SYNTHESIS AND BIOLOGICAL ACTIVITY OF 4′-THIO-L-XYLOFURANOSYL NUCLEOSIDES

A series of 4′-thio-L-xylofuranosyl nucleosides were prepared and evaluated as potential anticancer and antiviral agents. The details of a convenient and high-yielding synthesis of the carbohydrate precursor 1-O-acetyl-2,3,5-tri-O-benzyl-4- thio-L-xylofuranose (6) are presented. Proof of structure and configuration at all chiral centers of the nucleosides was obtained by proton and carbon NMR. All target compounds were evaluated in a series of human cancer cell lines in culture and as antiviral agents.     

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.     

SYNTHESIS AND IN VITRO ANTIVIRAL ACTIVITY EVALUATION OF 9-(2-AZIDO-2,3-DIDEOXY-β-D-THREO-PENTOFURANOSYL)ADENINE DERIVATIVES

9-(2-Azido-2,3-dideoxy-β-D-threo-pentofuranosyl)adenine derivatives (1a–e) containing a lipophilic function at the N-6 position in the purine ring were prepared and evaluated for their antiviral activity. The compounds 1a–e turned out to be inactive as antiviral agents.     

SYNTHESIS AND BIOLOGICAL ACTIVITY OF 2′-DEOXY-4′-THIO-PYRAZOLO[3,4-d]PYRIMIDINE NUCLEOSIDES

The coupling of 4-aminopyrazolo [3, 4-d]pyrimidine with the appropriate thio sugar gave a 3:1 ratio of α,β blocked 4-amino-1-(2-deoxy-4-thio-D-erythropentofuranosyl)- 1H pyrazolo[3,4-d]pyrimidine nucleosides. The mixture was deblocked, both the anomers were separated, and the β-anomer was readily deaminated by adenosine deaminase. The nucleosides have been characterized, and their anomeric configurations have been determined by proton NMR. All three nucleosides were evaluated against a panel of human tumor cell lines for cytotoxicity in vitro. The details of a convenient and high yielding synthesis of these nucleosides are described.     

COMPARISON OF THE ANTIVIRAL ACTIVITY OF HYDROPHOBIC AMINO ACID PHOSPHORAMIDATE MONOESTERS OF 2′, 3′-DIDEOXYADENOSINE (DDA) AND 3′-AZIDO-3′-DEOXYTHYMIDINE (AZT)

A series of hydrophobic, water soluble and non-toxic amino acid phosphoramidate monoesters of dideoxyadenosine (ddA) and 3′-azido-3′-deoxythymidine were shown to inhibit the replication of HIV-1 in human peripheral blood mononuclear cells (PBMC) from two donors. The tryptophan methyl ester phosphoramidates of AZT and ddA were equally potent (EC₅₀S = 0.3–0.4 μM), while the phenyl methyl ester of ddA was 40- to 100- fold more potent than the AZT derivatives. The alaninyl methyl ester of AZT was found to be 70- fold more potent than the ddA derivative. The methyl amide derivatives were found to be 5–20 fold less active than the methyl esters for the ddA series, while for AZT the derivatives were found to be of similar potency or 60- to 166- fold more potent than the methylesters.     

SYNTHESIS AND ANTIPROLIFERATIVE ACTIVITY OF SOME 4′-C-HYDROXYMETHYL-α- AND -β-D-ARABINO-PENTOFURANOSYL PYRIMIDINE NUCLEOSIDES

A suitably protected 4-C-hydroxymethyl-arabino-pentofuranose was prepared and condensed with the following nucleobases: uracil, 5-fluorouracil and thymine. The corresponding cytosine and 5-fluorocytosine derivatives have also been obtained respectively from the uracil and 5-fluorouracil nucleosides. Separation of the anomeric mixtures followed by deprotection afforded the target compounds that were found to be non-cytotoxic to CCRF-CEM leukemia cells.     

SYNTHESIS OF SOME 2′-FLUORO-2′-DEOXY-3′-C-ETHYNYL AND 3′-C-VINYL-β-D-LYXOFURANOSYL NUCLEOSIDES

1-(2-Fluoro-2-deoxy-β-D-arabinofuranosyl)uracil (5) and 1-(2-fluoro-2-deoxy-β-D-arabinofuranosyl)cytosine (6) were synthesized as reported earlier. Both of these compounds were converted into 2′-fluoro-2′-deoxy-3′-C-ethynyl and 3′-C-vinyl-β-D-lyxofuranosyl nucleosides (16–19) by a multistep sequence. All these new nucleosides were evaluated against seven human tumor cell lines in vitro.     

