Labile Functional Groups Research Articles

Novel Synthetic Route of Coelenterazines -2-: Synthesis of Various Dehydrocoelenterazine Analogs

The novel synthetic route to introduce various substituents into 5-position of coelenteramine is described. Difficulties, however, are observed in the attempted synthesis of some analogs having labile functional groups. This is due to the strong acid conc. H 2 SO 4 after Suzuki-Miyaura coupling, so that the route was limited only to the synthesis for aminopyrazines having acid-stable functional groups. In this report, we describe alternative success in the deprotection of N-tosyl-animopyrazine triflate before the cross coupling; thus, we obtained the aminopyrazine triflate in high yield. This compound enables us to synthesize various coelenterazine analogs. This triflate was proven to be so important intermediate that the versatile synthesis for coelenterazine and dehydrocoelenterazine analogs was established through Suzuki-Miyaura or Sonogashira coupling.

A Novel and Efficient Method for Inside Selective Esterification of Terminal vic‐Diols.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A novel and efficient method for inside selective esterification of terminal vic-diols

A novel and highly efficient procedure for inside selective esterification of terminal vic-diols has been achieved in one-pot via Yb(OTf)3-catalyzed formation and partial hydrolysis of cyclic orthoesters. This method offers several advantages including wide compatibility with acid labile functional groups, and good to high regioselectivity and yields.

Current Concepts for Optimizing the Therapeutic Index of Glucocorticoid Receptor Ligands for Oral and Inhalative Use: Basic Considerations and Clinical Reality

Glucocorticoid receptor agonists are most potent anti-inflammatory agents and indispensable for the treatment of a broad array of inflammatory and immunological disorders. The first compounds introduced into therapy were derived from the natural corticosteroid hydrocortisone. First structural modifications of the core molecule aimed at the increase in selectivity to the glucocorticoid over the mineralocorticoid receptor. Based on a better understanding of structure-activity relationships the next generation of compounds displayed higher receptor affinities and thus higher efficacy. For topically applied glucocorticoids, further progress was achieved by drug targeting, e.g. by inhalation of corticosteroid preparations. Recent developments focussed on the best possible reduction of adverse effects by introducing metabolically labile functional groups into the active molecule to minimize systemic exposure. High affinity to the therapeutic target tissue was recognized as a property that warrants a favorable redistribution kinetics into systemic circulation. These concepts led to a significant improvement of the therapeutic index defined as the ratio of undesired metabolic effects to beneficial antiinflammatory activity for topically applied glucocorticoids. In contrast, no comparable progress has been achieved for systemically administered glucocorticoids yet. However, new insights into alternate pathways of receptor activation suggest the potential for an agonist-driven differentiation between transactivation and transrepression mechanisms. This molecular effector selectivity gives rise to the hope for the development of compounds exhibiting predominantly therapeutically desired effects. This review discusses structure-property relationships of orally and inhalative administered glucocorticoid receptor ligands with steroidal and non-steroidal structure and their translations into clinically observed efficacy and adverse effects. Keywords: Glucocorticoid, non-steroidal

The Lindlar Catalyst Revitalized: A Highly Chemoselective Method for the Direct Conversion of Azides to N‐(tert‐Butoxycarbonyl)amines.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The Lindlar Catalyst Revitalized: A Highly Chemoselective Method for the Direct Conversion of Azides to N-(tert-Butoxycarbonyl)amines

An exceptionally chemoselective method for the direct conversion of azides to N-(tert-butoxycarbonyl)-protected amines under catalytic transfer-hydrogenation conditions, using the Lindlar catalyst, is reported. The extremely labile functional groups such as N-Cbz, benzyl ester are shown to be inert under the reaction conditions. The present method allows us to synthesize orthogonally protected (N-Cbz & N-Boc) 1,2-diamino systems, which will be immensely useful in organic synthesis. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Prodrug and antedrug: two diametrical approaches in designing safer drugs.

The prodrug and antedrug concepts, which were developed to overcome the physical and pharmacological shortcomings of various therapeutic classes of agents, employ diametrically different metabolic transformations. The prodrug undergoes a predictable metabolic activation prior to exhibiting its pharmacological effects in a target tissue while the antedrug undergoes metabolic deactivation in the systemic circulation upon leaving a target tissue. An increased therapeutic index is the aspiration for both approaches in designing as well as evaluation criteria. The recent research endeavors of prodrugs include the gene-directed and antibody-directed enzymatic activation of a molecule in a targeted tissue, organ specific delivery, improved bioavailabilities of nucleosides and cellular penetration of nucleotides. As for antedrugs, emphasis in research has been based upon the design and synthesis of systemically inactive molecule by incorporating a metabolically labile functional group into an active molecule.

