurs in the metabolism of these quaternary ammonium compounds in the rat liver.

Ring‐opening reactions. 6. eliminative ring fission of aziridinium and azetidinium ions

AbstractThe reactivity ratio between the three‐ and four‐membered cyclic ammonium ions in ring‐opening elimination reactions was measured. The comparison with the analogous ratio obtained in a previous study on ring‐opening substitution reactions suggests a substantial difference in the effect of the stereochemical factors governing the two ring‐opening reactions and confirms the anomalous behaviour of small rings in the ring‐opening substitution reaction.

Diastereo- and enantio-selectivity in the Pictet–Spengler reaction

The factors that control the relative and absolute stereochemistry of 1,3-disubstituted and 1,2,3-trisubstituted tetrahydro-β-carbolines formed via the Pictet–Spengler reaction are discussed. In particular, the stereochemical factors that lead to the predominance of cis-1,3-disubstituted products under conditions of kinetic control are presented, with the aid of X-ray crystallographic data on a number of compounds; methods for assigning relative stereochemistry on the basis of NMR data are given; the mechanism by which racemisation can occur during the Pictet–Spengler reaction has also been studied, and procedures for eliminating this problem are given.

Clinical pharmacokinetics: current requirements and future perspectives from a regulatory point of view.

1. There is an increasing appreciation of the relevance of pharmacokinetics of drugs during evaluation of their safety for human clinical use. Regulatory requirements for clinical pharmacokinetic data have progressively evolved to emphasize and address these safety implications. 2. Historically the dose schedules usually recommended have been too high, often with serious consequences. Therefore, the need to establish reliable dose response (both therapeutic and toxic) relationships must be an important objective. 3. Concurrent developments in our understanding of the pharmacological effects (therapeutic or toxic) of metabolites, the interethnic and interindividual differences in drug responses and the toxicological aspects of drug chirality now provide compelling reasons for the roles of bioactivation, pharmacogenetics and stereochemical factors to be addressed in pharmacokinetic studies during the clinical development of drugs. 4. Apart from the traditional pharmacokinetic studies following single and multiple doses in healthy volunteers, patients and special subgroups, reliable dose-response curves for therapeutic and toxic effects must be established in well-designed controlled studies using a wide range of doses. Often, doses lower than those recommended have a much improved risk/benefit ratio. 5. Secondary pharmacology of the drug and its active metabolites must be defined for assessment of safety (adverse reactions and pharmacokinetic and pharmacodynamic drug-drug interactions) in high dose/concentration situations. 6. The enzyme systems responsible for the metabolism of a drug must be identified followed by rational investigations of drug-drug and drug-disease interactions both from the efficacy and safety viewpoints. Factors responsible for alterations in the functional expression of this enzyme system must be identified and the safety and efficacy implications of these findings at interethnic, inter- and intraindividual levels must be fully explored during all phases of the clinical development of the drug. This should lead to carefully designed patient subgroup-specific dose schedules which maximize the risk/benefit ratio for all patients. 7. Drugs operate in a chiral environment and, not surprisingly, enantiomers of a drug differ significantly in their pharmacokinetics and pharmacodynamics. The possibility of interactions between enantiomers of a drug and of enantioselective interactions should be examined. These should be thoroughly investigated and the decision to market a racemic mixture or one of its enantiomers must be justified. 8. Analysis of population pharmacokinetics offers an approach by which to examine the roles of various factors which are likely to be clinically relevant for the safe and effective use of drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

On the factors that affect the mode of cyclization of α-silyl radicals: A method for angular hydroxymethylation by the 5-exo cyclization

The steric and stereochemical factors which favor the 5-exo cyclization of a 5-substituted 2-sila-5-hexen-1-yl radical have been probed. This radical cyclization approach constitutes a highly efficient and convenient means for the stereospecfic introduction of an angular hydroxymethyl group.

Zacopride and its optical isomers produce stereoselective antagonism of a 2-methylserotonin discriminative stimulus

The serotonin 5-HT 3 receptor antagonist effects of zacopride and its optical isomers were evaluated in rats trained to discriminate 5.0 mg/kg of 2-methylserotonin (2-Me 5-HT) from saline in a 2-lever operant task. Zacopride and its enantiomers potently antagonized the 2-Me 5-HT stimulus; on the basis of 50% inhibition (ID 50) of drug lever responding the order of potency is S(−)-zacopride (ID 50 = 0.05 μg/kg) > (±)-zacropride (ID 50 = 0.60 μg/kg) > R(+-zacopride (ID 50 = 1.6 μg/kg). The stereoselectivity and potency ratio of zacopride's isomers for antagonizing the 2-Me 5-HT stimulus parallels their previously reported results in binding studies. It is concluded that zacopride's isomers produce antagonism of a 2-Me 5-HT stimulus by stereoselective interaction at 5-HT 3 receptors and that stereochemical factors are important in evaluating the stimulus properties of 5-HT 3 agents.

