Synthesis of N-Arylinosines

Abstract

2′,3′,5′-Tri-O(tetrahydropyran-2-yl)inosine 1 was treated with iodobenzene or 2-bromopyridine in the presence of cuprous oxide in pyridines to give the N¹ -aryl derivatives 2a, b. Deprotection of the products afforded N¹ -arylinosines 3a, b.     

Nucleosides and Nucleotides. 192. Toward the Total Synthesis of Cyclic ADP-Carbocyclic-Ribose. Formation of the Intramolecular Pyrophosphate Linkage by a Conformation-Restriction Strategy in a Syn-form Using a Halogen Substitution at the 8-Position of the Adenine Ring

Abstract

The synthesis of cyclic ADP-carbocyclic-ribose (2), as a stable mimic for cyclic ADP-ribose, was investigated. Construction of the 18-membered backbone structure was successfully achieved by condensation of the two phosphate groups of 19, possibly due to restriction of the conformation of the substrate in a syn-form using an 8-chloro substituent at the adenine moiety. SN2 reactions between an optically active carbocyclic unit 8, which was constructed by a previously developed method, and 8-bromo-N ⁶-trichloroacetyl-2′,3′-O-isopropylideneadenosine 9c gave N-1-carbocyclic derivative, which was deprotected to give 5′,5′-diol derivatives 18. When 18 was treated with POCl₃ in PO(OEt)₃, the bromo group at the 8-position was replaced to give N-1-carbocyclic-8-chloroadenosine 5′,5′-diphosphate derivative 19 in 43% yield. Treatment of 19 with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride gave the desired intramolecular condensation product 20 in 10% yield. This is the first chemical construction of the 18-membered backbone structure containing an intramolecular pyrophosphate linkage of a cADPR-related compound with an adenine base.     

Ribosylation of the Base Residue of Inosine Derivatives by Phase-Transfer Catalysis

Abstract

Reaction of 2′,3′,5′-O-silylated inosine derivative 1 with 2, 3-O-isopropylidene-5-O-tritylribosyl chloride (3) in a two-phase (CH₂Cl₂-aq. NaOH) system in the presence of Bu₄NBr gave three products, i. e., 6-O-α-, 6-O-β-, and N ¹-β-isomers of glycosides 4, 5a, and 5b. A similar PTC reaction of 1 with 2, 3, 5-tri-O-benzylribosyl bromide (9) gave four regio- and stereo-isomers involving the N¹-β-glycoside 10. Reaction of 1 with 2, 3, 5-tri-O-benzoylribosyl bromide (11) afforded three products involving the desired N¹-β-glycoside 12b, which could be deprotected to give N ¹-ribosylinosine (15b) as a useful intermediate for the synthesis of cIDPR.

     

Oxidative Cyclization of 2′,3′-O-Isopropylidene-Adenosines into 5′-O,8-Cycloadenosines with Lead Tetraacetate: Remarkable Effect of N6-Substituents on the Oxidation

Abstract

Oxidation of 2′,3′-O-isopropylideneadenosines (1) with lead tetraacetate (LTA) in dry benzene resulted in the formation of the corresponding 5′-O,8-cyclo-2′,3′-O-isopropylideneadenosines (2), which has a new methodological implication for the chemical modification of adenosines. The occurrence of the oxidative cyclization was remarkably affected by the nature of N⁶-substituents: N⁶-benzoyl substitution prominently accelerated the oxidative cyclization in comparison with none and dimethyl substitutions. In the oxidation of N⁶,N⁶-dimethyladenosine (1d), an intriguing oxidative demethylation was observed.     

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.     

Isomerization of Cytidine 2′,3′-Thionocarbonates

Abstract

N⁴,5′-Profecied cytidine 2′,3′-thionocarbonaies isomerize at elevated temperatures to 2′-deozy-2″-thiocylidine 2′,3′ -carbonates.     

Conformation Analysis of Two Anti-HIV Nucleoside Analogues 2′,3′-Dideoxy-3′-fluorocytidine and Its N4-Dimethylaminomethylene Prodrug Derivative

Abstract

Crystal structure analysis of 2′,3′-dideoxy-3′-fluorocytidine (1) and its prodrug derivative, N⁴-dimethylaminomethylene-2′,3′-dideoxy-3′-fluorocytidine (2), active anti-HIV nucleoside analogues, reveals that both structures adopt an anti conformation about the glycosyl bond. The furanose ring is C2′-endo for (2) and C2′-endo/C1′-exo and C2′-endo/C3′-exo for the two independent molecules of (1), respectively.     

