Enantiomeric forms of 9-(5-deoxy-beta-erythro-pent-4-enofuranosyl)adenine and a new preparation of 5-deoxy-D-lyxose.

Methyl 5-deoxy-5-iodo-2,3-O-isopropylidene-beta-D-ribofuranoside (3) was obtained in three steps from D-ribose. Exchange of the isopropylidene group for benzoate groups and acetolysis gave 1-O-acetyl-2,3-di-O-benzoyl-5-deoxy-5-iodo-D-ribofuranose which was coupled with 6-benzamidochloromercuripurine by the titanium tetrachloride method to afford the blocked nucleoside. Treatment with 1,5-diazabicyclo[5.4.0]undec-5-ene in N,N-dimethylformamide and removal of the blocking groups have 9-(5-deoxy-beta-D-erythro-pent-4-enofuranosyl)adenine (9). A similar route starting from methyl 5-deoxy-5-iodo-2,3-O-isopropylidene-alpha-D-lyxofuranoside (14) afforded the enantiomeric nucleoside, 9-(5-deoxy-beta-L-erythro-pent-4-enofuranosyl)adenine (20). Methyl 2,3-O-isopropylidene-alpha-D-mannofuranoside was treated with sodium periodate and then with sodium borohydride to give methyl 2,3-O-isopropylidene-alpha-D-lyxofuranoside (11). Acid hydrolysis afforded D-lyxose. Tosylation of 11 gave methyl 2,3-O-isopropylidene-5-O-p-tolylsulfonyl-alpha dp-lyxofuranoside (12) which was converted into 14 with sodium iodide in acetone. Reduction of 12 gave methyl 5-deoxy-2,3-O-isopropylidene-alpha-D-lyxofuranoside which was hydrolyzed to give 5-deoxy-D-lyxose.     

Synthesis and biological evaluation of 9-(beta-L-arabinofuranosyl)adenine

For the first time, the stereospecific synthesis of 9-(beta-L-arabinofuranosyl) adenine was carried out. Unfortunately, and unlike its "natural" D-counterpart Vidarabine, this L-enantiomer did not show significant activity when evaluated against a broad range of viruses.     

Synthesis of 9-(2,3-dideoxy-2,3-difluoro-beta-D-arabinofuranosyl)adenine

Convergent synthesis of 9-(2,3-dideoxy-2,3-difluoro-beta-D-arabinofuranosyl)adenine is described starting from methyl 5-O-benzyl-2-deoxy-2-fluoro-alpha-D-arabinofuranoside.     

Synthesis of 9-[2-(phosphonomethoxy)ethylamino]adenine and 9-[(phosphonomethoxy)acetamido]adenine, analogues of a potent anti-HIV acyclonucleotide

9-[2-(Phosphonomethoxy)ethylamino]adenine (5) and 9-[*phosphonomethoxy)acetamido]adenine (6) were synthesised and tested for antiviral activity.     

Synthesis and Biological Properties of 9-(2, 4-Dihydroxybutyl) Adenine and Guanine: New Analogues Of 9-(2, 3-Dihydroxyprqpyl)adenine (Dhpa) and 9-(2-Hydroxyethoxymethyl)guanine (Acyclovir)

Abstract

New analogues of antiviral agents 9-(2, 3-dihy-droxyproply) adenine (DHPA, 1a.) and 9-(2-hydroxyethoxymethyl) guanine (acyclovir, Ib) - compounds Ic and Id were prepared and their biological activity was investigated. Racemic 1, 2, 4-butanetriol (2) was converted to the corresponding benzylidene derivative (3a) by acetalation with benzalde-hyde and triethyl orthoformate. Acetal 3a and p-toluene- sul-fonyl chloride in pyridine gave the corresponding p-toluenes fonate 3b. Alkylation of adenine 5a via sodium salt of 5a with 3b in dimethylformamide or in the presence of tetra-n-butylammonium fluoride in tetrahydrofuran gave intermediate 6a. Reaction of 2-amino-6-chloropurine (5b) with 3b effected by K₂CO₃ in dimethylsulfoxide gave compound 6b and a smaller amount of 7-alkylated proauct 7. A similar transformation catalyzed by tetra-n-butylammonium fluoride afforded only intermediate 5b. Acid-catalyzed de-protection (hydrolysis) of 6b and 6a gave the title compounds Ic and Id. The S-enantiomer of Ic was deaminated with adenosine deaminase. Our results argue against the presence of a methyl group-binding site of adenosine deaminase. Compounds Ic and Id exhibited little or no activity in antiviral assays with several DNA and RNA viruses.     

