Nucleosides,XLVI1 Syntheses and Reactions of 6- and 7-p-Chlorophenyllumazine Nucleosides

Abstract

The syntheses of 6-(4) and 7-p-chlorphenyl-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-lumazine (6), was well as the debenzoylation to the corresponding free nucleosides 5 and 7, were improved. Thiation of 4 and 6 by P₄S₁₀ led in excellent yields to 4-thiolumazine nucleosides (8, 10) which could be deblocked to 9 and 11 and converted on treatment with ammonia into the isopterin-N-1- ribofuranosides 13 and 14. 2,2′-Anhydro-nucleoside formation worked well with 5 and 7 respectively to give 15 and 16, which formed on acid hydrolysis the 6- and 7-substituted 1-β-D-arabinofuranosyl-lumazines 18 and 19. The new nucleosides have been characterized by UV and ¹H-NMR spectra.     

The Effect of Universal Fluorinated Nucleobases on the Catalytic Activity of Ribozymes

Abstract

Four fluoro modified universal nucleobases have been synthesized. The universal nucleobases 1 and 2 , containing a 2,4-difluorobenzene as nucleobase and a 4,6-difluorobenzimidazole, respectively, were chemically incorporated into a selected hammerhead ribozyme sequence which has already been retrovirally expressed as an anti-HIV ribozyme to investigate their effect on the catalytic activity of the ribozymes. The substitution of the natural nucleosides with either 1 or 2 results only in a small decrease of the catalytic activity. The K_m value for the monosubstituted ribozyme with a 2,4-difluorobenzene is 309 nM^?1, the corresponding k_cat is 2.91 · 10^?3 min^?1. A disubstituted hammerhead ribozyme carrying one of each modification has also been synthesized. For a further stabilization of the ribozyme/substrate complex 2′-(β-aminoethoxy) modified fluorinated nucleosides 15 and 16 have been developed.     

2′,3′-Dideoxyadenosine Analogs of the Nucleoside Antibiotics Tubercidin,Toyocamycin and Sangivamycin

Abstract

Application of previously described methodologies, for the synthesis of 2′,3′-dideoxy-2′,3′-didehydro nucleosides from the parent ribonucleosides, to the antibiotics tubercidin (1), toyocamycin (6) and sangivamycin (10) has provided the corresponding 2′,3′-unsaturated nucleosides 4, 9, and 13. A reduction of the 2′,3′-unsaturated moiety has afforded the 2′,3′-dideoxynucleoside antibiotics 5, 14, and 15.     

Improved and Reliable Synthesis of 3′‐Azido‐2′,3′‐dideoxyguanosine Derivatives

An improved synthesis of N²‐protected‐3′‐azido‐2′,3′‐dideoxyguanosine 20 and 23 is described. Deoxygenation of 2′‐O‐alkyl (and/or aryl) sulfonyl‐5′‐dimethoxytritylguanosine coupled with [1,2]‐hydride shift rearrangement gave protected 9‐(2‐deoxy‐threo‐pentofuranosyl)guanines ( 10 , 12 and 16 ). This rearrangement was accomplished in high yield with a high degree of stereoselectivity using lithium triisobutylborohydride (l‐Selectride®). Compounds 10 , 12 and 16 were transformed into 3′‐O‐mesylates ( 18 and 21 ), which can be used for 3′‐substitution. The 3′‐azido nucleosides were obtained by treatment of 18 and 21 with lithium azide. This procedure is reproducible with a good overall yield.     

Nucleosides,XL1 Synthesis and Properties of lin-Naphthamidazole-Ribonucleosides

Abstract

The fusion reaction between 1-trimethylsilyl-naphth[2,3-d]imidazole (3) and its 2-methyl derivative (4) with 2, 3, 5-tri-O-benzoyl-1-bromo-D-ribofuranose (6) leads to anomeric mixtures of the corresponding 2', 3', 5'-tri-O-benzoyl-1α- and β-D-ribofuranosylnaphth[2,3-d]imidazoles (7, 11 and 13). Separation of the anomers was achieved by chromatographical means and debenzoylation yielded the corresponding nucleosides (8, 12 and 10, 14). Structural proofs are based on elementary analysis, UV- and ¹H-NMR spectra.     

Synthetic Studies on the Isomeric N -Methyl Derivatives of C-Ribavirin

Abstract

The syntheses of all three of the mono-N-methy1 derivatives of C-ribavirin (3-β-D-ribofuranosyl-1, 2, 4-triazole-5-carboxamide, 2) have been accomplished. Reaction of 1-(β-D-ribofuranosyliminomethyl)-2-methyl-hydrazine ( 7 ) with ethyl oxamate (8) in boiling ethanol gave the N′-methyl-C-ribavirin ( 3 ). A similar treatment of β-D-ribofuranosyl-1-carboximidic acid methyl ester ( 6 ) with N′-methyloxamic hydrazide ( 10 ) furnished the N²-methyl-C-ribavirin ( 4 ). Direct methylation of unprotected 2 with methyl iodide in the presence of potassium carbonate in dimethyl sulfoxide gave N ⁴-methyl isomer ( 5 ) as the major product. Structural assignments of 3 , 4 , and 5 were based on the unequivocal synthetic sequences, ¹H and ¹³C NMR data and confirmed by single crystal X-ray diffraction analysis.     