8-Aza-1-deazapurine Nucleosides as Antiviral Agents

Abstract

2′,3′-Dideoxy-8-aza-1-deazaadenosine (21) and its α-anomer (20) were synthesized via glycosylation of 7-chloro-3H-1,2,3-triazolo[4,5-b]pyridi-ne with 2,3-dideoxy-5-O-[(1, 1)-dimethylethyl)diphenylsilyl]-D-glycero-o-pen-tofuranosyl chloride. The reaction gave a mixture of α- and β-anomers of N³-, N⁴- and N¹-glycosylated regioisorners (12–15). The α- and β-anomers of the N⁴-glycosylated isomer 26 and 27 were also synthesized through the glycosylation of 8-aza-1-deazaadenine with 1-acetoxy-2,3-dideoxy-5-O-f(1,1-di-methylethyl)dimethylsilyl]-D-glycero-pentouranose. These dideoxynucleo-sides and a series of previously synthesized 8-aza-1-deazapurine nucleosidcs were tested for activity against several DNA and RNA viruses, HIV-1 included. The α- and β-anomers of 7-chloro-3-(2-deoxy-D-erythro-pentofuranosyl)-3H-1,2,3-triazolo[4,5-b]pyridine (3a and 4) showed activities against Sb-1 and Coxs viruses. The α- and β-anomers of 2′,3′-dideoxy-8-aza-1-deazaadenosine (20 and 21) were found active as inhibitors of adenosine deaminase.     

An Improved Synthesis of 1-β-D-Arabinofuranosylcytosine 5′-Phosphate-L-1,2-diacylglycerols

Abstract

5′-O-MMTr-cytosine arabinoside was prepared on a large scale from 5′-O-MMTr-cytidine with diphenyl carbonate via 5′-protected cytidine-2′,3′-carbonate-aracytidine-2′,2-anhydro derivative at a 67 % yield. The synthesis of 1,2-L-dipalmitoyl-snglycerol, 1,2-L-distearoyl-sn-glycerol and 1,2-L-dioleoyl-sn-glycerol described here using 9-fluorenylmethoxycarbonyl (FMOC) group for protection of 3-position of glycerol which can be selectively removed by Et₃N treatment on the overall 60–70 % yield based on 1.2,-isopropilidene-sn-glycerol. These glycerols were phosphorylated first with 2-chlorophenyl-phosphoro-bis-triazolide quantitatively¹ in order to avoid acyl migration, then the glycerophosphate intermediates were condensed with 2′,3′,N⁴-trileulinyl-l-β-D-arabinofuranosylcytosine in the presence of 2-mesytilenesulphonyl chloride (MsCl) and 1 -methylimidazole (Melm)-which was used in the coupling of nucleotides²-^? in an 85–95 % yield compared with the low yielding diester method of Ryu³. Deblocking was carried out in two steps with tetrabutylammonium fluoride (TBAF) and hydrazine hydrate, producing target compouns (14a, 14b, 14c) at a 50 % yield.     

Isolation and Characterization of a Free Gibberellin and Glucosyl Esters of Gibberellins in Mature Seeds of Phaseolus vulgaris

Treatment of N⁶,N⁶,5′-O-tribenzoyl-2′,3′-O-isopropylidenetubercidin (VI) with aqueous acetic acid afforded N⁶,5′-O-dibenzoyltubercidin (V), which was mesylated to yield the dimesylate X. On treatment of X with sodium iodide and zinc dust, the 2′,3′-unsaturated derivatives of tubercidin XI and XIII were obtained.

N⁶,5′-O-Dibenzoyltubercidin 2′,3′-thionocarbonate (XIV), prepared from V by treatment with Corey-Winter reagent, was converted to the 1-methyl-2′,3′-unsaturated derivative XV in refluxing trimethyl phosphite.     

Bromine-Induced Selective N-Monodemethylation of N6, N6-Dimethyl-2′,3′-O-isopropylideneadenosine

Abstract

Bromination of the title compound 1 with bromine in phosphate buffer has led to 8-bromo-N⁶, N⁶-dimethyl-2′,3′-0-isopropylidene-adenosine (2) and 2′,3′-0-isopropylidene-N⁶-methyladenosine (3). Under similar conditions, compound 2 gave 8-bromo-2′,3′-0-isopropylidene-N⁶-methyladenosine (4). The transformations 1 → 3 and 2 → 4 represent biomimetic models of in vivo N⁶-demethylation of antibiotic puromycin.     