Synthesis and Biological Evaluation of 2-(2-Deoxy-D-erythro-pent-1-enofuranosyl)pyridine C-Nucleosides

Abstract

2-(2-Deoxy-D-erythro-pent-1-enofuranosyl)pyridine and its methyl analogues have been prepared by treatment of the corresponding 2′,3′-O-isopropylidene-D-ribofuranosyl derivatives with several bases such as sodium amide, tert.BuOK, EtONa, lithium tetramethylpiperidide (LTMP) and phenyl lithium (PhLi). PhLi and tert.BuOK gave the best results. The products thus obtained showed cytostatic activity against human tumor cell lines, in particular MT-4, a human T-lymphocyte cell line. No antiviral activity was noted at subtoxic concentrations.     

Quantum chemical calculation of the (S)-9-(2,3-dihydroxypropyl)adenine molecule.

Quantum chemical calculations of conformational maps of the molecule of a new virostatic agent (S)-9-(2,3-dihydroxypropyl)adenine were performed. The thermodynamically most advantageous conformation I corresponds, for the D-series, to the alpha-ribo configuration, while the following minima, which are close in energy (II,III), correspond to beta-ribo and beta-xylo configurations.     

Synthesis of 9-[1-(substituted)-2-(phosphonomethoxy)ethyl]adenine derivatives as possible antiviral agents

Various C-1'-substituted acyclic N9 adenine nucleosides were prepared from 9-[(1-hydroxymethyl)(3-monomethoxytrityloxy)propyl]-N6-monomethoxytrityladenine. The hydroxymethyl was modified to the phosphonomethoxy derivative, and the 3-monomethoxytrityloxy was converted to hydroxyl, methoxy, azido, and amino. Other substituents, such as ethyl and ea-hydroxyethyl were also prepared. The resulting phosphonomethoxy derivatives were converted to prodrugs.     

Radical-Mediated Cyclization of A 6-Chloro-9-(2-Deoxy--d erythro-pent-1-enofuranosyl)-8-(2,2-dibromovinyl) purine

Abstract

A vinyl radical generated from a 6-chloro-9-(2-deoxy--d eryrhro-pent-l-enofuranosyl)-8-(2,2-dibromovinyl) purine effected cyclization either at the 1′-or at the 2′-position. The result is discussed in comparison with our previous study of the corresponding uracil derivative.     

Synthesis of 9-[1-(substituted)-3-(phosphonomethoxy)propyl]adenine derivatives as possible antiviral agents

Acyclic N9 adenine nucleosides substituted at C-1' position were prepared by the Mitsunobu reaction of 1-tert-butyldimethylsilyl-4-pivaloylbutan-1,2,4-triol (5) with adenine. Pivaloyl hydroxyl was modified to the phosphonomethoxy derivatives, and the tert-butyldimethylsilyl hydroxyl was converted to methoxy, azido, amino, fluoro, and c-hydroxyethyl and was eliminated to give vinyl. The resulting phosphonic acids were converted to prodrugs also.     

Synthesis and antiherpetic activity of (Z)- and (E)-isomers of 9-(3-phosphonomethoxyprop-1-en-yl)adenine

9-(3-Phosphonomethoxyprop-1-en-yl)adenine (Z)- and (E)-isomers were synthesized. The stereoselectivity of double bond formation was studied by variation of sulfonyl groups. The resulting phosphonates exhibited a moderate antiherpetic activity in a culture of Vero cells infected with herpes simplex type 1 virus. The Z-isomer was shown to be more effective inhibitor of virus reproduction in the case of both wild and acyclovir-resistant strain.     

