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.     

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.     

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.     

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.

     

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.     

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).     

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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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.     

Nucleosides and Nucleotides. 125. Synthesis and Biological Evaluation of 2′,3′-Dideoxy-3′-fluoro-2′-methylidene Pyrimidine Nucleosides

Abstract

Reaction of 2′-deoxy-2′-methylidene-5′-O-trityluridine (1) with diethylamino-sulfur trifluoride (DAST) in CH₂Cl₂ resulted in the formation of a mixture of (3′R)-2′,3′-dideoxy-3′-fluoro-2′-methylidene derivative 3 and 2′,3′-didehydro-2′,3′-dideoxy-2′-fluoromethyl derivative 4 (3:4 = 1:1.5) in 65% yield. A similar treatment of 1-(2-deoxy-2-methylidene-5-O-trityl-β-D-threo-pentofuranosyl)uracil (19) with DAST in CH₂Cl₂ afforded (3′S)-2′,3′-dideoxy-3′-fluoro-2′-methylidene derivatives 20 and 4 in 38% and 17% yields respectively. Transformation of the uracil nucleosides 4, 12, and 20 into cytosines followed by deprotection furnished the corresponding cytidine derivatives 29, 18, and 25, respectively. The corresponding thymidine congener 27 was also synthesized in a similar manner. All of the newly synthesized nucleosides were evaluated for their inhibitory activities against HIV and for their antiproliferative activities against L1210 and KB cells.     

Nucleic acid-like structures III. Oligomerization of 3′-deoxyadenosine 2′,5′-diphosphoimidazolide

Summary The activated dimonophosphate of 3-deoxyadenosine (cordycepin) undergoes oligomerization to produce a new family of pyrophosphate-linked oligomers in which the average repeating unit involves a nine-atom structural group. The presence of a poly(U) template increase the relative yields of higher oligomers, although the template-free reaction is itself extremely efficient.For the previous paper in this series see Schwartz et al. (1987)     

Conformationally Locked Nucleoside Analogs. Synthesis of 2′-Deoxy-2′-C, 4′-C-Bridged Bicyclic Nucleosides

Abstract

1-α-Methylarabinose was converted, in three steps, to 2-deoxy-2-methyleneribose derivative 3, which was subjected to hydroboration to give 2-α-hydroxymethyl derivative 4 exclusively. 4 was converted to 2,4-bis(hydroxymethyl)ribose derivative 6 in four steps. Mesylation, detritylation, and ring closure, followed by hydrolysis of the mesyl group at O5, gave 3,6-dioxabicyclo[3,2,1]octane derivative 8. After acetylation, 8 was coupled with silylated 6-chloropurine to give desired α- and β-bicyclic-sugar nucleosides.     

Modified Nucleosides. II.1 Economical Synthesis of 2′,3′-Dideoxycytidine

Abstract

An economical two pot synthesis of 2′,3′-dideoxycytidine (2) from N⁴-acetyl-cytidine (4) has been developed. The key feature of this sequence is the in situ reductive elimination of a mixture of 1-(3-bromo-3-deoxy-2,5-di-O-acetyl-β-D-xylofuranosyl)-N⁴-acetylcytosine (5) and 1-(2-bromo-3-deoxy-3,5-di-O-acetyl-β-D-arabinofuranosyl)-N⁴-acetylcytosine (6) and subsequent hydrogenation of the resultant olefin over palladised charcoal.     

The amino acid sequence of cytochrome c′ from Alcaligenes sp. N.C.I.B. 11015

The amino acid sequence of the cytochrome c' from Alcaligenes sp. N.C.I.B. 11015 (Iwasaki's ;Pseudomonas denitrificans') has been determined. This organism is the only non-photosynthetic bacterium in which the protein has been found. The protein consists of a single polypeptide chain of 127 residues, with a single haem covalently attached to two cysteines. Unlike normal cytochromes c, the haem attachment site is very close to the C-terminus. The amino acid sequence around the haem attachment site is very similar to that of Chromatium vinosum D cytochrome c'. Detailed evidence for the amino acid sequence of the protein has been deposited as Supplementary Publication SUP 50022 at the British Library (Lending Division), (formerly the National Lending Library for Science and Technology), Boston Spa, Yorks. LS23 7BQ, U.K., from whom copies may be obtained on the terms given in Biochem. J. (1973) 131, 5.     