Nucleosides,I Ribosylation of 8-Substituted Theophylline Derivatives

Abstract

The attempted ribosylation reaction of 8-nitro-theophylline (2) with 1-o-acetyl-2, 3, 5-tri-o-benzoyl-D-ribo-furanose (5) failed to give any nucleoside product, whereas the reaction of 8-chlorotheophylline (3) with 5 afforded the 8-chloro-7-(2,3,5-tri-o-benzoyl) β-D-ribofuranosyltheophylline (6) in good yield. The product 6 reacted with benzylamine producing the 8-benzylamino-7-(2, 3, 5-tri-O-benzoyl) β-D-ribo-furanosyltheophylline (10), which could also be synthesised by ribosylation of 8-benzylaminotheophylline (8) with 5. Debenzoylation of 6 and 10 gave the corresponding 7-β-D-ribofuranosyltheophylline nucleosides (7) and (11), respectively. Compound 7 could be converted into 11 by reaction with benzylamine. The newly synthesised compounds have been characterised by elemental analysis, ¹H-NMR and UV spectra.     

Nucleosides,XLVIII. Syntheses and Properties of Quinazoline N-1-Ribofuranosides

Abstract

Several 6- and 7-substituted quinazoline-2, 4-(1H, 3H)-diones (1–7) have been ribosylated with 1-0-acetyl-–2, 3, 5-tri-0-benzoyl-β-D-ribofuranose (8)via the “silyl”-method and Lewis acid catalysis in a highly regioselective manner to give the corresponding protected N-1 ribosides 9–15. Debenzoylation to the free nucleosides 16–22 was achieved by sodium methoxide. Thiation of 9–15 by Lawesson's reagent effected the conversion of the 4-oxo into the 4-thioxo function (23–29). Removal of the sugar protecting groups in these derivatives worked best with potassium carbonate in anhydrous MeOH to form in high yields 30–35. Treatment of the peracylated 4-thioxo quinazoline nucleosides with methanolic ammonia resulted in deacylation of the sugar moiety and in displacement of the sulfur function to give the corresponding 4-amino-1-β-D-ribofuranosylquinazolin-2(1H)-ones 36–41. The newly synthesized, nucleosides have been characterized by elemental analysis, UV- and ¹H-NMR-spectra.     

Synthesis and Biological Evaluation of some Acyclic Nucleoside Cyclic Phosphoramidate Derivatives

Abstract

The acyclic nucleosides 2 were treated with 2-chloro-3-methyl-1-oxa-3-aza-2-phosphacyclopentane (3) in the presence of diisopropylethylamine to give the corresponding phosphoramidite derivatives (4). The phosphoramidite intermediates (4) were oxidized with m-chloroperbenzoic acid to the phosphoramidate derivatives (5). Treatment of 5a,b with ZnBr₂ in CH₃NO₂ gave the corresponding acyclic nucleoside cyclic phosphoramidates (6a,b). Attempts to desilylation of 5c by tetrabutylammonium fluoride (TBAF) resulted in opening of the phosphoramidate ring. The newly synthesized compounds were evaluated for antiviral and antitumor cell activity.     

N4-(3-Methyl-2-Butenyl)-2-(Methylthio)Tubercidin and Its α-Anomer - 7-Deazapurine Nucleosides with Potential Anticytokinin Activity

Abstract

Phase-transfer catalysis of pyrrolo[2,3-d]pyrimidine 4a with the halogenose 5 yields the anomers 6a and 7a. Deprotection with boron trichloride gives the chloro nucleosides 6b and 7b, which are converted into the potential anticytokinin 2 and its α-anomer 3.     

Synthesis of Some Novel 1-(5-Thio-ß-D-glucopyranosyl)-6-azauracil Derivatives - Thiosugar Nucleosides

Abstract

The chemical syntheses of 1-(2,3,4,6-tetra-0-acety]-5-thio-β-D-glucopyranosyl)-6-azauracil (4) and the 5-bromo analogue 6 are described. Deblocking of 4 and 6 with sodium methoxide afforded the free nucleosides 5 and 7, respetively. Treatment of 6 with benzylmercaptan in basic medium led to the formation of 6-benzylthio-1-((2,3,4,6-tetra-0-acetyl-5-thio-β-D-glucopyranosyl)-6-azauracil (8), in good yield, which was deblocked to 9 on treatment with sodium methoxide. Reaction of 6 with benzlamine gave 5-benzylamino-1-(5-thio-β-D-glucopyranosyl)-6-azauracil (10).     

Synthesis of Pyrrolo[3,2-C]Pyridine 2′-Deoxy-D-Ribo-, 2′,3′-Dideoxy-D-Ribo-, and D-Arabinofuranosyl Nucleosides

Abstract

New pyrrolo[3,2-c]pyridine nucleosides (e.g. 2, 2, 4) have been prepared via solid-1iquid phase-transfer glycosylation. Additionally, building blocks for oligonucleotide synthesis are described.     

