Asymmetric Synthesis of Cyclopropyl Carbocyclic Nucleosides

Abstract

A number of nucleosides have been synthesized as potential antiviral and antitumor agents.¹ More recently, various dideoxynucleosides have been synthesized and found to be potent anti-HIV agents.² As a part of our drug discovery program for the treatment of HIV and HBV, we have initiated to synthesize cyclopropyl carbocyclic nucleosides as potential antiviral agents. Several papers regarding the synthesis of cyclopropyl carbocyclic nucleosides have appeared in the literature.^3–5 However, they are all reported as racemic mixtures. In this abstract, we wish to report the asymmetric synthesis of cylopropyl carbocyclic nucleosides from optically active common intermediates, 6 and 11.     

Synthesis and Antiviral Activities of Enantiomeric 1-[2-(Hydroxymethyl) Cyclopropyl] Methyl Nucleosides

Abstract

Cyclopropyl carbocyclic nucleosides have been synthesized from the key intermediate 2 which was converted to the mesylated cyclopropyl methyl alcohol 3. Condensation of compound 3 with various purine and pyrimidine bases gave the desired nucleosides. All synthesized nucleosides were evaluated for antiviral activity and cellular toxicity. Among them adenine 22 and guanine 23 derivatives showed moderate antiviral activity against HIV-1 and HBV. None of the other compounds showed any significant antiviral activities against HIV-1, HBV, HSV-1 and HSV-2 in vitro up to 100μM.     

A Convenient Approach to the Synthesis of Azido-Acyclic Nucleosides

Abstract

The azidation of unprotected acyclic nucleosides (4) was carried out in a one-pot reaction by means of the reagent triphenylphosphine-carbon tetraiodide-sodium azide to give the corresponding mono-azido-acyclic nucleosides (6) in good yields without by-products such as the di-azido-acyclic nucleosides.     

FUNCTIONALIZATION OF PYRIMIDINE AND PURINE NUCLEOSIDES AT C4 AND C6: C-NUCLEOPHILIC SUBSTITUTION OF THEIR C4- AND C6-(1,2,4-TRIAZOL-1-YL) DERIVATIVES

A study of C-nucleophilic substitution at the C4-position on pyrimidine and C6-position on 2′-deoxyguanosine to produce novel nucleosides is presented with the spectroscopic properties of their respective substitution products. C4-(1,2,4-triazol-1-yl) pyrimidine nucleosides 1 were treated with nitroalkanes, malononitrile, acetylacetone, ethyl nitroacetate, acetoacetate and cyanoacetate at 100°C in dioxane in the presence of DBU resulting in the production of novel nucleosides 2–11. To explore the application of this methodology to purine chemistry, this approach was used to produce novel analogs from 2′-deoxyguanosine. We found that the triazolo derivative 12 undergoes C-nucleophilic substitution with nitromethane, malononitrile, acetylacetone, ethyl nitroacetate and cyanoacetate in the presence of potassium carbonate (K₂CO₃) in DMF at 100°C to give novel nucleosides 13–7.     

Deamination of 9-(Hydroxymethylated cycloalkyl)-9H-adenines (Carbocyclic Adenine Nucleosides) by Adenosine Deaminase: Effect of High-Pressure Upon Deamination Rate and Enantioselectivity

Abstract

The deamination of eight kinds of racemic carbocyclic adenine nucleosides by adenosine deaminase under high-pressure (400 MPa) was examined and the result was compared with that obtained from the reaction under atmospheric pressure. The deamination of all carbocyclic nucleosides irrespective to their ring size of carbocycles was facilitated remarkably high-pressure. The reaction of three and five membered carbocyclic nucleosides resulted in the very high enantioselectivity both under high- and atmospheric Plessure whereas the enantioselectivity of six membered carbocyclic nucleosides was suppressed under high-pressure. However, the enantioselectivity of four membered nucleosides was low under both conditions.

