Pummerer Rearrangement of Selenium-Containing Uracil Nucleosides

Abstract

Pummerer-type rearrangement of uracil nucleosides having a phenylseleno group in the 2′-, 3′-, and 5′-positions took place upon oxidation with MCPBA in CH₂Cl₂ followed by treatment with acid anhydrides to yield α-acyloxyselenides.     

Coupling of 2,6-Dichloropurine and 2,6-Dichlorodeazapurines with Ribose and Ribose Modified Sugars

Abstract

Substituted purine and deazapurine nucleosides are of great interest in medicinal chemistry. Furthermore, 3′-deoxynucleosides exhibit a number of biological activities. In this research the coupling of 2,6-dichloro-1- or 3-deazapurine with protected 3′-deoxyribose is reported. Depending upon coupling conditions and base structure, different anomeric and isomeric mixtures have been obtained. Extensive studies, utilizing chemical and physical methods, have been performed to assign the correct configuration to the resulting nucleosides.     

Synthesis and Biologic Evaluation of 8-Substituted Derivatives of Nebularine (9-β-D-Ribofuranosylpurine)

Abstract

A series of 8-substituted purine ribonucleosides were prepared from 2′, 3′, 5′-tri-O-acetyl-8-bromoadenosine and evaluated for cytotoxicity and antiviral activity. Four of these nucleosides (6b-9b) were significantly toxic to both HEp-2 and L1210 cells in culture but the most cytotoxic one (9b) was inactive against the P388 leukemia in mice. None of these nucleosides showed significant antiviral activity against Herpes Simplex 1 or 2, vaccinia, or influenza A.     

New Sulphonamide and Carboxamide Derivatives of Acyclic C-Nucleosides of Triazolo-Thiadiazole and the Thiadiazine Analogues. Synthesis,Anti-HIV,and Antitumor Activities. Part 2

A new series of acyclic C-nucleosides 1′,2′-O-isopropylidene-D-ribo-tetritol-1-yl)[1,2,4] triazolo[3,4-b][1,3,4]thiadiazoles bearing arylsulfonamide (5–8) and arylcarboxamide (9–12) residues have been synthesized under microwave irradiation. Thiadiazines 13–15 have been analogously prepared, and upon acid hydrolysis, afforded the free nucleosides 16–18. The new synthesized compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compound 7 was also screened against a panel of tumor cell lines consisting of CD4 human T-cells.     

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.

     

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.     

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.     

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.     

A Reinvestigation of Sulfenyl Groups as Amino Protecting Groups for the Synthesis of Oligonucleotides on Solid Support by Phosphoramidite Chemistry†

Abstract

Although sulfenyl groups as protectors of heterocyclic amines of nucleosides appeared satisfactory during the synthesis of DNA and RNA via the phosphotriester approach, their usefulness in automated synthesis of oligonucleotides using phosphoramidite chemistry has not been investigated. Herein, we examined the stability and efficiency of 2-nitrophenylsulfenyl- and tritylsulfenyl-nucleosides upon the conditions applied in oligonucleotide synthesis by the phosphoramidite approach.

     

Synthesis and triplex forming properties of pyrimidine derivative containing extended functionality.

Two pyrimidine nucleosides have been synthesized containing extended hydrogen bonding functionality. In one case the side chain is based upon semicarbazide and in the second monoacetylated carbohydrazide was employed. DNA sequences could be prepared using both analogue nucleosides in a reverse coupling protocol, and provided that the normal capping step was eliminated and that the iodine-based oxidizing solution was replaced with one based upon 10-camphorsulfonyl oxaziridine. Both derivatives exhibited moderate effects in targeting selectively C-G base pairs embedded within a polypurine target sequence.     

C-Glycosylation of Substituted Heterocycles Under Friedel-Crafts Conditions (II): Ribosylation of Multi-Functionalized Thiophenes and Furans for the Synthesis of Purine-Like C-Nucleosides

Abstract

In our continuing studies of the Friedel-Crafts glycosylation of preformed heterocycles, we have observed that while the SnCl₄ catalyzed glycosylation of methyl 4-(formylamino)thiophene-3-carboxylate (5) gives readily the C-nucleosides 7b and 7a, the corresponding Et₂AlCl catalyzed reaction gives exclusively the N-nucleoside 11. These nucleosides can be further elaborated into the bicyclic thieno[3,4-d]-pyrimidine system. Similarly, methyl 4-(formylamino)furan-3-carboxylate (19) gave the expected C-nucleosides 2Ob and 2Oa upon glycosylation in the presence of SnCl₄. However, these nucleosides could not be converted into the furo[3,4-d]pyrimidine system. Interestingly, several of the N-formamido compounds exhibit pronounced rotational isomerism, which was demonstrated by ¹H NMR spectroscopy     

Synthesis of Nucleoside 3′-Thiophosphates in One Step Procedure

Abstract

A mild and efficient one-step method of thiophosphorylation was devised for acid-sensitive nucleosides. The procedure is based on thiophosphorylation of nucleoside magnesium alkoxide by 2-chloro-2-thio-1,3,2-dioxaphospholane. The utility and efficiency of this method combined with deprotection of the resulting cyclic triester were demonstrated by its application to the synthesis of both adenosine 3′- and 5′-thiophosphates. The procedure does not require protection of the exocyclic amino group and can be successfully used for the thiophosphorylation of nucleosides that are unusually sensitive to depurination.     

Acyclic Nucleosides other than Acyclovir as Potential Antiviral Agents

Abstract

In the past few years interest in the synthesis and biological properties of acyclic nucleosides has been generated based largely upon the development of acyclovir [9-[(2-hydroxyethoxy)methyll guanine, 1a] as an antiviral agent for the treatment of certain herpesvirus infections. The literature in the area covers a variety of different heterocycles, a variety of different side chains, and spans research that is strictly synthetic to research that is strictly biological. Two compounds, 9-[(2-hydroxy-l-(hydroxymethyl)ethoxy)methyl] guanine (1b) and 9-(S)-(2,3-dihydroxypropyl)adenine (2), have received the most attention, but many others have been made.     

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.     

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.     

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 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.     

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.