Nucleosides. LIV1 Synthesis and Properties of 3′-Azido- and 2′,3′-Dideoxy-6,7-diphenyllumazine Nucleosides

Abstract

The best approach for the synthesis of1-(3-azido-2,3-dideoxy-β-D-erythro-pento-furanosyl)lumazine (5) and its 6,7-dimethyl- (4) and 6,7-diphenyl derivatives (3) has been found in the interconversion of the corresponding 1-(2-deoxy- β-threo-pentofuranosyl)-lumazines. Monomethoxytritylation at the 5′-position (1 7, 3 4, 4 9) followed by mesylation at the 3′-OH group and subsequent nucleophilic displacement by lithium azide afforded 1 9, 2 9 and 4 7 which were deprotected by acid treatment to give 3–5 in good yields. The syntheses of 1-(2,3-dideoxy-β-D-glycero-pentofuranosyl)-6,7-diphenyllumazine (6) and its 6,7-dimethyl derivative (7) were achieved from 1-(2-deoxy-β-D-erythro-pentofuranosyl)-6,7-diphenyllumazine and the corresponding 6,7-dimethyllumazine (2 6) via their 5′-O-p-toluoyl- (2 0, 3 0), and 3′-deoxy-3′-iodo derivatives (2 4, 3 1) to form, after radical dehalogenation and final deprotection, 6 and 7. The newly synthesized lumazine nucleosides have been characterized by elemental analyses, UV-and NMR spectra.     

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     

Nucleosides. 124. 3-Amino-3-deoxyhexopyranosyl Nucleosides. 7. 1-(3-Deoxy-3-Nitro-β-D-glucopyranosyl) Uracil and Its Galactopyranosyl Isomer1

Abstract

Crystalline 1-(3-deoxy-3-nitro-β-D-glucopyranosyl) uracil (3), originally prepared by nitromethane condensation of “uridine dialdehyde,” was found to contain the galactosyl isomer (4). Each isomer was obtained in pure form by 4′,6′-O-benzylidenation of the mixture of 3 and 4, followed by chromatographic separation and subsequent O-debenzylidenation. The structure of each isomer was established by chemical conversion of the isomer into the corresponding known 3′-acetamido-2′,4′,6′-tri-O-acetyl derivative.     

Nucleosides and Nucleotides. 140. Synthesis and Antileukemic Activity of 5-Carbon-Substituted 1-β-d-Ribofuflranosylimidazole-4-Carboxamides

Abstract

Synthesis of 5-carbon-substituted 1-β-d-ribofuranosylimidazole-4-carboxamides are described. Treatment of 5-iodo derivative 8 with methyl acrylate in the presence of palladium catalyst gave (E)-5-(2-carbomethoxyvinyl)-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)imidazole-4-carboxamide (9), followed by appropriate manipulations to afford various 5-carbon-substituted imidazole derivatives 1–7. The antileukemic activities of these imidazole nucleosides are also described.

     

Nucleosides. LXV. Synthesis of New Pteridine–N8–Nucleosides

A general synthetic approach to various isoxanthopterin‐nucleosides starting from 6‐methyl‐2‐methylthio‐4(3H), 7(8H)‐pterdinedione (1) has been developed. Ribosylation with 1‐O‐acetyl‐2,3,5‐tri‐O‐benzoyl‐β‐d‐ribofuranose via the silyl‐method led to 2 and reaction with 1‐chloro‐2‐deoxy‐3,5‐di‐O‐p‐toluoyl‐α‐d‐ribofuranose using the DBU‐method afforded 28. Protection of the amide function at O⁴ by benzylation to 5 and by a Mitsunobu reaction with 2‐(4‐nitrophenyl)ethanol to 29 gave soluble intermediates which can be oxidized to the corresponding 2‐methylsulfonyl derivatives 8 and 30, respectively. Nucleophilic displacement reactions of the highly reactive 2‐methylsulfonyl functions by various amines proceeded under mild conditions to isoxanthopterin‐N₈‐ribo‐ (11–17) and 2′‐deoxyribomucleosides (31–33). Debenzylation can be achieve by Pd‐catalyzed hydrogenation (9 to 19) and cleavage of the npe‐protecting group (31, 32 to 34, 35) works well with DBU by β‐elimination.     