P1-(Thymidine 5′-)P1-amino-triphosphate: Synthesis,Hydrolysis and Reaction with Cytidine in Alkali1

Abstract

The title compound 1 is prepared from thymidine 5′-phos-phorodiamidate (2) and inorganic pyrophosphate (3) in anhydrous DMF, at 30–32°C. The products of alkaline hydrolysis of 1, at room temperature, are: thymidine 5′-phosphoramidate (4), thymidine 3′-phosphoramidate (8) and thymidine (9) as well as 3 and inorganic trimetaphosphate (10). In 1 N NH₄OH, 1 reacts with cytidine (15) to form cytidylyl-/2^T(3′)-5′/-thymidine (16) and a mixture of cytidine 2′,3′-cyclic phosphate (17) and 9.     

The tRNA “Wobble Position” Uridines. IV. The Synthesis of 2′-O-Methyl-5-methoxycarbonylmethyluridine and its Derivatives

Abstract

2′-O-Methyl-5-methoxycarbonylmethyluridine (1) was synthesized via N³, 5′, 3′-O-protected intermediate 6. Nucleoside 1 was transformed to the next “wobble uridines”, 2 and 3, by hydrolysis and ammonolysis, respectively.     

The tRNA “WOBBLE POSITION” Uridines. III.1 the Synthesis of 5-[S-Methoxycarbonyl (Hydroxy)Methyl] Uridine and its 2-Thio Analogue

Abstract

The diastereoisomers 2a, 2b and their 2-thio analogues 4a and 4b were obtained by three-step transformation of uridine and 2-thiouridine, respectively. The absolute configuration at C-5¹ in 2a and 2b was established by CD, while for 4a and 4b the configurational assignment was based on the chemical correlation. The acids 1 and 3 were obtained by alkaline hydrolysis of 2a and 4a, respectively.     

Synthesis and Biological Activity of 5-halo-2-Pyrimidinone 3′-Azido-2′,3′-Dideoxyribosides

Abstract

The synthesis of two nucleosides, 1-(3-azido-2,3-dideoxy-β-D-ribofuranosyl)-5-iodo- and -5-bromo-2(1H)-pyrimidinone, 1a and 1b, is described. Neither 1a nor 1b exhibited significant inhibition of T, lymphocyte growth. However, both compounds were unable to protect T, lymphocytes from the cytopathic effects of HIV.     

Conformation of Diastereomers of Adenosine Cyclic 3′, 5′-Phosphorothioate

Abstract

¹H and ³¹P NMR spectra of cAMP (1) and both diastereomers of cAMPS (2 and 3) were compared with these of structurally related bicyclic phosphate 4 and phosphorothioates 5 and 6. Conformational analysis was also performed by NMR techniques for bicyclic phosphoranilidates 7 and 8 and (Rp)-cdAMP anilidate (9). Chair conformation is predominant for all investigated compounds 1–8, while the phosphoranilidate 9 exists in solution in chair-twist equilibrium. Thus, antagonistic properties of (Rp)-cAMPS with respect to cAMP are inferred by the change in the overall molecular shape caused by the presence of the bulky sulfur atom in the equatorial position of the cAMPS molecule.     

Nucleosides,XLIV1 Synthesis,Properties and Biological Activity of Indazole Nucleosides

Abstract

Various new haloindazole-1-β-D-ribofuranosides (10-17,20,21) and a 2-β-D-ribofuranoside (18) have been synthesized by the fusion method and by direct halogenations, respectively. The new nucleosides have been characterized by UV and ¹H NMR spectra as well as pK_a determinations. Indazole ribofuranosides behave in aqueous acid like purine and benzimidazole nucleosides showing the same mechanism of cleavage of the glycosidic bonds. Toxicity studies against various cell populations indicate only little biological activities.     

Nucleosides,XLIII1) Synthesis and Properties of 04-Alkylthymidines

Abstract

Various 0⁴-alkylthymidines 14–20 have been synthesized by two different methods. 0⁴-Alkylation takes place with 3′,5′-di-0-acetyl- (2) and 3′,5′-di-0-benzoylthymidine (3) respectively in a silver ion catalysed reaction with alkyl halides, whereas the azolide approach makes use of a nucleophilic displacement of the appropriate intermediate by alkoxides and subsequent deacylation to the free nucleosides. Structural proofs are based on elemental analyses, UV- and ¹H-NMR-spectra.     

Synthesis of the Selenium Analog of the Cytokinin 6-(3-Methyl-2-Butenylamino)-2-Methylthio-9-(β-D-Ribofuranosyl)Purine

Abstract

6-(3-methyl-2-butenylamino)-2-methylthio-9-(β-D-ribofuranosyl)purine (1) is a naturally occurring nucleoside with potent cytokinin activity. It has been isolated and identified in the t-RNA of E. coli,^1,2 the t-RNA from wheat germ^3,4 and from Staphylococcus epidermidis.⁵ In addition, compound 1 has been found in t-RNA species corresponding to each of six amino acids whose codons start with uridine, i.e., t-RNA^Cys