     

Ring Opening Reaction of Pyrazolo[3,4-c]Maleimide Nucleosides

Abstract

Synthesis of pyrazolo[3,4-c]maleimide nucleosides was attempted, but ring opening reaction of the maleimide part was observed during ammonolysis of sugar-protected pyrazolo[3,4-c]maleimide nucleosides. The isolated pyrazole nucleosides were characterized by NMR spectra and X-ray analysis.     

Synthesis and Testing of New Modified Nucleosides

Abstract

New efficient routes for the high-yielding synthesis of several classes of modified nucleosides have been developed. We have prepared both the D- and L-enantiomers of the methylene-expanded oxetanocin isonucleosides 1a-c and the L-2′,3′-dideoxy isonucleosides 2abc (both the oxa and thia analgoues) as well as new routes for the preparation of L-ribose and 2-deoxy L-ribose 3ab and their modified nucleosides 4.     

Urinary Modified Nucleosides as Tumor Markers

Abstract

Extracts of urinary nucleosides have been sequentially purified and examined by mass spectrometric analysis. Seventeen modified nucleosides have been unequivocally identified and a further five provisionally identified. While several nucleosides were found only in a small number of extracts, the occurrence and levels of others were found to correlate with the tumour type and stage.     

8-Substituted Adenine β-D-Xylofuranosides and α-L-Arabinofuranosides

Abstract

9-(β-D-Xylofuranosyl) adenine and 9-(α-L-arabinofuranosyl)-adenine have been modified to give a series of 8-amino-substituted nucleosides. Convenient methods of halogenation of these nucleosides and reactions of 8-halogenated nucleosides with various amines are described. No significant cytotoxic or antiviral activity was found.     

Properties of Oligonucleotides Containing the Transition Bases P and K

Abstract

The properties of the degenerate nucleosides dP and dK, in templates and primers were determined. dP was copied as either pyrimidine, dK as either purine. In primers, an equimolar mixture of the two nucleosides functioned as a universal base equivalent in both sequencing and the polymerase chain reactions. Cloning of DNA containing dP or dK produced transition mutations in vivo.     

Synthesis and Anti-HIV Properties of 1,2,4,6-Thiatriazin-3-one 1,1-Dioxtoe Nucleosides

Abstract

Synthesis of 1,2,4,6-thiatriazine 1,1-dioxide nucleosides is now reported for the first time. In order to know the conformation of the nucleosides, a NMR study has been carried out. Anti-HIV-1 and HIV-2 properties of the nucleosides have been tested. These compounds have not shown activity at subtoxic concentrations.     

SYNTHESIS AND BIOLOGICAL ACTIVITY OF 4′-C-HYDROXYMETHYL-2′-FLUORO- D-ARABINOFURANOSYLPURINE NUCLEOSIDES

A series of 4′-C-hydroxymethyl-2′-fluoro-D-arabinofuranosylpurine nucleosides was prepared and evaluated for cytotoxicity. The details of a convenient synthesis of the carbohydrate precursor 4-C-hydroxymethyl-3,5-di-O-benzoyl-2-fluoro-α-D-arabinofuranosyl bromide (13) are presented. Proof of the structure and configuration at all chiral centers of the sugars and the nucleosides were obtained by proton NMR. All five target nucleosides were evaluated for cytotoxicity in human tumor cell lines. The 4′-C-hydroxymethyl clofarabine analogue (16β) showed slight cytotoxicity in CCRF-CEM leukemia cells.     

SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME 4-SUBSTITUTED 1-[1-(4-HYDROXYBUTYL)-1,2,3-TRIAZOL-(4 & 5)-YLMETHYL]-1H-PYRAZOLO-[3,4-d]PYRIMIDINES

The synthesis of 1-[1-(4-hydroxybutyl)-1,2,3-triazol-(4 and 5)-ylmethyl] -1H-pyrazolo[3,4-d]pyrimidines 11a,b, 12a,b and 13–17 as carboacyclic nucleosides is described. The compounds 8a,b were condensed, separately, with compound 7 via 1,3-dipolar cycloaddition reaction to afford, after separation and deprotection, 1,4-regioisomers 11a,b and 1,5-regioisomers 12a,b. The deprotected carboacyclic nucleosides 11a served as precursor for the preparation of 4-amino 13, 4-methylamino 14, 4-benzylamino 15, 4-methoxy 16 and 4-hydroxy 17 analogues. All deprotected carboacyclic nucleosides were evaluated for their inhibitory effects against the replication of HIV-1(III_B), HIV-2(ROD), various DNA viruses, a variety of tumor-cell lines and tuberculosis. No marked biological activity was found.     

SYNTHESIS AND BIOLOGICAL ACTIVITY OF 4′-C-HYDROXYMETHYL-2′-FLUORO-D-ARABINOFURANOSYLPURINE NUCLEOSIDES

A series of 4′-C-hydroxymethyl-2′-fluoro-D-arabinofuranosylpurine nucleosides was prepared and evaluated for cytotoxicity in human tumor cell lines. A convenient synthesis of the carbohydrate precursor 4-C-hydroxymethyl-3,5-di-O-benzoyl-2-fluoro-α-D-arabinofuranosyl bromide (13) was developed. Coupling of 13 with the sodium salt of 2,6-dichloropurine led to five target purine nucleosides.     

Configurational and Conformational Analysis of Regular and Modified Nucleosides by 1D-NOE Difference Spectroscopy

Abstract

1D-Nuclear Overhauser enhancement (NOE) spectroscopy on regular and modified nucleosides provides qualitative and semiquantitative information about configurational and conformational parameters. The formula scheme shows selected nucleosides which were studied with this technique.     

Synthesis of Quinoxaline Azido and Amino Reverse Ribofuranoside and Their O-Regioisomers

A series of quinoxaline azido reverse nucleosides 3a-c and their O-regioisomers 4a-c was prepared by reaction of quinoxaline 1a-c with 3-azido-3-deoxy-1,2-O-isopropylidene-5-p-toluenesulfonyl-D-ribofuranose (2) in the presence of sodium hydride. Structure modification of these interesting structures includes reduction and the subsequent acetylation reactions to give quinoxaline amino and acetyl amino reverse nucleosides and their O-regioisomers.     

A Versatile Synthesis of Dihydropyrimidinone C‐Nucleosides

A versatile synthesis of N‐substituted dihydropyrimidinone C‐nucleosides (20–29) is described. Glycosyl amino esters (3–9), obtained by reductive alkylation of glycosyl amino esters 1 and 2, on condensation with different isocyanates afforded respective ureido derivatives (10–19) in good to quantitative yields. The latter on cyclative amidation with a combination of DBU/TBAB (tetrabutylammonium bromide)/4Å molecular sieve gave the corresponding nucleosides (20–29) in good yields.     

Synthesis and Antitumor Activity of N-Sulfonyl Derivatives of Nucleobases and Sulfonamido Nucleoside Derivatives

Abstract

The introduction of sulfonamido group on the C-2 position of pyrimidine nucleosides was achieved by ring opening of 2,2′- and 2,3′-anhydronucleosides. N-sulfonyl derivatives of nucleobases and sulfonamido derivatives of nucleosides were assayed for in vitro antitumor activity.     

Preparation of 15N Labeled Nucleosides and Large Scale Synthesis of Labeled Oligonucleotides with a New Type DNA-Synthesizer

Abstract

Microbiological and chemical methods for the preparation of ¹⁵N labeled nucleosides are described. Oligonucleotides are synthesized from the labeled nucleosides on a large scale by the phosphoramidite procedure using a self-developed DNA - Synthesizer. Preliminary ¹⁵N-NMR studies are reported.