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.     

Chemical Conversion of Uridine to 3′-Branched Sugar Nucleosides (Nucleosides and Nucleotides. 421.)

Abstract

Deamination of 1-(3-amino-3-deoxy-β-D-glucopyranosyl)-uracil gave a ring contracted nucleoside, 3′-deoxy-3′-formyluridine as a hemiacetal form, and uracil. Similar treatment of the 2′-deoxyderivative, 1-(3-amino-2,3-dideoxy-β-D-glucopyranosyl)uracil, gave the corresponding 2′,3′-dideoxy-3′-formyluridine in high yield. The 3′-epimerization of the 3′-formyluridine derivative was achieved and after reduction of the formyl groups, 2′,3′-dideoxy-3′(R and S)-hydroxymethyluridine were obtained.     

Modified Nucleosides. II.1 Economical Synthesis of 2′,3′-Dideoxycytidine

Abstract

An economical two pot synthesis of 2′,3′-dideoxycytidine (2) from N⁴-acetyl-cytidine (4) has been developed. The key feature of this sequence is the in situ reductive elimination of a mixture of 1-(3-bromo-3-deoxy-2,5-di-O-acetyl-β-D-xylofuranosyl)-N⁴-acetylcytosine (5) and 1-(2-bromo-3-deoxy-3,5-di-O-acetyl-β-D-arabinofuranosyl)-N⁴-acetylcytosine (6) and subsequent hydrogenation of the resultant olefin over palladised charcoal.     

Nucleosides and Nucleotides. 106. Synthesis and Biological Activity of 1-(2-Deoxy-2-hydroxyimino- or Methoxyimino-β-D-erythro-pentofuranosyl)-thymine and -Cytosine§,1

Abstract

Reaction of 1-(3,5-Otetraisopropyldisiloxan-1,3-diyl-β-D-erythro-2-pentofuran-2-ulosyl)uracil (8) with hydroxylamine hydrochloride in pyridine at room temperature for 24 h or at 80°C for 3 h gives the 2′-deoxy-2′-hydroxyiminouridine derivative 9 in good yield. Similarly, oximation of 8 with methoxyamine has been done to obtain 2′-deoxy-2′-methoxyimino derivatives 11 in a high yield. Compound 9 was converted into 1-(2-deoxy-2-hydroxyimino-β-D-erythro-pentofuranosyl)cytosine (3). Cytotoxicity in vitro of these nucleosides against murine leukemia L1210 cells was also examined.     

5′-Hydrogenphosphonates and 5′-Methylphosphonates of Sugar Modified Pyrimidine Nucleosides as Potential Anti-HIV-1 Agents.1

Abstract

A number of nucleoside 5′-hydrogerphosphonates and nucleoside 5′-methylphosphonates were prepared, to study their ability to inhibit replication of HIV-1. Two compounds, the 5′-hydrogenphosphonate of 3′-azido-3′-deoxythymidine (AZT-HP, IVc) and of 3′-deoxy-3′-fluorothymidine (FLT-HP, IVa), exhibit potent anti-HIV-1 activity with selectivity indices similar to or better than those of their parent nucleosides.     

Synthesis of 2′-Deoxy-6,2′-Ethano-Cyclouridine1 (Nucleosides and Nucleotides. Part 57)

Abstract

Synthesis of a carbon-bridged cyclouridine,2′-deoxy-6,2′-ethano-cyclouridine, was accomplished starting from a 2′-ketouridine via the 2′-deoxy-2′-iodoethyl-5-chlorouridine derivative through a radical cyclization.     