Metabolism of 2,4,4′-Trichlorobiphenyl by Acinetobacter sp. P6

Metabolism of 2,4,4′-trichlorobiphenyl by Acinetobacter sp. strain P6 has been studied. When the incubation was carried out without shaking at 15°C, two isomeric monohydroxy compounds, a dihydrodiol compound, a dihydroxy compound, a meta-cleaved yellow compound and a dichlorobenzoic acid were detected by combined gas liquid chromatograph-mass spectrometry. As an additional metabolite, dichlorodihydroxy biphenyl, a dechlorinationhydroxylation product, was also detected. When the incubation mixture was shaken at 30°C, a meta-cleaved yellow compound was readily produced and predominantly accumulated in the reaction mixture upon further incubation. The major pathway of 2,4,4′-trichlorobiphenyl by Acinetobacter sp. P6 was considered to proceed oxidatively via 2.′3′-dihydro-2′,3′-diol compound, concomitant dehydrogenated 2′,3′-dihydroxy compound and then the 1′,2′-meta-cleaved yellow compound, i.e., 3-chloro-2-hydroxy-6-oxo-6(2,4-dichlorophenyl)hexa-2,4-dienoic acid.     

Relative Reactivity of Ribosyl 2′-OH vs. 3′-OH in Concentrated Aqueous Solutions of Phosphoimidazolide Activated Nucleotides

Phosphoimidazolide activated ribomononucleotides (*pN, see structure) are useful substrates for the non-enzymatic synthesis of oligonucleotides. In the presence of metal ions, aqueous solutions of *pN yield primarily the two internucleotide-linked (pN^2'pN and pN^3'pN) and the pyrophosphate-linked (N^5'ppN) dimers. Small amounts of cyclic dimers and higher oligomers are also produced. In this study the relative reactivity of 2-OH vs. 3-OH was determined from the ratio of the yields of pN^2'pN vs. pN^3'pN. Experiments were performed at 23 °C in the range 7.2 pH 8.4 with substrates that differ in nucleobase (guanosine (G), cytidine (C), uridine (U), and adenosine (A)) and leaving group (imidazole (Im), 2-methylimidazole (2-MeIm) and 2,4-dimethylimidazole (2,4-diMeIm)). Two metal ions (Mg²⁺ or Mn²⁺) were employed as catalysts. The conditions used here, i.e. a substrate concentration in the range 0.1 M to 1.0 M and metal ion concentration in the range 0.05 M to 0.2 M, favor base-stacking interactions. The ratio pN^2'pN: pN^3'pN = 2-5: 3-5 was found independent of nucleobase and typically varied between 2 to 3 indicating that the 2-OH is about 2 to 3 times more reactive than the 3-OH. *pN with Im, compared to 2-MeIm and 2,4-diMeIm leaving group, produce lower yields of internucleotide linked dimers, and a higher pN^2'pN: pN^3'pN ratio. Trends in the data, observed with all three leaving groups, suggest an increase in pN^2'pN: pN^3'pN ratio with decreasing substrate concentration (up to 5.47 with 0.051 M ImpG). The observations are in accord with earlier studies reporting a relative reactivity 2'-5': 3'-5'= 6 to 9 obtained with Im as the leaving group, in dilute nucleotide solutions and under conditions that disfavor stacking. It is speculated that the concentration induced change in the relative reactivity is the result of self-association via base-stacking that enhances selectively the proximity of the 3-OH of one molecule to the reactive P-N bond of an other molecule. The implication of these conclusions for oligomerization/ligation reactions is discussed.