Ultrafast laser analysis of nitro-PAHs using laser desorption/femtosecond ionization mass spectrometry

Analytical interest in nitrated polycyclic aromatic hydrocarbons (nitro-PAHs) is related to their high mutagenicity and potential presence in a variety of environmental media such as diesel exhaust and urban air particulate matter. Furthermore, fundamental interest in these molecular systems stems from the photophysics of the labile NO2 functional group, which has been investigated using mass spectrometry. The nitro-PAHs, 1-nitronaphthalene, 9-nitroanthracene, and 1-nitropyrene, have been studied using both femtosecond (λ = 395 and 790 nm) and nanosecond (λ = 266 nm) lasers coupled to a reflectron time of flight mass spectrometer. Analysis of mass spectra taken over a range of intensities (1014–1015 W/cm2) has demonstrated that structurally specific ions can be observed for each molecule, with little or no fragmentation at lower intensities. It has also been found that an intact parent ion can be detected using femtosecond ionization at 395 nm in each case. This work demonstrates the potential use of laser desorption/femtosecond laser mass spectrometry (LD/FLMS) as an analytical technique for the detection of nitro-PAHs and other environmental pollutants and as a means of studying the photodynamics of labile molecular systems.

Palladium and Raney Nickel Catalyzed Methanolic Cleavage of Stable Borane−Amine Complexes

[figure: see text] Palladium and Raney nickel were found to catalyze the methanolysis of borane-amine adducts. Hence, strongly complexed amines can now be liberated by simple treatment with Pd/C or Raney Ni in methanol. The method is applicable to primary, secondary, tertiary, and aromatic amines, and the mildness of the reaction conditions allows preservation of otherwise labile functional groups.

Glycoprotein analysis by delayed extraction and post-source decay MALDI-TOF-MS

Matrix-assisted laser desorption-ionization (MALDI)-MS analysis of glycoprotein samples is usually affected by metastable fragmentation, particularly in reflectron instruments. Use of delayed extraction (DE) is shown to minimize the observed metastable fragmentation. In the case of the CHO IL-4, which contains complex-type N-linked glycans, the disialylated component gives the most abundant MALDI signal with a dramatically improved resolution and mass accuracy over the non-DE linear TOF analysis. This increased resolution is advantageous for the 30 kDa Sf9-derived IL-4 receptor, where it is possible to differentiate the individual glycans, but not for higher mass and more heterogeneous glycoproteins. It is also shown that MALDI analysis of proteins with labile functional groups is more superior and reliable with linear DE-TOF systems rather than reflectron TOF analyzers. Further structural information on the sequence and disulfide mapping, as well as glycopeptide identification can be obtained by post-source decay (PSD) analysis of peptide and glycopeptide isolated fractions. The PSD formation of a characteristic triplet of ions separated by 33 Da in mass can be used to identify disulfide-paired peptides, even from complex digest mixtures of proteins.

Monolayer Damage in XPS Measurements As Evaluated by Independent Methods

The damage caused to amphiphilic n-alkane monolayers under XPS measurement conditions was assessed in a combined XPS-FTIR study supplemented by additional AFM imaging and contact angle measurements. Nine different self-assembled monolayer/substrate systems were examined, comprising a long chain silane (C18, OTS), a short chain silane (C1, MTS), a functional (COOH-terminated) long chain silane (C18, NTSox), a long chain carboxylic acid (C20, AA), and four different solid substrates (silicon, quartz, glass, and ZnSe). Significant differences were observed in the behavior of the various examined monolayer systems under identical X-ray irradiation conditions. These are interpreted in terms of effects associated with the specific mode of layer-to-surface and intralayer coupling, the size of the monolayer hydrocarbon core, and the presence of radiation-sensitive functional groups in the layer. All these factors and their influence on the degradation path followed by a particular monolayer upon exposure to the X-rays were found to be interrelated, giving rise to a variety of possible damage patterns, including an unexpected overall stabilization effect initiated by the preferential rapid loss of a labile top functional group (NTSox). XPS is shown to be insufficient as a tool for the evaluation of the radiation-induced damage in such ultrathin films, because of its insensitivity to loss of hydrogen and to structural transformations that occur without a net loss of carbon from the surface. Independent methods of surface analysis (mainly FTIR), applied in conjunction with XPS, provide a more comprehensive picture of the induced damage, thus permitting a realistic interpretation of the XPS experimental data as well as the design of improved data acquisition procedures. This could also assist in the tailoring of monolayers with predetermined degradability, for specific purposes. Finally, results of combined AFM-XPS-FTIR-contact angle measurements suggest the possible formation of a “diamond-like” surface film upon extensive X-ray irradiation of an OTS/Si monolayer.