SYNTHESIS AND IN VITRO ANTI-HCV ACTIVITY OF β-D- and L-2′-DEOXY-2′-FLUORORIBONUCLEOSIDES

Based on the discovery of β-D-2′-deoxy-2′-fluorocytidine as a potent anti-hepatitis C virus (HCV) agent, a series of β-D- and l-2′-deoxy-2′-fluororibonucleosides with modifications at 5 and/or 4 positions were synthesized and evaluated for their in vitro activity against HCV and bovine viral diarrhea virus (BVDV). The introduction of the 2′-fluoro group was achieved by either fluorination of 2,2′-anhydronucleosides with hydrogen fluoride-pyridine or potassium fluoride, or a fluorination of arabinonucleosides with DAST. Among the 27 analogues synthesized, only the 5-fluoro compounds, namely β-D-2′-deoxy-2′,5-difluorocytidine (5), had anti-HCV activity in the subgenomic HCV replicon cell line, and inhibitory activity against ribosomal RNA. As β-D-N4-hydroxycytidine (NHC) had previously shown potent anti-HCV activity, the two functionalities of the N4-hydroxyl and the 2′-fluoro were combined into one molecule, yielding β-D-2′-deoxy-2′-fluoro-N4-hydroxycytidine (12). However, this nucleoside showed neither anti-HCV activity nor toxicity. All the l-forms of the analogues were devoid of anti-HCV activity. None of the compounds showed anti-BVDV activity, suggesting that the BVDV system cannot reliably predict anti-HCV activity in vitro.     

SYNTHESIS OF NOVEL 3′-DEOXY-3′-C-HYDROXYMETHYL NUCLEOSIDES WITH CONFORMATIONALLY RIGID SUGAR MOIETY AS POTENTIAL ANTIVIRAL AGENTS

Based on the fact that the ring expanded 3′-C-hydroxymethyl analogue of oxetanocin A exhibited potent antiviral activity, two types of conformationally rigid 3′-C-hydroxymethyl derivatives in which 2′-hydroxyl group is linked to the 4′-position or to the 6′-position were synthesized starting from 1,2;5,6-di-O-isopropylidene-D-glucose, respectively.     

A NEW APPROACH TO THE SYNTHESIS OF 4′-CARBON-SUBSTITUTED NUCLEOSIDES: DEVELOPMENT OF A HIGHLY ACTIVE ANTI-HIV AGENT 2′, 3′-DIDEHYDRO-3′-DEOXY-4′-ETHYNYLTHYMIDINE

Oxidation of 3′-O-TBDMS-4′,5′-unsaturated thymidine 3 with dimethyldioxirane (DMDO) allowed the isolation of the epoxide 4. Upon reacting with organosilicon reagents in the presence of SnCl₄, 4 underwent stereoselective ring opening to give 4′-α-allyl (6), 4′-α-(2-bromoallyl) (7), 4′-α-(cyclopenten-3-yl) (8), and 4′-α-cyano (9) derivatives of thymidine. Reactions of the 3′-epimer 12 with organoaluminum reagents gave 4′-α-methyl (13), 4′-α-vinyl (14), and 4′-α-ethynyl (15) analogues. Compounds 13–15 were transformed into corresponding 2′,3′-didehydro-3′-deoxy derivatives. Evaluation of their ability to inhibit the replication of HIV in cell culture showed that 4′-ethynyl-d4T (19) is more potent and less toxic than the parent compound d4T.     

3′-AZIDO-3′-DEOXY-5′-O-ISONICOTINOYLTHYMIDINE,A NEW PRODRUG OF ZIDOVUDINE. SYNTHESIS,SOLID STATE CHARACTERIZATION AND ANTI HIV-1 ACTIVITY

ABSTRACT

Synthesis, solid state characterization and anti HIV-1 activity of 3′-azido-3′-deoxy-5′-O-isonicotinoylthymidine (2), a new prodrug of zidovudine (AZT, 1), are described. Two solid forms of 2 prepared by crystallization from ethyl acetate-petroleum ether (form α) and from a melt sample of form α (amorphous form) were characterized by X-ray diffractometry, infrared spectroscopy, differential scanning calorimetry (DSC) and thermogravimetry (TGA) techniques. The novel nucleoside exhibited antiviral activity against standard and resistant strain panels of HIV-1 as well as cytotoxicity similar to that of AZT.     

