Determination of the Group Electronegativity of CF3 Group in 3′-O-CF3-Thymidine by 1-NMR

Abstract

The interplay of enthalpy of the gauche effect (ΔH°_GE) of the [X3′-C3′-C4′-O4′] fragment in various 3′-substituted (X) 2′,3′-dideoxythymidine derivatives 1–7 and the inherent anomeric effect drives the two-state North ? South equilibrium in the constituent sugar moiety. The group electronegativity of 3′-OCF₃ substituent in Marriott's, Inamoto's and Mullay's scales has been determined from simple calibration graphs correlating the group electronegativity of various 3′-substituents (X) in 2′,3′-dideoxythymidine derivatives 1–7 with the experimental strength (ΔH°_GE) of the [X3′-C3′-C4′-O4′] gauche effect. ΔH°_GE has been experimentally determined from pseudorotational analyses of temperature-dependent ³J_HH coupling constants, and can be used as an unambiguous tool for direct experimental estimation of the group electronegativity of a specific substituent covalently attached to 3′-carbon of 2′,3′-dideoxythymidine, which can be compared, in turn, with the theoretical estimation carried out according to Marriott's or Inamoto's procedure. Inconsistency found between theoretical values in Marriott's and Inamoto's scales, on the one hand, and between our experimental estimate and the theoretical value in Marriott's scale, on the other, have been solved by refining the electronegativity scale using our experimental data for 1–7.     

C1′ Acylated Derivatives of 2′-Deoxyuridine. Photolabile Precursors of 2′-Deoxyuridin-1′-yl

Abstract

ABSTRACT

C1′ acylated derivatives of 2′-dcoxyuiidinc (1a-c) were synthesised from 1-[3-deoxy-β-D-psieofiiraiiosylliii.acil (6). The acyl group is introduced via the C1′ aldehyde (11). Following nucleophilic addition, the ketones (1a-c) are obtained via periodinane oxidation and desilylation with NH₄F.     

Nucleosides and Nucleotides. 232. Synthesis of 2′-C-Methyl-4′-thiocytidine: Unexpected Anomerization of the 2′-Keto-4′-thionucleoside Precursor

The synthesis of 2′-C-methyl-4′-thiocytidine (16) is described. Since the 2′-keto-4′-thiocytidine derivative 2β unexpectedly isomerized to 2α and the methylation of 2β proceeded predominantly from the less hindered α-face to give 7, the desired product 16 was synthesized via the Pummerer reaction of the sulfoxide 14 and N ⁴ -benzoylcytosine.     

Synthesis of 2′-Substituted Inosine Analogs via Unusual Masking of the 6-Hydroxyl Group

2′-Modified inosine analogs have been synthesized from 6-chloropurine riboside via 6-dimethylaminopurine or 6-benzyloxypurine intermediates. The dimethylaminopurine intermediate was obtained via an unusually facile dimethylamine transfer from dimethylformamide.

Graphical Abstract:      

A New 5′-Protecting Group for Use in Solid-Phase Synthesis of Oligoribonucleotides

Abstract

The 2-(2,4-dinitrobenzenesulphenyloxymethyl)benzoyl (DNBSB) group is proposed as a protecting group for the 5′-position of nucleosides. The DNBSB group may be removed under mild non-acidic conditions and may have potential in solid-phase synthesis of oligoribo- and oligodeoxyribonucleotides.     

The 4′-Hydroxyl Group of Resveratrol Is Functionally Important for Direct Activation of PPARα