Potential metabolic bioactivation pathways involving cyclic tertiary amines and azaarenes.

A major theme explored in this review is the MAO-and cytochrome P450-catalyzed alpha-carbon oxidations of selected cyclic tertiary amines to give iminium metabolites that undergo further chemical modifications to form known or potentially toxic products. The most dramatic illustration of this type of bioactivation process is the conversion of the parkinsonian-inducing neurotoxin MPTP (23) by brain MAO-B to the iminium (dihydropyridinium) metabolite 24 which is oxidized further to the pyridinium species MPP+ (25). The selective destruction of nigrostriatal neurons by MPP+ is dependent on a unique sequence of events (transport into the nerve terminals by the dopamine transporter, localization in the inner mitochondrial membrane by electromotive forces, and inhibition of complex I of the mitochondrial electron transport chain) that, fortunately, are unlikely to be encountered with many substances. A second example of a well-documented metabolic bioactivation sequence involves the highly toxic pyrrolizidine alkaloids (102). These compounds undergo cytochrome P450-catalyzed alpha-carbon oxidation which converts the 3-pyrrolinyl moiety present in the parent alkaloids into a pyrrolyl-containing metabolite (105). The presence of labile functional groups results in the spontaneous conversion of 105 to reactive electrophilic products (106 and 108) that undergo Michael addition reactions with nucleophiles on biomacromolecules leading to a variety of toxic outcomes. Less clearly defined are the potential contributions to neurodegenerative processes that may be mediated by low-level, long term exposure to less potent toxins. Examples of potential proneurotoxins are the endogenously formed tetrahydroisoquinolines (such as 40-50) and tetrahydro-beta-carbolines (such as 54) that may be biotransformed to neurotoxic isoquinolinium (such as 51) and beta-carbolinium (such as 52) species in the brain. A similar argument can be made for 4-piperidinols (compounds that are at the same oxidation state as the tetrahydropyridines) which may be metabolized via iminium intermediates to amino enols that spontaneously convert to dihydropyridinium species and hence to pyridinium metabolites (67-->68-->69-->70-->71, Scheme 10). This type of reaction sequence has been well documented with the parkinsonian-inducing neuroleptic agent haloperidol (72) which is metabolized in humans, baboons, and rodents to the pyridinium species HPP+ (75), a potent inhibitor of mitochondrial respiration. Finally, an appreciation of the alpha-carbon oxidations of fully reduced azacycles such as (S)-nicotine (61) and phencyclidine (82) to chemically reactive metabolites that form covalent adducts with proteins, including the enzymes that are responsible for their formation, may prove of toxicological importance when attempting to account for the effects of chronic abuse of these potent drugs.1

Cleavable surfactants

Abstract A brief review of cleavable surfactants, synthesized and characterized by the author and his co-workers, is presented. Two types of cleavable surfactants have been reported; each contains a labile functional group. Both single and double-chain first generation cleavable surfactants are cleaved to give nonsurfactant fragments: a water-insoluble organic compound and a water-soluble ionic compound. Single-chain second generation cleavable surfactants are cleaved to give another surfactant and a water-soluble organic compound; double-chain second generation surfactants are cleaved to give two single-chain surfactants. Cleavable surfactants allow the elimination of problems associated with the presence of aggregated surfactants after their beneficial use.

Matrix Dependence of Metastable Fragmentation of Glycoproteins in MALDI TOF Mass Spectrometry

Matrix-assisted laser desorption ionization (MALDI) mass spectrometry relies on the formation of intact molecular ions in order to achieve a high-accuracy molecular weight determination. Problems arising from metastable fragmentation strongly affect MALDI results in reflectron instruments due to the mass separation of the fragment ions with the reflectron. In this paper, it is shown that the extent of metastable fragmentation for proteins is strongly related to the matrix compound used. Among the matrix compounds tested, 3-hydroxypicolinic acid proved to be a highly superior matrix for MALDI analysis of proteins and it even allowed for desorption of intact glycoproteins containing labile functional groups, e.g., sialic acids, in a reflectron analyzer, whereas 4-hydroxy-α-cyanocinnamic acid induced strong metastable fragmentation even for standard proteins such as apomyoglobin

Synthesis and biological activity of ketomethylene pseudopeptide analogues as thrombin inhibitors.