SYNTHESIS AND ANTIVIRAL EVALUATION OF 3′-C-TRIFLUOROMETHYL NUCLEOSIDE DERIVATIVES BEARING ADENINE AS THE BASE

3′-deoxy-3′-C-trifluoromethyl- (3), 2′,3′-dideoxy-3′-C-trifluoromethyl- (5) and 2′,3′-dideoxy-2′,3′-didehydro-3′-C-trifluoromethyladenosine (6) derivatives have been synthesized and their antiviral properties examined. All these derivatives were stereospecifically prepared by glycosylation of adenine with a trifluoromethyl sugar precursor (1), followed by appropriate chemical modifications. The prepared compounds were tested for their activity against HIV, but they did not show an antiviral effect.     

SYNTHESIS,HYDROLYSIS AND ANTI-EBV ACTIVITY OF A SERIES OF 3′-MODIFIED cycloSal-BVDUMP PRONUCLEOTIDES

A series of cycloSal-BVDUMP phosphate triesters has been prepared. The prototype compound was 3-methyl-cycloSal-BVDUMP 2. Furthermore, a series of 3′-O-acyl-modified derivatives having carboxylic acids with different lipophilicity or a L-configurated α-amino acid (phenylalanine) was prepared. The hydrolysis properties in phosphate buffer PBS as well as in PBS containing pig liver esterase (PLE) will be described. Finally, the biological activity against EBV has been determined.     

SYNTHESIS OF NOVEL 8-SUBSTITUTED CARBOCYCLIC ANALOGS OF 2′,3′-DIDEOXYADENOSINE WITH ACTIVITY AGAINST HEPATITIS B VIRUS

ABSTRACT

Synthesis and antiviral activity of several new 8-substituted carbocyclic analogs of D-2′,3′-dideoxyadenosine are described. The new 8-substituted analogs were synthesized via lithiation of carbocyclic 2′,3′-dideoxy adenosine followed by quenching with electrophiles. This methodology allows for a divergent synthesis of a variety of 8-substituted analogs from carbocyclic 2′,3′-dideoxyadenosine in high yields. 8-Methyl and 8-halogenated carbocyclic 2′,3′-dideoxyadenosine analogs showed 6–25 fold more activity against hepatitis B virus than the unsubstituted carbocyclic D-2′,3′-dideoxyadenosine.     

2′-C-ALKOXY AND 2′-C-ARYLOXY DERIVATIVES OF N-(2-PHOSPHONOMETHOXYETHYL)-PURINES AND -PYRIMIDINES: SYNTHESIS AND BIOLOGICAL ACTIVITY

A series of novel, unusual type of acyclic phosphonate-based nucleotide analogues related to well-known antivirals (PMEA and HPMPA) was synthesized using easily available synthon. These compounds, which are distinguished for the presence of phosphonomethyl acetal linkage, form a group of derivatives that contribute to the understanding of structure-activity relationship within the area of acyclic nucleotide analogues.     

SYNTHESIS OF NOVEL D- AND L-3′-DEOXY-3′-C-HYDROXYMETHYL NUCLEOSIDE WITH EXOCYCLIC METHYLENE AS POTENTIAL RIBONUCLEOTIDE REDUCTASE INHIBITOR

D- and L-3′-Deoxy-3′-C-hydroxymethyl thymidine substituted with exocyclic methylene at 2′-position were synthesized, starting from D- and L-xylose as potential ribonucleotide reductase inhibitor, respectively, but they were found to be inactive against several tumor cell lines.     

SYNTHESIS AND ANTI-HIV ACTIVITY OF THYMIDINE ANALOGUES BEARING A 4′-CYANOVINYL GROUP AND SOME DERIVATIVES THEREOF

Treatment of 3′-O-tert-butyldimethylsilyl-2′,5′-dideoxy-5′-oxothymidine (4) with potassium or magnesium nitromethanide afforded in good yield the resolvable epimeric mixture of the expected blocked nitronucleosides 5 which upon dehydration led to the corresponding E-nitroenofuranosylthymidine 6. Nucleophilic attack of cyanide onto the nitrovinyl group led to a nucleoside analogue bearing a terminal 1-cyanovinyl group (7), a soft electrophilic group which, upon reaction with benzeneselenol, underwent a conjugate addition to the phenylselenonucleoside derivative 9. All these compounds, eventually de-O-silylated, were subject of in vitro biological testing, some exhibiting interesting cytotoxic or antiviral properties.     

SYNTHESIS OF 2′-C-METHYL-4′-THIO RIBONUCLEOSIDES

Starting from 2-C-methyl-ribonolactone, 1,2,3,5-tetra-O-acetyl-2-C-methyl-4-thioribofuranose was synthesized and condensed with heterocyclic bases to afford 2′-C-methyl-4′-thioribonucleosides.