Long-term moderate consumption of red wine is associated with a reduced risk of developing lifestyle-related diseases such as cardiovascular disease and cancer. Therefore, resveratrol, a constituent of grapes and various other plants, has attracted substantial interest. This study focused on one molecular target of resveratrol, the peroxisome proliferator activated receptor α (PPARα). Our previous study in mice showed that resveratrol-mediated protection of the brain against stroke requires activation of PPARα; however, the molecular mechanisms involved in this process remain unknown. Here, we evaluated the chemical basis of the resveratrol-mediated activation of PPARα by performing a docking mode simulation and examining the structure-activity relationships of various polyphenols. The results of experiments using the crystal structure of the PPARα ligand-binding domain and an analysis of the activation of PPARα by a resveratrol analog 4-phenylazophenol (4-PAP) in vivo indicate that the 4′-hydroxyl group of resveratrol is critical for the direct activation of PPARα. Activation of PPARα by 5 μM resveratrol was enhanced by rolipram, an inhibitor of phosphodiesterase (PDE) and forskolin, an activator of adenylate cyclase. We also found that resveratrol has a higher PDE inhibitory activity (IC₅₀ = 19 μM) than resveratrol analogs trans-4-hydroxystilbene and 4-PAP (IC₅₀ = 27-28 μM), both of which has only 4′-hydroxyl group, indicating that this 4′-hydroxyl group of resveratrol is not sufficient for the inhibition of PDE. This result is consistent with that 10 μM resveratrol has a higher agonistic activity of PPARα than these analogs, suggesting that there is a feedforward activation loop of PPARα by resveratrol, which may be involved in the long-term effects of resveratrol in vivo.     

Nucleosides and Nucleotides. 139. Stereoselective Synthesis of (2′S)-2′-C-Alkyl-2′-deoxyuridines

Abstract

A synthetic method for (2′S)-2′-C-alkyl-2′-deoxyuridines (9) has been described. Catalytic hydrogenation of 1-[2-C-alkynyl-2-O-methoxalyl-3,5-O-TIPDS-β-D-arabino-pentofuranosyl]uracils (5) gave 1-[2-C-(2-alkyl)-2-O-methoxalyl-3,5-O-TIPDS-β-D-arabino-pentofuranosyl]uracils (4) as a major product, which were then subjected to the radical deoxygenation, affording (2′S)-2′-alkyl-2′-deoxy-3′,5′-O-TIPDS-uridines (7) along with a small amount of their 2′R epimers.

     

Anti-anabolic effects of adenosine 3′:5′-cyclic monophosphate. Inhibition of protein synthesis

1. Evidence is presented that cyclic AMP inhibits the incorporation of l-[4,5-(3)H]leucine into protein in a cell-free system from rat liver. This inhibition occurs after aminoacyl-tRNA formation. 2. Microsomal fractions, isolated after the incubation of postmitochondrial supernatant with cyclic AMP and ATP, show a diminished ability to synthesize protein. Both cyclic AMP and ATP are required for this effect. 3. A possible physiological role for the anti-anabolic action of cyclic AMP is discussed in terms of the control of gluconeogenesis.     

S,X-Acetals in Nucleoside Chemistry. III1. Synthesis of 2′-and 3′-O-Azidomethyl Derivatives of Ribonucleosides

Abstract

2′- and 3′-O-azidomethyl derivatives of ribonucleosides were obtained by splitting the corresponding methylthiomethyl derivatives of ribonucleosides with bromine or SO₂Cl₂ followed by lithium azide treatment.     

Stereochemical considerations in the enzymatic phosphorylation and antiviral activity of acyclonucleosides. I. Phosphorylation of 2′-nor-2′-deoxyguanosine

The antiviral compound 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (2′-nor-2′-deoxyguanosine, 2′-NDG) is phosphorylated by the HSV-1-induced thymidine kinase to the monophosphate (2′-NDG-MP) and this is further phosphorylated by cellular kinases to the triphosphate (2′-NDG-TP) which is a potent inhibitor of DNA polymerases. Since phosphorylation of 2′-NDG creates a chiral center in the molecule, it was of interest to examine whether both monophosphate enantiomers were produced by the viral thymidine kinase, whether they both could be further phosphorylated by cellular kinases and, if so, whether the respective triphosphates were equally inhibitory to the DNA polymerases. The time course of the phosphorylation by GMP kinase of a chemically synthesized, racemic 2′-NDG-MP was compared to that of a 2′-NDG-MP preparation obtained by enzymatic phosphorylation of 2′-NDG with HSV-1 thymidine kinase. The results indicated (a) that the two enantiomeric monophosphates were phosphorylated by GMP kinase with different rates and (b) that phosphorylation of 2′-NDG by HSV-1 thymidine kinase gave only one of the isomers, whose structure was determined to be S. Both enantiomeric diphosphates were further phosphorylated to the respective triphosphates and it was shown that, in contrast to the triphosphate obtained from the 2′-NDG-MP prepared by viral thymidine kinase which was a potent inhibitor of HSV-1 DNA polymerase, the triphosphate obtained from the slow-reacting R isomer had little or no inhibitory activity against this enzyme.     