Ketomethylene pseudopeptide analogues Aa-Pro-Arg psi (COCH2) Gly-pip, 1, where Aa are D- or L-amino acids (Dpa, beta, beta-diphenylalanine; alpha Nal, alpha-naphthylalanine; beta Nal, beta-naphthylalanine; Fgl, fluorenylglycine) with highly lipophilic side chains and psi (COCH2) is a ketomethylene pseudopeptide bond, have been synthesized through a modified Dakin-West reaction under very mild conditions with a high yield using tripeptide 4 with a labile functional group directly on the side chain. Their enzymatic assay of thrombin inhibition has been carried out. The structure-activity relationship study indicated that a lipophilic side chain on the amino acid in the P3 position is very important for binding to the apolar site of thrombin. Compound 1a with D-Dpa at the P3 position has a Ki of 0.2 microM and it doubles thrombin clotting time at only 3 times higher concentration. These values are about 7 times better than those of the corresponding D-Phe analogues. Furthermore, 1a shows poor inhibitory activity against plasmin, factor Xa, urokinase, and kallikrein. Preliminary in vivo testing (3-4-kg rabbit as the animal model) shows no observable side effect (change of blood pressure and accumulation of blood platelet in lungs) at a dose of 1 mg/kg.

Synthesis by post-synthetic substitution of oligomers containing guanine modified at the 6-position with S-, N-, O-derivatives

6-(2,4-dinitrophenyl)thioguanine phosphoramidite monomers with the 2-amino group of the base protected by either the isobutyryl or phenylacetyl group were incorporated into oligodeoxynucleotides with an automatic DNA synthesizer. N 2-protection with the isobutyryl group was unsatisfactory because of the difficulty of removing it after synthesis of the oligemer. However, post-synthetic conversion of the N 2-phenylacetyl protected 6-(2,4-dinitrophenyl)thioguanine gives oligomers containing 6-thioguanine, 2,6-diaminopurine, 2-amino-6-methylaminopurine, O 6-methylguanine or guanine in high yield and purity. Potentially oligemers containing other labile functional groups at the 6-position could be produced by the procedure. DNA duplexes containing 6-thioguanine paired to cytosine had a markedly lower melting temperature (Tm) than counterparts containing G:C. However a DNA duplex containing 4-thiothymine paired to A had a Tm similar to that of a DNA duplex containing T:A. The distortion in DNA structure caused by 6-thioguanine may play a role in the biological effect of this compound.

Phosphorus-31 NMR spectroscopic analysis of labile hydrogen functional groups: identification with a dithiaphospholane reagent

Six chlorophospholanes (2-7) are evaluated as 31 P NMR tagging reagents for labile hydrogen functional groups known to be present in coal materials. In this series, 2 (ClPSCH 2 CH 2 S) is demonstrated to be best for resolving the 31 P NMR chemical shifts of a variety of model compounds within a given functional group class, as well as for the separation of the shift ranges among the various classes

Influence of cross-linking on tar formation during pyrolysis of low-rank coals

In this paper the pyrolysis behaviour of two Spanish low-rank coal in the 275–600° C range is studied. Gases evolved from pyrolysis were analyzed by on-line Fourier transform infrared spectroscopy (EGA-FTIR) and gas chromatography and the changes in the macromolecular structure of coal by a solvent swelling technique. The studied coals cross-link very early and the differences found in their tar yields can be explained in terms of cross-linking reactions. Cross-linking of chars correlates with the evolution of CO 2 and pyrolysis water and the extent of the cross-linking reactions is related to the coal's initial content of labile functional groups, namely carboxyl and hydroxyl groups.

多重官能性炭素化合物の化学

The chemistry of compounds containing a carbon atom bearing three or four different labile functional groups has received little attention. These compounds should have considerable significance in theoretical and synthetic organic chemistry. Among the compounds with multifunctional structures, those having both carbonyl and halogen groups in addition to other heteroatom groups seem especially valuable from a synthetic viewpoint. Their potential as probes in pure and applied synthetic chemistry has not been exploited, because of structural instability and a paucity of synthetic approaches. Keeping with the background mentioned above in mind, we focused on the synthesis of a new class of multifunctional carbon compounds (structure A in Fig.1), in which ester carbonyl, halogen (Br or F), and other non-carbon (N, O, and/or S) functional groups are directly attached to the central carbon atom. Fluorine was chosen as the halogen because of the inherent stability of the C-F bond and because of the fundamental chemical and biological interest in fluorine-containing compounds. Synthesis, reactions, spectral data, optical resolution, and absolute configuration determination of various multifunctional carbon compounds are described. Some applications of fluorine-containing multifunctional compounds are also discussed.

Carbamates : A method of synthesis and some syntehtic applications

Alcohols are converted into unsubstituted carbamates by treatment with trichloroacetyl isocyanate followed by hydrolysis on Al 2O 3. This extremely mild procedure tolerates various labile functional groups. The synthetic utility of the carbamate moiety as a control element is demonstrated on epoxidation and epoxide opening.