Synthesis of Heterocyclic Monomers Designed to Produce Conducting Polymer with Specific Redox Requisites and to Evaluate Stereochemical Factors Influencing the Conductivity

ABSTRACTAccording to the “spacer” strategy we have previously proposed the monomers candidate for providing conductive polymers endowed with special properties should contain the polymerogenic rings (pyrrole or thiophene), as terminal units, linked to a central π-conjugatively active frame; we describe how it is possible in this way to control the redox potentials E of the polymers derived from such monomers. This control is beneficial because it is possible to increase the E° value of polypyrrole-type systems and decreases the E° value of polythiophene-type systems. Also, the “spacer”may be further functionalised and, being remote from the polymerisation site, cannot alter the conductivity characteristics typical of the polymer derived from the parent heterocycle (pyrrole or thiophene): such a functionalisation may provide the final, tailored, conductive polymer with special properties (e.g. solubility). If the central ring, acting as a spacer, is formed linking two positions of a di-heterocycle with a saturated chain, it is possible to partially control the twist angle between the heterocyclic units. Crystal and molecular structures have shown that dipyrrole units further linked through the nitrogen atoms are quite sensitive to the central ring size. With respect to the conductivity of unsubstituted polypyrrolc, the conductivity of the polymers derived from such monomers is dependent from the twist angle between the rings. This result is relevant to describe conditions of conjugation between the heterocyclic units of a monomer required to produce upon doping a conductive polymer.

Molecular mechanics analysis of the stereochemical factors influencing monofunctional and bifunctional binding of cis-diamminedichloroplatinum(II) to adenine and guanine nucleobases in the sequences d(GpApGpG).cntdot.d(CpCpTpC) and d(GpGpApG).cntdot.d(CpTpCpC) of A- and B-DNA

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMolecular mechanics analysis of the stereochemical factors influencing monofunctional and bifunctional binding of cis-diamminedichloroplatinum(II) to adenine and guanine nucleobases in the sequences d(GpApGpG).cntdot.d(CpCpTpC) and d(GpGpApG).cntdot.d(CpTpCpC) of A- and B-DNATrevor W. HambleyCite this: Inorg. Chem. 1991, 30, 5, 937–942Publication Date (Print):March 1, 1991Publication History Published online1 May 2002Published inissue 1 March 1991https://doi.org/10.1021/ic00005a012RIGHTS & PERMISSIONSArticle Views64Altmetric-Citations57LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (765 KB) Get e-AlertsSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts

Structural and stereochemical relationships between Langmuir monolayers and calcium carbonate nucleation

The structural and stereochemical factors involved in the oriented nucleation of CaCO3 under compressed Langmuir monolayers have been studied by optical and electron microscopy, and X-ray and electron diffraction. The effect of headgroup charge, stereochemistry and changes in supersaturation have been investigated. At total (Ca)=9 mM, monolayers with carboxylate headgroups induce the oriented nucleation of calcite with the (11.0) axis perpendicular to the organic surface. At (Ca)=4.5 mM, oriented vaterite with the (00.1) axis normal to the monolayer, is deposited. The common features of these interactions are: Ca accumulation at the stearate headgroups, geometric matching of lattice distances (calcite only) and stereochemical correspondence between carboxylate and carbonate groups at the monolayer/crystal interface. In contrast, nucleation under positively charged octadecylamine monolayers was independent of (Ca) and gave vaterite aligned either along the (00.1) or (11.0) crystallographic axes. Although Ca binding is absent on these films, there is the possibility of stereochemical matching between bidentate binding of bicarbonate and the corresponding anions in the (00.1) and (11.0) crystal surfaces. Crystals (calcite and vaterite) grown under liquid-phase stearate monolayers were of increased size and uniformity in particle size distribution compared with those nucleated under fully compressed films. CaCO3 crystallization under octadecanol monolayers was inhibited and crystals grown in the presence of cholesterol films were the same as in the control experiments.