Synthesis and hybridization properties of oligonucleotides containing (2S,3R)-9-(2,3,4-trihydroxybutyl)adenine

The synthesis and properties of oligonucleotides (ONs) containing 9-(2,3,4-trihydroxybutyl)adenine, A(C2) and A(C3), are described. The ON containing A(C2) involves the 3'-->4' and 3-->5' phosphodiester linkages in the strand, whereas that containing A(C3) possesses the 3'-->4' and 2'-->5' phosphodiester linkages. It was found that incorporation of the analogs, A(C2) or A(C3), into ONs significantly reduces the thermal and thermodynamic stabilities of the ON/DNA duplexes, but does not largely decrease the thermal and thermodynamic stabilities of the ON/RNA duplexes as compared with the case of the ON/DNA duplexes. It was revealed that the base recognition ability of A(C2) is greater than that of A(C3) in the ON/RNA duplexes.     

Synthesis of 9-[1-(1 -hydroxyethyl)-3-(phosphonomethoxy)propyl]adenine and prodrug as possible antiviral agents

The appropriately protected C-1'-hydroxyethyl-3-hydroxypropyl-N9-adenine nucleoside was prepared from 1-pivaloyloxy-5-tert-butyldiphenylsilyloxy-3-pentanol and adenine through the Mitsunobu reaction. One of the terminal hydroxyls was converted to the phosphonomethoxy derivative and the prodrug.     

X-ray study of an antiviral agent (S)-9-(2,3-dihydroxypropyl)adenine

The molecular and crystal structures of the antiviral compound, (S)-9-(2,3-dihydroxypropyl)adenine, was established. The space group is P21, unit-cell parameters a 5,546(1), b 8,381(1), c 10,119(1), beta 91,979(9) degrees, Z2. The structure was solved by the direct method and refined by a full-matrix least-squares procedure to R 4,2%. All non-hydrogen atoms of this compound are concentrated in two planes. The first one involves the atoms of the purine moiety and N(6) and C(1'), while the second one accommodates C(2'), C(3'), O(2') and O(3'). The angle between these planes is 54,3 degrees. The conformation of the compound in crystal was compared with that deduced from theoretical analysis.     

Stereospecific syntheses of 9-(S)-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (HPMPA)

9-(S)-(3-Hydroxy-2-phosphonylmethoxypropyl)adenine (HPMPA) was prepared from 9-(S)-(2,3-dihydroxypropyl)adenine (DHPA) via its 3-O-chloromethanephosphonate. The latter compound is obtained by treatment of DHPA with chloromethanephosphonyl dichloride and the 3'-isomer separated from its 2'-congener by ion-exchange chromatography. The 3'-isomer is prepared selectively by the same method starting from 2',6-dibenzoyl derivative of DHPA. The 3'-ester is transformed to HPMPA by treatment with aqueous alkali. Alternatively, 9-(S)-(2-hydroxy-3-triphenylmethoxypropyl)-N6-benzoyladenine can be converted to HPMPA by reaction with dialkyl p-tolylsulfonyloxymethane-phosphonates in the presence of NaH followed by successive acid and alkaline treatment.     

New Prodrugs of 9-(2-Phosphonomethoxyethyl)adenine [PMEA]: Synthesis and Stability Studies

Abstract

The synthesis, and stability in different media of new PMEA prodrugs, with S-acylthioethyl (SATE) as enzyme-labile phosphonate protecting groups, are described in comparison with the already known Bis(POM)- and Bis(DTE)PMEA.     

Synthesis and in vitro antiviral activity evaluation of 9-(2-azido-2,3-dideoxy-beta-D-threo-pentofuranosyl)adenine derivatives

9-(2-Azido-2,3-dideoxy-beta-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 of N6-substituted 9-[3-(phosphonomethoxy)propyl]adenine derivatives as possible antiviral agents

A number of N6-substituted 9-[3-(phosphonomethoxy)propyl]adenine derivatives having hydroxymethyl at C-1' position were prepared from the appropriate 6-chloroadenine derivative. The syntheses of the corresponding prodrugs of these compounds are also reported. These compounds showed poor activity against HCV in replicon assay.