The Dual Role of the 2′-OH Group of A76 tRNATyr in the Prevention of d-tyrosine Mistranslation

Aminoacyl-tRNA-synthetases are crucial enzymes for initiation step of translation. Possessing editing activity, they protect living cells from misincorporation of non-cognate and non-proteinogenic amino acids into proteins. Tyrosyl-tRNA synthetase (TyrRS) does not have such editing properties, but it shares weak stereospecificity in recognition of d-/l-tyrosine (Tyr). Nevertheless, an additional enzyme, d-aminoacyl-tRNA-deacylase (DTD), exists to overcome these deficiencies. The precise catalytic role of hydroxyl groups of the tRNA^Tyr A76 in the catalysis by TyrRS and DTD remained unknown. To address this issue, [³²P]-labeled tRNA^Tyr substrates have been tested in aminoacylation and deacylation assays. TyrRS demonstrates similar activity in charging the 2′ and 3′-OH groups of A76 with l-Tyr. This synthetase can effectively use both OH groups as primary sites for aminoacylation with l-Tyr, but demonstrates severe preference toward 2′-OH, in charging with d-Tyr. In both cases, the catalysis is not substrate-assisted: neither the 2′-OH nor the 3′-OH group assists catalysis. In contrast, DTD catalyzes deacylation of d-Tyr-tRNA^Tyr specifically from the 3′-OH group, while the 2′-OH assists in this hydrolysis.     

Purification of 5′-O-Trityl-on Oligoribonucleotides. Investigation of Phosphate Migration During Purification and Detritylation.

Abstract

Synthetic oligoribonucleotides (RNA) are efficiently prepared with 2′-O-tert-butyldimethylsilyl nucleoside 3′-O-phosphoramidites with labile base-protection; A_dmf or A_Pac, G_dmf, C_ibu, U. After cleavage from the polystyrene support, the exocyclic amine protecting groups are removed with conc. NH₄OH: ethanol/3:1 by heating at 55°C for 3–5 h. The 2′-O- silyl protecting groups are removed with tetra-n-butylammonium fluoride in THF or more conveniently with neat triethylamine trihydrofluoride. To gain the advantages of increased capacity on reverse phase HPLC and the convenience of cartridge based purification (OPC, Oligonucleotide Purification Cartridge), the 5′ trityl was left on the RNA as the final protecting group to be removed. The mild conditions which are effective for trityl removal are shown to preserve 3′-5′ phosphate linkage integrity in RNA. The absence of phosphate migration is demonstrated by model studies, utilizing N⁴ -isobutyryl-5′-O-DMT-3′-O-TBDMS-2′-O-(2-cyanoethyl-N,N-diisopropylphosphoramidite) as a control monomer and digestion by 3′-5′ selective P1 nuclease and alkaline phosphatase and HPLC analysis. Oligoribonucleotides were analyzed by Microgel capillary electrophoresis, anion-exchange HPLC, and the enzymatic digest/HPLC method.

     

The British Species of the Plagiothecium denticulatum–P. silvaticum Group

Abstract

Anomodon viticulosus was subjected to several different patterns of alternating wet and dry periods, and assimilation was measured at intervals over 49 days. Short periods of desiccation intercalated between 6-day moist periods had little effect on subsequent performance. Short moist periods breaking otherwise continuous desiccation had a very pronounced effect in mitigating desiccation damage. The results provide some evidence for a fairly slight, but probably cumulative, specific deleterious effect of drying and remoistening.     

