Amide Modification Research Articles

Structural analogues of 5-OMe-BPAT: synthesis and interactions with dopamine D 2, D 3, and serotonin 5-HT 1A receptors

Several structural analogues of 5-methoxy-2-[ N-(2-benzamidoethyl)- N- n-propylamino]tetralin (5-OMe-BPAT, 1), a representative of a series of 2-aminotetralin-derived benzamides with potential atypical antipsychotic properties, were synthesized and evaluated for their ability to bind to dopamine D 2A, D 3, and serotonin 5-HT 1A receptors in vitro. The structure–affinity relationships revealed that the aromatic ring of the benzamide moiety of 1 contributes to the high affinities for all three receptor subtypes. Furthermore, 1 may interact with the dopamine D 2 and D 3 receptors through hydrogen bond formation with its carbonyl group. Investigation of the role of the amide hydrogen atom by amide N-alkylation was not conclusive, since conformational aspects may be responsible for the decreased dopaminergic affinities of the N′-alkylated analogues of 1. The effects of the amide modifications on the serotonin 5-HT 1A receptor affinity were less pronounced, suggesting that the benzamidoethyl side-chain of 1 as a whole enhances the affinity for this receptor subtype probably through hydrophobic interactions with an accessory binding site. The structural requirements for the substituents at the basic nitrogen atom supported the hypothesis that the 2-aminotetralin moieties of the 2-aminotetralin-derived substituted benzamides may share the same binding sites as the 2-( N, N-di- n-propylamino)tetralins.

Neutronenbeugung an der Tieftemperaturmodifikation von Rubidiumdeuteroamid

Neutron Diffraction of the Low Temperature Modification of Rubidium Deutero Amide A polycrystalline sample of RbND2 was prepared by reaction of liquid ND3 and Rb (320 K, 4 d). Rietveld refinement of neutron powder diffraction data collected on the E2 (HMI-BENSC, Berlin) yielded the deuterium positions and allowed the temperature factors of all atoms to be refined anisotropically: space group P21/m, Z = 2, a = 4.846(1) Å, b = 4.136(1) Å, c = 6.396(2) Å, β = 98.051(7)°, N(I/σ(I) > 1) = 179, N(Var.) = 25, RP = 0.025, wRP = 0.032, RB(I/σ(I) > 1) = 0.095. In a monoclinic distorted rock salt structure the amide ions are oriented antiferroelectrically in almost planar zick-zack chains.

PHVSICOCHEMICAL MODIFICATION OF COPPER EXTRACTANTS. A REVIEW.

ABSTRACT The modification of hydroxyoximes, ester and amides of pyridine carboxylic acids with various oxygen containing modifiers (alcohols, alkylphenols, ketones, esters, etc.) is reviewed. The modifiers form co-associates with the copper extractants changing, in this way, the active concentration of the monomer and blocking the active groups of the extractants. The structures of such associates predicted by molecular modeling are given.

Effect of structural modification of enol-carboxamide-type nonsteroidal antiinflammatory drugs on COX-2/COX-1 selectivity.

Meloxicam (5), an NSAID in the enol-carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. In subsequent screening in microsomal assays using human COX-1 and COX-2, we discovered that it possessed a selectivity profile for COX-2 superior to piroxicam and other marketed NSAIDs. We therefore embarked on a study of enol-carboxamide type compounds to determine if COX-2 selectivity and potency could be dramatically improved by structural modification. Substitution at the 6- and 7-positions of the 4-oxo-1,2-benzothiazine-3-carboxamide, alteration of the N-methyl substituent, and amide modification were all examined. In addition we explored several related systems including the isomeric 3-oxo-1,2-benzothiazine-4-carboxamides, thienothiazines, indolothizines, benzothienothiazines, naphthothiazines, and 1,3- and 1,4-dioxoisoquinolines. While a few examples were found with greater potency in the COX-2 assay, no compound tested had a better COX-2/COX-1 selectivity profile than that of 5.

Backbone modifications for antisense oligonucleotides

Abstract

Replacement of the Phosphodiester Linkage in Oligonucleotides by a C==C Double Bond: Comparison of the cis and trans Isomers

The two olefinic backbone replacements III and IV were synthesized and incorporated into oligonucleotides. The hybridization properties of the modified oligonucleotides to DNA and RNA complements and conformational analyses of III and IV are compared to the corresponding amide modifications I and II.

Replacement of the phosphodiester linkage in oligonucleotides by a C=C double bond: Comparison of the cis and trans isomers

The two olefinic backbone replacements III and IV were synthesized and incorporated into oligonucleotides. The hybridization properties of the modified oligonucleotides to DNA and RNA complements and conformational analyses of III and IV are compared to the corresponding amide modifications I and II.

N5-methylasparagine and energy-transfer efficiency in C-phycocyanin.