Cyclic nucleotide esterification: relationship to phosphate ring geometry and growth regulation in synchronized human lymphocytes.

Infrared spectra of neutral aqueous solutions of nucleoside 3′,5′-cyclic monophosphates indicate an increase in the antisymmetric phosphoryl stretching frequency to 1236 cm^?1 from 1215 cm^?1 in trimethylene cyclic phosphates. A further increase to 1242 cm^?1 accompanies esterification of the 2′-ribose hydroxyl. The O²′-esterified and 2′-deoxy cyclic nucleotides examined display both reduced kinase binding and altered phosphoryl stretching frequencies, suggesting that modification of the phosphate ring represents a common feature in decreased kinase activation. Reversible inhibition of mitosis in thymidine-synchronized human lymphocytes by 2 mmN⁶,O²′-dibutyryladenosine 3′,5′-cyclic monophosphate and N⁶-monobutyryladenosine 3′,5′-cyclic monophosphate was observed. However, adenosine 3′,5′-cyclic monophosphate, O²′-monobutyryladenosine 3′,5′-cyclic monophosphate, butyric acid, and ethyl butyrate had no effect on mitosis when present at 2 mm concentrations during S and G2. These results are consistent with hydrolysis of O²′-monobutyryladenosine 3′,5′-cyclic monophosphate and adenosine 3′,5′-cyclic monophosphate by esterase and phosphodiesterase enzymes and suggest that modification of the N⁶ amino group is necessary for the antimitotic activity of N⁶,O²′-dibutyryladenosine 3′, 5′-cyclic monophosphate.     

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     

Nucleosides. IX. Synthesis of Purine N 3,5′‐Cyclonucleosides and N 3,5′‐Cyclo‐2′,3′‐seconucleosides via Mitsunobu Reaction as TIBO‐like Derivatives

The Mitsunobu reaction was applied to prepare, in one step, purine N ³,5′‐cyclonucleosides 10a–d. A subsequent ring opening in the ribose moiety of the resultant N ³,5′‐nucleosides by sodium periodate led to the corresponding N ³,5′‐cyclo‐2′,3′‐seconucleosides. These products consist of 5‐, 6‐, and 7‐membered tricyclic system which is the basic skeleton of TIBO derivatives, known antiviral agents.     

EFFICIENT METHODS FOR THE SYNTHESIS OF [2-15N]GUANOSINE AND 2′-DEOXY[2-15N]GUANOSINE DERIVATIVES

The nucleophilic addition–elimination reaction of 2′,3′,5′-tri-O-acetyl-2-fluoro-O ⁶-[2-(4-nitrophenyl)ethyl]inosine (8) with [¹⁵N]benzylamine in the presence of triethylamine afforded the N ²-benzyl[2-¹⁵N]guanosine derivative (13) in a high yield, which was further converted into the N ²-benzoyl[2-¹⁵N] guanosine derivative by treatment with ruthenium trichloride and tetrabutyl-ammonium periodate. A similar sequence of reactions of 2′,3′,5′-tri-O-acetyl-2-fluoro-O ⁶-[2-(methylthio)ethyl]inosine (9) and the 6-chloro-2-fluoro-9-(β-D-ribofuranosyl)-9H-purine derivative (11), which were respectively prepared from guanosine, with potassium [¹⁵N]phthalimide afforded the N ²-phthaloyl [2-¹⁵N]guanosine derivative (15; 62%) and 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-[¹⁵N]phthalimido-9H-purine (17; 64%), respectively. Compounds 15 and 17 were then efficiently converted into 2′,3′,5′-tri-O-acetyl[2-¹⁵N]guanosine. The corresponding 2′-deoxy derivatives (16 and 18) were also synthesized through similar procedures.     

