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.     

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.     

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.     

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.     

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.     

Synthesis and Biological Activity of 5-Fluoro-2-thiocytosine Nucleosides

Abstract

Two pathways are described for the synthesis of the 2′-deoxynucleosides of 2-thiocytosine and 5-fluoro-2-thiocytosine: (a) by nucleoside condensation, (b) by amination of the corresponding nucleosides of 2,4-dithiouracil. Biological activities vs two cell systems are described. The nucleosides are moderate to weak substrates of deoxycytidine kinase and, partly as a result of this, reasonable good inhibitors of the enzyme     

Nucleosides and Nucleotides. 98. Synthesis and Antitumor Activities of 5-Ethynylimidazole-4-carboxamide and -carbonitrile Derivatives

Abstract

5-Ethynyl-1-(2-deoxy-β-D-ribofuranosyl)imidazole-4-carbonitrile (4) and -carboxamide (5) and 5-ethynyl-1-(5-deoxy-β-D-ribofuranosyl)imidazole-4-carbonitrile (11) and -carboxamide (12) have been synthesized from the corresponding 5-iodo derivatives 2 and 7 by a palladium-catalyzed cross-coupling reaction with (tri-methylsilyl)acetylene. The aglycons, 5-ethynylimidazole derivatives 14 and 15 were synthesized by the hydrolytic cleavage of the corresponding nucleosides. The antileukemic activity of these nucleosides and base analogues are also described.     

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 of 1,1,2-trisubstituted cyclopropane nucleosides in enantiomerically pure forms

Abstract

Due to the unique rigid and small steric feature of cyclopropane, cyclopropane nucleosides (CPNs) in which the ribose (deoxyribose) of nucleosides are replaced by a hydroxy-substituted cyclopropane, are of great biological interest. Novel 1,1,2-trisubstituted cyclopropane nucleosides were synthesized in enantiomerically pure forms as potential antiviral agents. In the synthesis, two cyclopropane tosylates, which were prepared from chiral cyclopropane lactones previously reported by us, were used effectively as common intermediates for the CPNs. These CPNs are also potentially useful as nucleoside units to incorporate into oligonucleotides in nucleic acids chemotherapy studies.     

Synthesis of “Reversed” and “Double Headed” Nucleosides

Abstract

The synthesis of several partially and fully deprotected “reversed” nucleosides are described starting from “reversed” 5-iodouracil-1-yl nucleoside 1. The preparation of a novel purine-purine and mixed purine-pyrimidine “double headed” nucleosides via “reversed” purine nucleoside 12 is also described.     

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.     

Propeller Twisting in Single Crystals of Nucleosides

Abstract

Propeller twists were measured for base-paired nucleosides and nucleic acid bases. The occurrence of propeller twist outside a double helical framework is shown, and conclusions drawn on the relative magnitude of the effect in single nucleosides.     

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.     

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.     

Fluorescence Properties and Base Pair Stability of Oligonucleotides Containing 8-Aza-7-deaza-2′-deoxyisoinosine or 2′-Deoxyisoinosine

Abstract

The fluorescence and the base pairing properties of 8-aza-7-deaza-2′-deoxyisoinosine (1) are described and compared with those of 2′-deoxyisoinosine (2). The corresponding phosphoramidites (11,12) are synthesized using the diphenyl-carbamoyl (DPC) residue for the 2-oxo group protection. The nucleosides 1 and 2 base pair with 2′-deoxy-5-methylisocytidine in DNA duplexes with antiparallel chain orientation and with 2′-deoxycytidine in a parallel DNA. These base pairs are less stable than the canonical dA-dT pair and that of 2′-deoxyinosine (4) with 2′-deoxycytidine. The fluorescence of the nucleosides 1 and 2 is quenched (～95%) in duplex DNA. The residual fluorescence is used to determine the T_m-values, which are found to be the same as determined UV-spectrophotometrically.     

Carboxyamidation of Purine Nucleosides: New Secondary 8-Carboxamidopurine Nucleosides

Abstract

Palladium catalyzed carboxyamidation at the 8-position of 8-bromoadenosine and 8-bromoguanosine nucleosides is a versatile reaction, which allows primary, secondary, heterocyclic, aromatic mine and amino acids to be incorporated into purine nucleosides.     

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.