8-Aza Analogues of Deaza Purine Nucleosides. Synthesis and Biological Evaluation of 8-Aza-1-deazaadenosine and 2′-Deoxy-8-aza-1-deazaadenosine

Abstract

The syntheses of 7-amino-3-(β-D-ribofuranosyl)-3H-1,2,3-triazolo[4,5-b]pyridine (8-aza-1-deazaadenosine) (2) and 7-amino-3-(2-deoxy-β-D-erythro-pentofuranosyl)-3H-1,2,3-triazolo[4,5-b]pyridine (2′-deoxy-8-aza-1-deazaadenosine) (3) by glycosylation of the anion of 7-chloro-3H-1,2,3-triazolo[4,5-b]pyridine are described. The anomeric configuration as well as the position of glycosylation were determined by ¹H, ¹³ NMR, UV and N.O.E. difference spectroscopy. The cytotoxicity of these nucleosides against several murine and human tumor cell lines is discussed. Compounds 2 and 3 proved to be good inhibitors of adenosine deaminase.     

Synthesis of 4′-C-Ethynyl and 4′-C-Cyano Purine Nucleosides from Natural Nucleosides and Their Anti-HIV Activity

Abstract

Purine 2′-deoxynucleosides bearing an ethynyl or a cyano group at C-4′ of the sugar moiety were synthesized from the corresponding 2′-deoxynucleosides. These compounds exhibited very potent anti-HIV activity, and remained active against drug resistant HIV strains.     

Nucleosides. II. Synthesis and Properties of 3,4-Diaryl-4,5-dihydro-1-(β-D-ribofuranosyl)-1,2,4-triazole-5-thiones

Abstract

3,4-Diaryl-4,5-dihydro-1,2,4-triazole-5-thiones (1a-c) were silylated to give compounds (2a-c) which were condensed with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (3) in the presence of trimethylsilyl trifluoromethane sulfonate to afford the corresponding nucleosides 4a-c. Treatment of 4a-c with sodium methoxide in methanol at room temperature afforded the debenzoylated nucleosides 5a-c. The reaction of 5a with acetone in the presence of p-toluenesulfonic acid gave the 2′, 3′-isopropylidene derivative (6a). Phosphorylation of 6a with phosphoryl chloride and triethylphosphate followed by treatment with barium hydroxide afforded barium 3,4-diphenyl-4,5-dihydro(β-D-ribofuranosyl)-1,2,4-triazole-5-thione-5′- monophosphate, which gave after lyophilization the free acid (7a)     

5′-O-[N-(Amnoacyl)Sulfamoyl]Nucleosides. Synthesis and Antiviral and Cytostatic Activities

Abstract

5′-O-[N-(Aminoacyl)sulfamoyl]-uridines and -thymidines 4a-12a and 4b-12b have been synthesized and tested against Herpes Simplex virus type 2 (HSV-2) and as cytostatics. Condensation of 2′,3′-O-isopropylidene-5′-O-sulfamoyluridine and 3′-O-acetyl-5′-O-sulfamoylthymidine with the N-hydroxysuccinimide esters of Boc-L-Ser(Bzl), (2R, 3S)-3-benzyloxycarbonylamino-2-hydroxy-4-phenylbuta-noic acid [(2R, 3S-N-Z-AHPBA], (2R, 3S) and (2S, 3R)-N-Boc-AHPBA gave 4a,b-7a,b, which after removal of the protecting groups provided 1Oa,b-12a,b. A study of the selective removal of the O-Bzl protecting group from the L-Ser derivatives 4a,b, without hydrogenation of the pyrimidine ring, has been carried out. Only the fully protected uridine derivatives 4a-7a did exhibit high anti-HSV-2 activity, and none of the synthesized compounds showed significant cytostatic activity against HeLa cells cultures.     

Mechanistic and Synthetic Aspects of the C-1′ Radicals in Modified Nucleosides

Abstract

The direct and indirect production of C-1′ radicals has been achieved through the synthesis of modified nucleosides. Product studies and spectroscopic investigations have been used to study the structure and fate of C-1′ radical species under anoxic or aerobic conditions. The results are of fundamental importance in understanding the mechanism of DNA cleavage via C-1′ radicals. The mechanistic schemes of some very recent synthetic applications have also been revisited.     

Synthesis of 1′-C-Cyano Pyrimidine Nucleosides and Characterization as HCV Polymerase Inhibitors

Ribose modified 1′-C-cyano pyrimidine nucleosides were synthesized. A silver triflate mediated Vorbrüggen reaction was used to generate the nucleoside scaffold and follow-up chemistry provided specific ribose modified analogs. Nucleosides and phosphoramidate prodrugs were tested for their anti-HCV activity.     

Nucleosides. 140. Stereoselectivity of the Reaction of 1-(2,3-Anhydro-5-O-Benzoyl-β-D-Lyxofuranosyl)Uracil with Ammonium Azide. Isolation and Characterization of 2-Azido-XYLO-Nucleoside Derivatives.1

Abstract

The composition of the products of reaction of 1-(2,3-anhydro-5-O-benzoyl-β-D-lyxofuranosyl)uracil (1) with NH₄N₃ was studied by a reverse-phase HPLC system which was found to separate the 3-azido-arabino 2 and 2-azido-xylo 3 isomers that were formed. The use of a 10:1 ratio of NH₄N₃ to 1 in refluxing EtOH was found to minimize ring opening at C-2 (7%). The higher stereoselectivity of ring opening produced by using a large excess of NH₄N₃ was suppressed by conducting the reaction in DMF. Preventing the escape of the NH₃ by-product only resulted in debenzoylation. The isolation of pure, crystalline 3 was achieved by reverse-phase preparative HPLC. Separation from the arabino isomer was also effected by debenzoylation and selective acetonide formation with the xylo isomer, which allowed facile isolation of the latter by normal phase chromatography. Hydrolysis of the acetonide 7 provided unprotected 2-azido-xylo nucleoside 6, which was also obtained by NaOMe treatment of 3. The mechanistic basis for the stereo-selectivity of epoxide opening is discussed.     

Nucleosides. LXII. Synthesis of 6-Methyl-8-(2-deoxy-β-D-ribofuranosyl)-isoxanthopterin and Derivatives

Abstract

The syntheses of 6-methyl-8-(2-deoxy-ß-D-ribofuranosyl)isoxanthopterin (21) and its protected 3′-O-phosphoramidite 23 were achieved from 6-methyl-2-methylthio-8-(2-deoxy-3,5-di-O-p-toluoyl-ß-D-ribofuranosyl)-3H,8H-pteridine-4,7-dione (8) in several steps. The new building block for oligonucleotide syntheses is highly fluorescent and can be considered as a substitute for 2′-deoxyguanosine.     

Synthesis and Anticancer Activity of 3-(3-Oxoprop-1-enyl)-Substituted Analogues of Carbocyclic Pyrimidine Nucleosides and 2′,3′-Dideoxy Pyrimidine Nucleosides

Abstract

Various 2′, 3′ -dideoxy and carbocyclic pyrimidine nucleosides, and their corresponding 3-(3-oxoprop-1-enyl) derivatives, have been synthesized and evaluated against murine L1210 and P388 leukemias and Sarcoma 180 and human CCRF-CEM lymphoblastic leukemia. Among the compounds tested, 3-(3-oxoprop-1-enyl)-3′ -fluoro-3′ -deoxythymidine (17), 3-(3-oxoprop-1-enyl)-3′ -azido-3′ -deoxythymidine (15) and 3-(3-oxoprop-1-eny!)-(+)-1-[(lα, 3β, 4α)-3-hydroxy-4-(hydroxymethyl)cyclopentyl]-5-methyl-2,4 (lH,3H)pyrimidinedione (6) were found to be the most active with ED₅₀, values of 0.5,0.2,0.1, and 0.3 μM; 1.2, 0.5,1.0 and 1.0 μM; and 0.8,0.7,1.5, and 3.0μM, respectively. Our preliminary findings indicate that the 3-(3-oxoprop-1-enyl) derivative of carbocyclic thymidine is approximately 7 times more active than the 3-(3-oxoprop-1-enyl) derivative of carbocyclic thymine riboside against L1210 leukemia cells in vitro, with ED₅₀ values of 0.8 μM and 5.5 μM, respectively. These findings suggest that the cytotoxicity of these compounds not only is dependent upon the 3-(3-oxoprop-1-enyl)-substituted group, but also may vary with the sugar moiety.