Aldol Reaction of Nucleoside 5′-Carboxaldehydes with Acetone. Synthesis of 5′-C-Chain Extended Thymidine Derivatives

Abstract

Reaction of 3′-0-(t-butyldimethylsilyl)-2′-deoxythymidine-5′-carboxaldehyde and 2′,3′-dideoxythymidine-5′-carboxaldehyde with acetone afforded a 3:2 mixture of the two (5′R)- and (5′S)-5′-acetonylthymidine derivatives.     

TheS,X-acetals in nucleoside chemistry. I. The synthesis of 2′- and 5′-O-methylthiomethylribonucleosides

Ribonucleoside 2′- and 5′-O-methylthiomethyl derivatives were synthesized from selectively protected nucleosides by the action of a dimethyl sulfoxide-acetic anhydride-acetic acid mixture.     

Biologically Active Oligodeoxyribonucleotides. VII. Anti-HIV-1 Activity of Hexadeoxyribonucleotides Bearing 3′- and 5′-End-Modifications

Abstract

It has been determined that hexadeoxyribonucleotides (5′TGGGAG3′), which have modified aromatic groups such as the trityl group at the 5′-end, exhibit anti-HIV-1 activity in vitro. The 6-mer (S-1443) bearing a 3,4-dibenzyloxybenzyl (3,4-DBB) group at the 5′-end and a 2-hydroxyethylphosphate group at the 3′end exhibited the most potent activity and the least cytotoxicity. Moreover, it was found that the S-1443 was the most stable, when the 6-mer analogues were incubated with mouse, rat, or human plasma.     

MDPSCL2: A New Protecting Group for Chemoselective Synthesis of 2′-O-Alkylated Guanosines

Abstract

An improved strategy for the synthesis of 2′-O-methyl-guanosine (6) and 2′-MOE-guanosine (8) is reported. The regioselectivity of the alkylation was attained using a novel silicon-based protecting group, methylene-bis (diisopropyl-silylchloride) (MDPSCl₂, 2). The alkylation proceeded in a chemoselective manner using NaHMDS as the base and MeCl or MOE-Br as the appropriate electrophiles.     

Use of protoplasts in the improvement of filamentous microorganisms. I. Action of N-methyl-N′-nitro-N-nitrosoguanidine on protoplasts of Streptomycetes

Summary The effects of N-methyl-N–nitro-N-nitroso-guanidine (NTG) on protoplasts of Streptomycetes are markedly different from its action on spores, showing high mutagenic activity even at concentrations having no marked effect on protoplast survival. Strain improvement, eg in chlorotetracycline-producing strains of S. aureofaciens, was most effective when protoplasts were subjected to prolonged treatment (2 h) with low concentrations of NTG (50 /ug/ml).     

Partial Protection of Carbohydrate Derivatives. Part 19. Highly Regioselective 5′-O-Aroylation of 2′-Deoxyribonucleosides in Terms of Dilution - Drop-by-Drop - Addition Procedure

Abstract

Treatment of a 2′-deoxyribonucleoside in pyridine with an aroyl chloride, which was added dropwise as a dilute solution in pyridine, gave the corresponding 5′-O-aroyl-2′-deoxyribonucleoside in 84 - 93% yields.     

The utility of trnK intron 5′ region in phylogenetic analysis of Ulmaceae s. l.

The sequences of chloroplast trn K intron 5' region were determined for seven genera of Ulmaceae s.l. ( 12 species), two genera of Cannabaceae, two of Moraceae and one genus from each of the three families, i.e. , Urticaceae, Eucommiaceae and Malvaceae. The aligned sequences used in PAUP analyses were 805 bp, and the maximum parsimony analysis resulted in a single most parsimonious tree with tree length = 665, CI = 0.7714 and RI = 0.7965. The topology of the tree is relatively strongly supported by the bootstrap test and congruent with those generated from rbc L sequence analysis and cpDNA restriction site analysis. The phylogenetic tree indicated that Ulmaceae s. l. is polyphyletic, and that the monophyletic Ulmaceae s. str. is sister to the other Urticales taxa. Cannabaceae, represented by Humulus and Cannabis, is nested within Celtidaceae, revealing that Celtidaceae is a paraphyletic group. Gironniera and Aphananthe are both clades of Celtidaceae. 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