Synthesis of (E)-5-(2-cIOdovinyl)-3′-0-(1-Methyl-1,4-Dihydropyridyl-3 -Carbonyl)-2′-Fluoro-2′-Deoxyuridine (Ivfru-Cds) for Brain Targetted Delivery of Ivfru,an Antiviral Nucleoside

Abstract

(E)-5-(2-lodovinyl)-2′-fluoro-3′-0-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2′-deoxyuridine (11) was synthesized for future evaluation as a lipophilic, brain-selective, pyrimidine phosphorylase-resistant, antiviral agent for the treatment of Herpes simplex encephalitis (HSE). Treatment of (E)-5-(2-iodovinyl)-2′-fluoro-2′-deoxyuridine (6) with TBDMSCI in the presence of imidazole in DMF yielded the protected 5′-O-t-butyldimethylsilyl derivative (7). Subsequent reaction with nicotinoyl chloride hydrochloride in pyridine afforded (E)-5-(-2-iodovinyl)-2′-fluoro-3′-O-(3-pyridylcarbonyl)-5′-O-t-butyldimethylsily-2′-deoxyuridine (8). Deprotection of the silyl ether moiety of 8 with n-Bu₄N⁺F^? and quaternization of the resulting 3′-O-(3-pyridylcarbonyl) derivative 9 using iodomethane afforded the corresponding 1-methylpyridinium salt 10. The latter was reduced with sodium dithionite to yield (E)-5-(2-iodovinyl)-2′-fluoro-3′-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2′-deoxyuridine (11).     

The Three-Dimensional Structure of 3′-Deoxycytidine

Abstract

Structural analysis of 3′-deoxycytidine and comparison with 2′-deoxynucleosides reveals no noticeable effect on the conformation of the molecule due to the lack of 3′-oxygen atom. There are two crystallographically independent molecules and both adopt the anti conformation with C3′-endo sugar puckering. A ‘head-to-tail’ packing of the molecules along the b axis results in a virtual ‘2′-5′ polycytidylic acid chain.     

Synthesis and Antiherpetic Activities of Several Acyclic Analogues Of Guanosine

Abstract

Several acyclic analogues of guanosine, 2′-deoxy-2′, 3′-secoguanosine(3), 3′-deoxy-2′, 3′-secoguanosine (4), and 2′-, 3′-dideoxy-2′-, 3′-secoguanosine were synthesized from guanosine. In addition, the 3′-, 5′-cyclic phosphate (21) and 3′-, 5′-cyclic methylphosphonates (22a, b) of 3 were also prepared. At concentrations up to 300 μM none of these compounds had significant antiherpetic activity in antiviral assays in vitro.     

Interaction of (2′ -5′) and (3′ -5′) Linked 2-Aminoadenylyl-3-aminoadenosines with Polyuridylic Acid

Abstract

2′-5′ and 3′-5′ linked 2-aminoadenylyl-2-aminoadenosines [(2′-5′)n²Apn²A (1) and (3′-5′)n²Apn²A (2)] were synthesized by condensation of 5′-O-monomethoxytrityl-N ² N ⁶-dibenzoyl-2-aminoadenosine and N ²,N ⁶,2′,3′-O-tetrabenzoyl-2-aminoadenosine 5′-phosphate using dicyclohexylcarbodiimide (DCC). The conformational properties of these dimers 1 and 2 were examined by UV, NMR and CD spectroscopy. The results reveal that the 2′-5′-isomer 1 takes a stacked conformation, which contains a larger base-base overlap and is more stable against thermal perturbation with respect to the 3′-5′-isomer 2. Interactions of 1 and 2 with polyuridylic acid (Poly (U)) were also examined by Tm, mixing curves, UV and CD spectra. Both the dinucleoside isomers 1 and 2 formed a complex of 1 : 2 stoichiometry with poly(U), which was much more stable than that of the corresponding ApA isomer     

SYNTHESIS OF 5-ALKENYLATED D4T ANALOGUES VIA THE Pd-CATALYZED CROSS-COUPLING REACTION

The target compounds 5-[N-(6-amino-hexyl)-acrylamide]-2′,3′-didehydro-2′,3′-dideoxy-uridine (12) and 5-{N-[5-(methoxycarbonyl)-pentyl]-acrylamide}-2′,3′-didehydro-2′,3′-dideoxy-uridine (15) were prepared by the palladium acetate-triphenylphosphine-catalyzed reaction of the 5′-O-acetyl-5-iodo-d4T analogue (3). These compounds 12 and 15 can be used to prepare nucleotide probes carrying fluorescent labels and were nevertheless screened for their anti-HIV activity. The biological data demonstrated that none of them were active against HIV-1.     

Synthesis of Some 2′,3′-Dideoxy-2′-C-Methyl-Substituted Nucleosides

Abstract

Nucleoside analogues analogues1-(2′,3′-dideoxy-2′-C-hydroxymethyl-β-D-erythro-pentofuranos-yl)thymine (1), 2′,3′-dideoxy-2′-C-hydroxymethylcytidine (2), 2′,3′-dideoxy-2′-C-hydroxymethyladenosine (3), 1-(2′-C-azidomethyl-2′,3′-dideoxy-β-D-erythro-pento-furanosyl)thymine (4), 2′-C-azidomethyl-2′,3′-dideoxycytidine (5), and 2′3′-dideoxy-2′-C-methylcytidine (6) have been synthesized from (S)-4-hydroxymethyl-y-butyro-lactone (7)     

A Short High Yielding Synthesis of the Potent Anti-VZV Carbocyclic Nucleoside Analogue Carba-BVDU

Abstract

A short high yielding synthesis of the potent anti-varicella-zoster virus (VZV) carbocyclic nucleoside analogue carba-BVDU 1 starting from aminodiol 2 is described. Reaction of 2 with acyl carbamate 3 and subsequent ring closure under acidic conditions afforded 5-ethyl-2′-deoxy-4′a-carbauridine 5. In situ acetylation of 5 afforded 3′,5′-di-O-acetyl-5-ethyl-2′-deoxy-4′a-carbauridine 6 in 78% overall yield from 2. Radical bromination of 6 with either bromine or NBS and subsequent treatment with triethylamine gave an efficient conversion to 3′,5′-di-O-acetyl-5-(E)-(2-bromovinyl)-2′-deoxy-4′a-carbauridine 7. Deacetylation of 7 afforded 1 in an overall 45–53% yield from 2.     

SYNTHESIS OF 3′-THIOAMIDO-MODIFIED 3′-DEOXYTHYMIDINE-5′-TRIPHOSPHATES AND THEIR USE AS CHAIN TERMINATORS IN SANGER-DNA SEQUENCING

The thioamide derivatives 3′-deoxy-5′-O-(4,4′-dimethoxytrityl)-3′-[(2-methyl-1-thioxo-propyl)amino]thymidine 1 and 3′-deoxy-5′-O-(4,4′-dimethoxytrityl)-3′-{{6-{[(9H-(fluo-ren-9-ylmethoxy)carbonyl]-amino}-1-thioxohexyl}amino} thymidine 2 were synthesized by regioselective thionation of their corresponding amides 7 and 8 with 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphet-ane-2,4-disulfide (Lawesson's reagent). The thioamides were converted into the corresponding 5′-triphosphates 3 and 4. Compound 3 was chosen for DNA sequencing experiments and 4 was further labelled with fluorescein.     

Inhibition of 5-α-Reductase (TYPE-II) Expression by Antisense 3′-Deoxy-(2′-5′) Oligonucleotide Chimeras

Abstract

ABSTRACT: 3′-Deoxy-(2′-5′) oligonucleotides bind selectively to complementary RNA but not to DNA. 3′-Deoxy-(2′-5′) phosphorothioate ODN chimeras embedded with a short stretch of 3′-5′ phosphorothioate cassette are potent inhibitors of steroid 5-α-reductasc expression with significantly less non-specific interactions in cell culture.     

Nucleosides and Nucleotides. 104. Radical and Palladium-Catalyzed Deoxygenation of the Allylic Alcohol Systems in the Sugar Moiety of Pyrimidine Nucleosides§,1

Abstract

New methods for the synthesis of 2′,3′-didehydro-2′,3′-dideoxy-2′ (and 3′)-methyl-5-methyluridines and 2′,3′-dideoxy-2′ (and 3′)-methylidene pyrimidine nucleosides have been developed from the corresponding 2′ (and 3′)-deoxy-2′ (and 3′)-methylidene pyrimidine nucleosides. Treatment of a 3′-deoxy-3′-methylidene-5-methyluridine derivative 8 with 1,1′-thiocarbonyldiimidazole gave the allylic rearranged 2′,3′-didehydro-2′,3′-dideoxy-3′-[(imidazol-1-yl)carbonylthiomethyl] derivative 24. On the other hand, reaction of 8 with methyloxalyl chloride afforded 2′-O-methyloxalyl ester 25. Radical deoxygenation of both 24 and 25 gave 26 exclusively. Palladium-catalyzed reduction of 2′,5′-di-O-acetyl-3′-deoxy-3′-methylidene-5-methyluridine (32) with triethylammonium formate as a hydride donor regioselectively afforded the 2′,3′-dideoxy-3′-methylidene derivative 35 and 2′,3′-didehydro-2′,3′-dideoxy-3′-methyl derivative 34 in a ratio of 95:5 in 78% yield. These reactions were used on the corresponding 2′-deoxy-2′-methylidene derivatives. An alternative synthesis of 2′,3′-dideoxy-2′-methylidene pyrimidine nucleosides (43, 52, and 54) was achieved from the corresponding 1-(3-deoxy-β-D-thero-pentofuranosyl)pyrimidines (44 and 45). The cytotoxicity against L1210 and KB cells and inhibitory activity of the pathogenicity of HIV-1 are also described     

Aldol Reaction of Nucleoside 5′-Carboxaldehydes with Acetone. Synthesis of 5′-C-Chain Extended Thymidine Derivatives

Abstract

Reaction of 3′-0-(t-butyldimethylsilyl)-2′-deoxythymidine-5′-carboxaldehyde and 2′,3′-dideoxythymidine-5′-carboxaldehyde with acetone afforded a 3:2 mixture of the two (5′R)- and (5′S)-5′-acetonylthymidine derivatives.     

Improved Targeting of the Flanks of a DNA Stem Using α-Oligodeoxynucleotides.-The Enhanced Effect of an Intercalator

Abstract

2′-Deoxy-5′-0-(4,4′-dimethoxytrityl)-5-methyl-N ⁴-(1-pyrenylmethyl)-α-cytidine (5) was prepared by reaction of 1-pyrenylmethylamine with an appropriate protected 4-(l,2,4-triazolyl)-α-thymidine derivative 3 which was synthesized from 5-O-DMT protected α-thymidine 1. Aminolysis of 3 afforded 3′-O-acetyl-2′-deoxy-5′-O-(4,4′-dimethoxytrityl)-5-methyl-α-cytidine (8). Benzoylation of 8 and removal of acetyl afforded N ⁴-benzoyl-2-deoxy-5–0-(4,4′-dimethoxytrityl)-5-methyl-α-cytidine (10). The amidites of compounds 5and 10 were prepared and used in α-oligonucleotide synthesis. DNA three-way junction (TWJ) is stabilized when an α-ODN is used for targeting the dangling flanks of the stem in a DNA hairpin. Further stabilization of the TWJ is observed when 5 is inserted into the α-ODN at the junction region.

     

Synthesis of Some Nucleoside Cyclic Ethylene Phosphothionates

Abstract

This communication describes the synthesis of 5′-deoxy-5′-chloro-3′-(2-thio-1,3,2-dioxaphosphorinanyl)thymidine, N⁴,2′,3′-triacetyl-5′-(2-thio-1,3,2-dioxaphosphorinanyl)-1-β-D-arabinosyl-cytosine and N⁴-acetyl-5′-(2-thio-1,3,2-dioxaphosphorinanyl)-1-β-D-arabinosylcytosine.     

CHEMICAL AND ENZYMATIC SYNTHESIS OF 4′-THIO-β-D-ARABINOFURANOSYLCYTOSINE MONOPHOSPHATE AND TRIPHOSPHATE

N⁴-Acetyl-1-(2, 3-di-O-acetyl-4-thio-β-D-arabinofuranosyl)cytosine (2) was synthesized in three steps from 1-(4-thio-β-D-arabinofuranosyl)cytosine (1). The reaction of this partially blocked 4′-thio-ara-C derivative 2 with 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one gave the 5′-phosphitylate derivative 3, which on reaction with pyrophosphate gave the 5′-nucleosidylcyclotriphosphite 4. Product 4 was then oxidized with iodine/pyridine/water and deblocked with concentrated ammonium hydroxide to provide the desired 4′-thio-ara-C-5′-triphosphate 5. This triphosphate 5 was converted to 4′-thio-ara-C -5′-monophosphate 6 by treatment with snake venom phosphodiesterase I. The details of the synthesis, purification, and characterization of both nucleotides are described.     

Methodology for the Synthesis of Dinucleoside Monophosphates Containing A 2′-Deoxy-3-Isoadenosine Unit: 3-iso-dApT and Tp(3-iso-dA)

Abstract

2′ -Deoxy-3-isoadenylyl(3′-5′)thymidine and thymidylyl-(3′-5′)-2′-deoxy-3-isoadenosine have been synthesized by mild protection/deprotection methodology that circumvents facile N3-Cl′ hydrolytic cleavage of the 2′-deoxy-3-isoadenosine moiety.

     

Synthesis of 2′-Substituted Sulfide-Linked Dinucleotides

Abstract

3′-Deoxy-3′-(2-mesyloxyethyl)ribofuranosylthymine derivative 3, and its 2′-methoxy (16) and 2′-deoxy (38) analogs were condensed with 5′-deoxy-5′-thiothymidine 4 and 17 or 2′-O-methyl-5′-deoxy-5′-thiouridine 34 and 37 to provide, after standard functional group transformations, thymidine-thymidine and uridine-thymidine dimers 9, 21, 43 and 47. Oxidation of model sulfide dimer 48 with oxone gave sulfone 49. It was not stable to 27% ammonia.     

Synthesis,In Vitro Anti-HIV Activity,and Biological Stability of 5′-O-Myristoyl Analogue Derivatives of 3′-Fluoro-2′,3′-Dideoxythymidine (FLT) as Potential Bifunctional Prodrugs of FLT

Abstract

A group of 5′-O-myristoyl analogue derivatives of FLT (2) were evaluated as potential anti-HIV agents that were designed to serve as prodrugs to FLT. 3′-Fluoro-2′,3′-dideoxy-5′-O-(12-methoxydodecanoyl)thymidine (4) (EC₅₀ = 3.8 nM) and 3′-fluoro-2′,3′-dideoxy-5′-O-(12-azidododecanoyl)thymidine (8) (EC₅₀ = 2.8 nM) were the most effective anti-HIV-1 agents. There was a linear correlation between Log P and HPLC Log retention time for the 5 ′-O-FLT esters. The in vitro enzymatic hydrolysis half-life (t½), among the group of esters (3–8) in porcine liver esterase, rat plasma and rat brain homogenate was longer for 3′-fluoro-2′,3′-dideoxy-5 ′-O-(myristoyl)thymidine (7), with t½ values of 20.3, 4.6 and 17.5 min, respectively.     

Nucleosides and Nucleotides. 125. Synthesis and Biological Evaluation of 2′,3′-Dideoxy-3′-fluoro-2′-methylidene Pyrimidine Nucleosides

Abstract

Reaction of 2′-deoxy-2′-methylidene-5′-O-trityluridine (1) with diethylamino-sulfur trifluoride (DAST) in CH₂Cl₂ resulted in the formation of a mixture of (3′R)-2′,3′-dideoxy-3′-fluoro-2′-methylidene derivative 3 and 2′,3′-didehydro-2′,3′-dideoxy-2′-fluoromethyl derivative 4 (3:4 = 1:1.5) in 65% yield. A similar treatment of 1-(2-deoxy-2-methylidene-5-O-trityl-β-D-threo-pentofuranosyl)uracil (19) with DAST in CH₂Cl₂ afforded (3′S)-2′,3′-dideoxy-3′-fluoro-2′-methylidene derivatives 20 and 4 in 38% and 17% yields respectively. Transformation of the uracil nucleosides 4, 12, and 20 into cytosines followed by deprotection furnished the corresponding cytidine derivatives 29, 18, and 25, respectively. The corresponding thymidine congener 27 was also synthesized in a similar manner. All of the newly synthesized nucleosides were evaluated for their inhibitory activities against HIV and for their antiproliferative activities against L1210 and KB cells.     

Some Aspects of Ribonucleoside Chemistry

Abstract

New routes to the preparations of 2′-deoxy-3′-C-methyl uridine (2c) and 1-(5′-0-trityl-3′-deoxy-β-D-glycero-pentofuran-2-ulosyl)uracil (4) from 5′-0-trityl-2′-0-tosyl uridine (1) and 5′-0-trityl-3′-0-tosyl uridine (3) respectively are described.     

Oligonucleotides Incorporating 7-(Aminoalkyn-1-yl)-7-deaza-2′-deoxyguanosines: Duplex Stability and Phosphodiester Hydrolysis by Exonucleases

Abstract

Self-complementary {[5′-d(G-C)₄]₂} and non-selfcomplementary oligonucleotides [5′-d(TAG GTC AAT ACT) ? 3′-d(ATC CAG TTA TGA)] containing 7-(ω-aminoalkyn-1-yl)-7-deaza-2′-deoxyguanosines (1a–c) (1) and 7-deaza-2′-deoxyguanosine instead of dG were studied regarding their thermal stability as well as their phosphodiester hydrolysis by either 3′ → 5′- or 5′ → 3′ – phosphodi esterase studied by MALDI-TOF MS.