Comparison of cytokinin activities of the base,ribonucleoside and 5′- and cyclic-3′,5′-monophosphate ribonucleotides of N6-isopentenyl-, N6-benzyl or 8-bromo-adenine

The cytokinin activities of adenosine 3′,5′-monophosphate, N⁶,O^2″-dibutyryladenosine 3′,5−'monophosphate, 8-bromoadenosine 3′,5′-monophosphate, N⁶-(Δ²-isopentenyl)adenosine 3′,5′-monophosphate, and N⁶-benzyladenosine 3′,5′-monophosphate were determined in the tobacco bioassay and compared with the activities of the corresponding non-cyclic nucleotides, nucleosides and bases of the N⁶-isopentenyl-substituted, N⁶-benzyl-substituted, 8-bromo-substituted, and unsubstituted adenine series. In each of these series the cytokinin activities in decreasing order were: bases ⪢ nucleosides ⪖ nucleotides > cyclic nucleotides. All members of the N⁶-isopentenyl- substituted and N⁶-benzyl-substituted series were highly active cytokinins, reaching maximum activity at concentrations of 1 μM or less, whereas, as expected, all members of the unmodified adenine series were inactive in the tested concentration ranges of up to 180 and 200 μM for adenosine and adenine, and 40 μM for the adenine nucleotides. Members of the 8-bromo-substituted adenine series were much weaker cytokinins than the N⁶-substituted adenine derivatives but showed activity in the same sequence starting at a concentration of about 5 μM. Thus, in the cases of 8-bromoadenosine 3′,5′-monophosphate and N⁶,O^2′-dibutyryl-adenosine 3′,5′-monophosphate, both of which have been reported to promote cell division and growth of plant tissues, the cytokinin activity is related to the 8-bromo substituent and to the N⁶-butyryl substituent, respectively, rather than to the 3′,5′-cyclic monophosphate moiety.     

Chemical-Enzymatic Synthesis of 3′-Amino-2′, 3′-dideoxy-β-D-ribofuranosides of Natural Heterocyclic Bases and Their 5′-Monophosphates

Abstract

Treatment of O², 3′-anhydro-5′-O-trityl derivatives of thymidine (1) and 2′-deoxyuridine (2) with lithium azide in dimethylformamide at 150 °C resulted in the formation of the corresponding isomeric 3′-azido-2′, 3′-dideoxy-5′-O-trityl-β-D-ribofuranosyl N¹- (the major products) and N³-nucleosides (3/4 and 5/6). 3′-Amino-2′, 3′-dideoxy-β-D-ribofuranosides of thymidine [Thd(3′NH₂)], uridine [dUrd(3′NH₂)], and cytidine [dCyd(3′NH₂)] were synthesized from the corresponding 3′-azido derivatives. The Thd(3′NH₂) and dUrd(3′NH₂) were used as donors of carbohydrate moiety in the reaction of enzymatic transglycosylation of adenine and guanine to afford dAdo(3′NH₂) and dGuo(3′NH₂). The substrate activity of dN(3′NH₂) vs. nucleoside phosphotransferase of the whole cells of Erwinia herbicola was studied.     

A Simple,Preparative Procedure for N 3-Anisoyluridine and O 6-Diphenylcarbamoylguanosine 2′-O-(Tetrahydropyran-2-YL) Derivatives via The Corresponding 3′,5′-Dibenzoates

Abstract

3′,5′-Di-O-benzoyl-2′-O-(tetrahydropyran-2-yl)uridine and 3′,5′ -di-O-benzoyl-N ²-isobutyryl-2′-O-(tetrahydropyran-2-yl)guanosine are converted into-N ³-anisoyl-2′-O-(tetrahydropyran-2-yl)uridine (less and more polar diastereoisomers in 37% and 42% yields, respectively) and O ⁶-diphenyl carbamoylN ²-isobutyryl-2′-O-(tetrahydropyran-2-yl)- guanosine (less and more polar diastereoisomers in 15% and 59% yields, respectively), respectively, by N ³-anisoylation and O ⁶-diphenylcarbamoylation, followed by 3′,5′-di-O-debenzoylation.     

Acetylation of Nucleosides by Acetylsalicylic Acid (Aspirin)1

Abstract

Acetylsalicylic acid (aspirin) reacted with adenosine, cytidine, guanosine and their 2′-deoxynucleosides to give acetylated nucleosides. Cytidine and 2′-deoxycytidine gave N⁴-acetylated nucleosides in nitromethane while in pyridine fully acetylated products were obtained. Adenosine and 2′-deoxyadenosine also gave fully acetylated products. However, guanosine and 2′-deoxyguanosine gave 2′,3′,5′-tri-O-acetylribosyl and 3′,5′-di-O-acetyl-2′-deoxyribosyl nucleosides, respectively. The corresponding aglycons also gave acetylated heterocycles under various conditions.