A posttranslationally methylated asparagine residue, N5-methylasparagine, is found at the beta-72 site in many phycobiliproteins. Two mutations (Asp and Gln) in the beta-72 position of Agmenellum quadruplicatum C-phycocyanin were investigated to clarify the role of the wild-type N5-methylasparagine near the beta-84 "fluorescing" bilin tetrapyrrole chromophore. Chemical analysis for amide modification revealed that the beta-72Q protein was partially methylated with a stoichiometry of 0.27, suggesting that either the asparagine methyltransferase is nonspecific or a glutamine methyltransferase exists. Urea denaturation studies could detect no difference in protein stability for any of the C-phycocyanin species. Steady-state spectroscopic measurements demonstrate that Asp and Gln substitution for the C-phycocyanin beta-72 NMA affects both the ground to excited state transition and the excited-state characteristics of the beta-84 chromophore, while the rate of radiative energy transfer is unaffected. Energy-transfer efficiency within phycobilisomes (represented by steady-state fluorescence quantum yields) was also negatively impacted by the beta-72 substitutions. Time-resolved fluorescence emission spectroscopic studies with C-phycocyanin reveal three distinguishable fluorescence lifetimes. The longest fluorescence lifetime is diminished 7-10% by the Asp and Gln mutations in comparison to a control sample where beta-72 is NMA. Molecular dynamics calculations implicate a change in the bilin tetrapyrrole chromophore ring geometry as a likely source of the altered photophysics induced by the mutations. We conclude that N5-methylasparagine plays a special role in establishing the environment surrounding the beta-84 chromophore which minimizes the rates of nonradiative energy losses that would otherwise defeat the high quantum yield for energy transfer within the phycobilisomes.

Comparison of two amides as backbone replacement of the phosphodiester linkage in oligodeoxynucleotides

The two isomeric amide modifications 1 and 2 show similar effects on the melting temperature of RNA/DNA duplexes, when they replace the natural phosphodiester linkage in the DNA strand. The synthesis of the amide dimer 1 is presented.

An approach to the structure determination of nucleic acid analogues hybridized to RNA. NMR studies of a duplex between 2'-OMe RNA and an oligonucleotide containing a single amide backbone modification.

The backbone modification amide-3, in which -CH2-NH-CO-CH2- replaces -C5'H2-O5'-PO2-O3'-, is studied in the duplex d(G1-C2-G3-T4.T5-G6-C7-G8)*mr(C9-G10-C11-A12-A13-C14-G15+ ++-C16) where . indicates the backbone modification and mr indicates the 2'-OMe RNA strand. The majority of the exchangeable and non-exchangeable resonances have been assigned. The assignment procedure differs from standard methods. The methyl substituent of the 2'-OMe position of the RNA strand can be used as a tool in the interpretation. The duplex structure is a right-handed double helix. The sugar conformations of the 2'-OMe RNA strand are predominantly N-type and the 2'-OMe is positioned at the surface of the minor groove. In the complementary strand, only the sugar of residue T4 is found exclusively in N-type conformation. The incorporation of the amide modification does not effect very strongly the duplex structure. All bases are involved in Watson-Crick base pairs.

Identification of some abnormal haemoglobins by fast atom bombardment mass spectrometry and fast atom bombardment tandem mass spectrometry.

The characterization of two abnormal human haemoglobins by fast atom bombardment (FAB) mapping is presented. The first variant, called 'R', exhibits a tryptic FAB map identical to that of normal haemoglobin. However, using Staphylococcus protease V8, a peptide containing the carboxyl end of the beta-chain exhibits a mass shift down to 300 mass units. This clearly indicates the deletion of the two last amino acids of the beta-chain. The second variant, called 'Grenoble', is due to two different modifications of the beta-chain. The location of the Pro----Ser exchange on peptide T5 is achieved by the collisionally activated dissociation mass analyzed ion kinetic energy spectra of the corresponding [MH]+ ion. The m/z value of that peptide indicated a supplementary acid----amide modification, which was located by amino acid sequencing using chemical methods. This work concludes with the necessity of using complementary methods for achieving rapid determinations of abnormal proteins with minute amounts.

A 1H n.m.r. study of the role of the glutamate moiety in the binding of methotrexate to Lactobacillus casei dihydrofolate reductase.

The binding of a series of amide derivatives of methotrexate to Lactobacillus casei dihydrofolate reductase has been studied by inhibition constant measurements and by 1H n.m.r. spectroscopy. Amide modification of the alpha-carboxylate of methotrexate was found to prevent interaction of the gamma-carboxylate with the imidazole of His 28. Estimates of the contributions to the binding energy from the alpha-carboxylate-Arg 57 and gamma-carboxylate-His 28 interactions have been made from a combination of inhibition and n.m.r. data.

The Dyeing Properties of Esterified Wools

The effect of esterification of wool on its behavior toward acid dyes has been studied. Esterified wool shows an increase in dye affinity, and dyed esterified wool shows an increase in dye fastness to washing in soap and soap-soda. The process of esterification with methanol/hydrogen chloride is not entirely specific and also causes some modification of amide and other groups.