Stabilities of ternary complexes of cobalt(II), nickel(II), copper(II) and zinc(II) involving aminopolycarboxylic acids and heteroaromaticN-bases as primary ligands and benzohydroxamic acid as a secondary ligand

Stability constants of binary (ML, ML2) and ternary (MAL) complexes, where M=CoII, NiII, CuII or ZnII; A=iminodiacetic acid (ida), N-methyliminodiacetic acid (mida), anthranilatediacetic acid (ada), nitrilotriacetic acid (nta), 2,2′-bipyridine (bipy) andortho-phenanthroline (phen); LH=benzohydroxamic acid, have been determined at 25°C and an ionic strength of 0.1 M KNO3 by the Irving-Rossotti technique. The results are explained on the basis of astatistical factors; electrostatic effects, steric hindrance, change of electronegativity of the contral metal depending upon the σ-basic and π-acidic character of the primary ligands and also stereochemical factors.

A study of the stereochemical factors involved in multistep 1,2-hydride transfers

Synthetic routes to the all(cis- and the all-trans-1,2,3,4,5-pentamethylcyclopentyl cation have been developed. These cations both undergo very rapid multiple 1,2-hydride shifts, but the rate of this process is about 40 times faster in the all-trans case. This implies that the stereochemistry of the penultimate hydride in the rearrangement cascade can affect the rate of a given 1,2-hydride shift, i.e. that it is better if this penultimate hydride is located trans to the migrating one. A further implication of this work is that the hydride shifts in the parent cyclopentyl cation may be partially ordered and that rapid multiple hydride shifts in general may be subject to the same criteria

Astatistical aspects of the stabilities of ternary complexes of cobalt(II), nickel(II), copper(II) and zinc(II) involving aminopolycarboxylic acids as primary ligands and salicylaldoxime as a secondary ligand

Stability constants of binary (ML, ML2) and ternary (MAL) complexes, where M=CoII, NiII, CuII and ZnII; A-iminodiacetic acid (ida),N-methyliminodiacetic acid (Me-ida), anthranilatediacetic acid (ada), nitrilotriacetic acid (nta); LH2=salicylaldoxime have been determined at 25° C at 0.1M KNO3 ionic strength by the Irving-Rossotti technique. KMALMA is always lower than KMLM and KMI2ML. In the ternary systems studied, the KMALML values lie in the sequence: KM(ida)LM(ida)>KM(Me-ida)LM(Me-ida)>KM(nta)LM(nta)>KM(ada)LM(ada). For CuII, the KCu(nta)LCu(nta) and KCu(ada)LCu(ada) values are significantly reduced compared to all other primary ligands. For different primary ligands, the KMALMA sequence is reversed compared to KMAM, but for A=ada and nta their relative positions remain unaltered in both binary and ternary systems. The results have been explained in the light of different astatistical factors such as electrostatic effects, steric hindrance, change of electronegativity of the central metal and stereochemical factors.

Reactions of carbonyl compounds in basic solutions. Part 13. The mechanism of the alkaline hydrolysis of 3-(3-substituted phenoxy)phthalides, -3-methyl-phthalides, -3-phenylphthalides, naphthalides, -3-phenylnaphthalides, and phenanthralides, and of 3-substituted 3-methoxyphthalides

Rate coefficients have been measured for the alkaline hydrolysis of 3-(3-substituted phenoxy)phthalides, -3-methylphthalides, -3-phenylphthalides, naphthalides, -3-phenylnaphthalides, and phenanthralides at 30.0 and 50.0 °C and for a series of methyl pseudo-2-acylbenzoates at several temperatures in 70%(v/v) dioxane–water. The enthalpies and entropies of activation have been evaluated. The effects of substitution on the phenoxy esters have been assessed by means of, the Hammett equation. The results for the methyl esters are related to the steric effect of substituents using the Taft equation. All the pseudo-esters are hydrolysed with rate-determining attack by hydroxide anion at the carbonyl group, followed by rapid ring fission to form the carboxylate anion of the corresponding acid as the product. Reactivity–selectivity is not shown over the whole range of the six series of the phenyl pseudo-esters. These results are discussed in terms of the structure of the transition state and the steric, stereochemical and polar factors influencing reactivity.

Electronic and stereochemical factors contributing to the lability of trans-aquomethyl(tetraazamacrocycle) cobalt(III) complexes. Kinetic and molecular mechanics studies

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTElectronic and stereochemical factors contributing to the lability of trans-aquomethyl(tetraazamacrocycle) cobalt(III) complexes. Kinetic and molecular mechanics studiesJohn F. Endicott, Krishan Kumar, Carolyn L. Schwarz, Marc W. Perkovic, and Wang Kan LinCite this: J. Am. Chem. Soc. 1989, 111, 19, 7411–7420Publication Date (Print):September 1, 1989Publication History Published online1 May 2002Published inissue 1 September 1989https://doi.org/10.1021/ja00201a021RIGHTS & PERMISSIONSArticle Views134Altmetric-Citations18LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (2 MB) Get e-AlertsSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts