In Honor of the President of the Congress: A. N. Leont'Yev-Lenin Prize Laureate

The editorial staff of the journal Voprosy psikhologii and the Soviet psychological community heartily congratulate Aleksey Nikolayevich Leont'yev on receiving the highest scientific award — the Lenin Prize — for his book Problemy razvitiya psikhiki [Problems of mental development].     

Targets for the Antiviral and Antitumor Activities of Nucleoside,Nucleotide and Oligonucleotide Analogues

Abstract

The following targets can be considered in the development of antiviral agents: (i) DNA polymerase via dThd kinase, (ii) S-adenosylhomocysteine hydrolase; and in the development of antitumor agents: (iii) dTMP synthetase and (iv) protein synthesis via the 2–5A pathway.     

Studies on the Dehydration of New 2- (Pentitol-1-YL) Pyridines Having D-Gulo,D-IDO,and L-Manno Configurations

Abstract

Fusion of 2-trimethylsilylpyridine and tetra-O-acetyl-aldehydo-D-xylose or 2,3:4,5-di-O-isopropylidene-aldehydo-L-arabinose led, after removing of the protecting groups, to 2-(pentitol-1-yl)pyridines of D-gulo and D-ido or L-manno configurations. Dehydration of the sugar-chain with D-gulo and D-ido configurations gave the corresponding 2′,5′-anhydro derivatives, whereas 2-(5-O-isopropyl-L-manno-pentitol-1-yl)-pyridine was the only compound formed by dehydration of the sugar-chain with L-manno configuration. Structural proofs are based on ¹H and ¹³C NMR spectra.     

Synthesis of Certain 5′-Substituted Derivatives of Ribavirin and Tiazofurin

Abstract

The synthesis of several 5′-substituted derivatives of ribavirin (1) and tiazofurin (3) are described. Direct acylation of 1 with the appropriate acyl chloride in pyridine-DMF gave the corresponding 5′-O-acyl derivatives (4a-h). Tosylation of the 2′, 3′-O-isopropylidene-ribavirin (6) and tiazofurin (11) with p-toluenesulfonyl chloride gave the respective 5′-O-p-tolylsulfonyl derivatives (7a and 12a), which were converted to 5′-azido-5′-deoxy derivatives (7b and 12b) by reacting with sodium/lithium azide. Deisopropylidenation of 7b and 12b, followed by catalytic hydrogenation afforded 1-(5-amino-5-deoxy-β-D)-ribofuranosyl)-1, 2, 4-triazole-3-carboxamide (10b) and 2 - (5 -amino- 5-deoxy- β-D-ribofuranosyl) thiazole-4-carboxamide (16), respectively. Treatment of 6 with phthalimide in the presence of triphenylphosphine and diethyl azodicarboxylate furnished the corresponding 5′-deoxy-5′-phthaloylamino derivative (9). Reaction of 9 with n-butylamine and subsequent deisopropylidenation provided yet another route to 10b. Selective 5′-thioacetylation of 6 and 11 with thiolacetic acid, followed by saponification and deisopropylidenation afforded 5′-deoxy-5′-thio derivatives of 1-β-D-ribofuranosyl-1, 2, 4-triazole-3-carboxamide (8a) and 2-β-D-ribofuranosylthiazole-4-carboxamide (15), respectively.     

Synthetic Nucleosides and Nucleotides. XX1. Synthesis of Various 1-β-D-Xylofuranosyl-5-Alkyluracils and Related Nucleosides

Abstract

Treatment of D-xylose (1) with 0.5% methanolic hydrogen chloride under controlled conditions followed by benzoylation and acetolysis afforded crystalline 1-O-acetyl-2, 3, 5-tri-O-benzoyl-α-D-xylofuranose (4) in good yield. Coupling of 4 with 2, 4-bis-trimethylsilyl derivatives of 5-alkyluracils (methyl, ethyl, propyl and butyl) (5a-5d), 5-fluorouracil (5e) and uracil (5f) in acetonitrile in the presence of stannic chloride gave 1-(2,3,5-tri-O-benzoyl-β-D-xylofuranosyl)-nucleosides (6a-6f). Saponification of 6 with sodium methoxide afforded 1-β-D-xylofuranosyl-5-substituted uracils (7a-7f). Condensation of 4 with free adenine in similar fashion and deblocking gave carcinostatic 9-β-D-xylofuranosyladenine (7g).     

Synthesis and X-Ray Crystal Structure of 3-Amino-1-β-D-Ribofuranosyl-s-Triazolo[5, 1-c]-s-Triazole

Abstract

The first chemical synthesis of 3-amino-1-β-D-ribofuranosyl-s-triazolo[5,1-c]-s-triazole (6) is described. Direct glycosylation of 3-amino-5(7)H-s-triazolo[5,1-c]-s-triazole (2) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (3) in the presence of TMS-triflate gave 3-amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-s-triazolo[5, 1-c]-s-triazole (4) which, on ammonolysis, gave 6. The absolute structure of 6 is determined by X-ray diffraction techniques employing Mo Kα radiation. The structure is solved by direct methods and refined to the R value of 0.044 by using a full-matrix least-squares method. The sugar of 6 has a ³T₂ configuration. The torsion angles about the C5′–C4′ bond are both gauche and the torsion angle about the glycosidic bond is in the anti range. Each azole ring of the aglycon is planar and the dihedral angle between the planes of the rings is 3.6°.     

Synthesis of Pyrazolo[3, 4-d]Pyrimidine Ribonucleoside 3′, 5′-Cyclic Phosphates Related to cAMP,cIMP and cGMP1

Abstract

The synthesis of pyrazolo[3,4-d]pyrimidine ribonucleoside 3′, 5′-cyclic phosphates related to cAMP, cIMP and cGMP has been achieved for the first time. Phosphorylation of 4-amino-6-methylthio-1-β-D-ribo-furanosylpyrazolo[3,4-d]pyrimidine (1) with POCl₃ in trimethyl phosphate gave the corresponding 5′-phosphate (2a). DCC mediated intramolecular cyclization of 2a gave the corresponding 3′, 5′-cyclic phosphate (3a), which on subsequent dethiation provided the cAMP analog 4-amino-1-β-D-ribofuranosylpyrazolo[3, 4-d]pyrimidine 3′, 5′-cyclic phosphate (3b). A similar phosphorylation of 6-methylthio-1-β-D-ribofuranosylpyrazolo[3, 4-d]pyrimidin-4(5H)-one (5), followed by cyclization with DCC gave the 3′, 5′-cyclic phosphate of 5 (9a). Dethiation of 9a with Raney nickel gave the cIMP analog 1-β-D-ribofuranosylpyrazolo[3, 4-d]pyrimidin-4(5H)-one 3′, 5′-cyclic phosphate (9b). Oxidation of 9a with m-chloroperoxy benzoic acid, followed by ammonolysis provided the cGMP analog 6-amino-1-β-D-ribofuranosylpyrazolo [3, 4-d] pyrimidin-4(5H)-one 3′, 5′-cyclic phosphate (7). The structural assignment of these cyclic nucleotides was made by UV and H NMR spectroscopic studies.     

Conformational Analysis of 6-Substituted Uridine Analogues: Crystal Structures of Uridine-6-Thiocarboxamide and 6-Cyanouridine

Abstract

Crystal structure analyses of uridine-6-thiocarboxamide (I) and 6-cyanouridine (II) show that both structures adopt a syn conformation about the glycosyl bond. The conformation of I is similar to that of orotidine (III). The furanose ring conformation of I is C4′-exo, unusual for syn conformers, and is C3′-endo in II. These results have a bearing on the inhibition of orotidylate decarboxylase by the 5′-phosphate of I.     

Synthesis of Brunfelsamidine Ribonucleoside and Certain Related Compounds by the Stereospecific Sodium Salt Glycosylation Procedure

Abstract

A synthesis of 2,4-dideazaribavirin ( 2 ), brunfelsamidine ribonucleoside ( 8c ) and certain related derivatives are described for the first time using the stereospecific sodium salt glycosylation procedure. Glycosylation of the sodium salt of pyrrole-3-carbonitrile ( 4 ) with 1-chloro-2, 3-O-t-isopropylidene-5-O-t-butyldimethylsilyl-α-D-ribofuranose ( 5 ) gave exclusively the corresponding blocked nucleoside ( 6 ) with β-anomeric configuration, which on deprotection provided 1-β-D-ribofuranosylpyrrole-3-carbonitrile ( 7 ). Functional group tranformation of 7 gave 2 , 8c and related 3-substituted pyrrole ribonucleosides. These compounds are devoid of any significant antiviral/antitumor activity invitro.     

Synthesis and Antiviral Activity of 5′-O-Sulfamoyluridine Derivatives

Abstract

A series of 5′-O-[[[[(alkyl)oxy]carbonyl] amino] sulfonyl] uridines have been synthesized by reaction of cyclohexanol, palmityl alcohol, 1,2-di-O-benzoylpropanetriol and 2,3,4,6-tetra-O-benzoyl-L-glucopyranose with chlorosulfonyl isocyanate and 2,3′-O-isopropylidene-uridine. Another series of 5′-O-(N-ethyl and N-isopropylsulfamoyl) uridines have been prepared by reaction of 2′,3′-O-isopropylidene and 2′,3′-di-O-acetyluridine with N-ethylsulfamoyl and N-isopropylsulfamoyl chlorides. All compounds were tested against HSV-2, VV, SV and ASFV viruses. 2′,3′-Di-O-acetyl-5′-O-(N-ethyl and N-isopropylsulfamoyl) uridine showed significant activities against HSV-2. 5′-O-[[[[(2,3,4,6-Tetra-O-benzoyl-β-L-glucopyranosyl)oxy]carbonyl]amino] sulfonyl]-2′,3′-O-isopropylideneuridine was very active against ASFV.     

The tRNA “WOBBLE POSITION” Uridines. III.1 the Synthesis of 5-[S-Methoxycarbonyl (Hydroxy)Methyl] Uridine and its 2-Thio Analogue

Abstract

The diastereoisomers 2a, 2b and their 2-thio analogues 4a and 4b were obtained by three-step transformation of uridine and 2-thiouridine, respectively. The absolute configuration at C-5¹ in 2a and 2b was established by CD, while for 4a and 4b the configurational assignment was based on the chemical correlation. The acids 1 and 3 were obtained by alkaline hydrolysis of 2a and 4a, respectively.     

Synthesis of Some Novel Acyclolumazine N-1 Nucleosides

Abstract

Reactjon of (2-acetoxyethoxy)methyl bromide with the silylated lumazine bases (1-6) in the presence of n-Bu₄NI leads to the formation of the nucleosides 8, 10, 12, 14, 16 and 18 respectively. Deacetylation with methanolic ammonia afforded the free nucleosides 9, 11, 13, 15, 17 and 19, respectively, in good yields. Structural proofs of the newly synthesized compounds are based on elemental analyses, UV and ¹H-NMR spactra. None of the acyclic nucleosides exhibited antiviral activity against HSV-1 in vitro.     

6,7-Dimethyl-3-β-D-Erythrofuranosyl-1-Phenyl- and 1-p-Fluorophenyl-Pyrazolo[3,4-b]QUINOXALINE∗

Abstract

The C-nucleoside analogs 6,7-dimethyl-3-β-D-erythrofuranosyl-1-phenylpyrazolo[3,4-b]quinoxaline 4 and 3-β- D -erythrofuranosyl-1-p-fluorophenylpyrazolo[3,4-b]quinoxaline 8 were prepared by dehydration of the polyhydroxyalkyl chain of 6,7-dimethyl-1-phenyl-3-( D -arabino-tetritol-1-yl)-pyrazolo[3,4-b]quinoxaline 3 and 1-p-fluorophenyl-3-( D -arabino-tetritol-1-yl)-pyrazolo[3,4-b]quinoxaline 7, respectively. The structure and anomeric configuration of the products were determined by n.m.r. spectroscopy. The mass spectra and biological activities in connection with chemical constitution are discussed.     

New Acyclic C-Nucleosides of the Imidazole

Abstract

Acid catalyzed isomerization of 1-aryl-(1,2-dideoxy-D-glycero-β-L-gluco-heptofuranose) [1,2-d]-2-imidazolines (4) yields 1-aryl-4-(D-galacto-pentitol-1-yl)imidazoles (8) which can be also obtained by reductive desulphuration of 1-aryl-2-benzylthio-4-(D-galacto-pentitol-1-yl)imidazoles (6). Compounds (4) were obtained by desulphuration with Raney nickel from 1-aryl-(1,2-dideoxy-D-glycero-β-L-gluco-heptofuranose) [1,2-d]-imidazolidine-2-thiones (1) or 1-aryl-2-benzylthio-(1,2-dideoxy-D-glycero-β-L-gluco-heptofuranose) [1,2-d]-2-imidazolines (2).     

Preparation of New Glycoheptofurano[2,1-d]Imidazolidine-2-Thiones., Isomerizations to Acyclic-Sugar C-Nucleoside Analogues of Imidazole

Abstract

1-Methyl- and 1-aryl-(1,2-dideoxy-D-glyofurano)[2,1-d]-imidazolidine-2-thiones having the configurations β-D-glycero-L-gluco (4), β-D-glycero-D-ido (5—8), α-D glycerol-D-galacto (9—10) and β-D-glycero-D-talo (11, 12) are prepared by reaction of 2-amino-2-deoxy-aldoses with methyl and aryl isothiocyanates. 1-Aryl-(1,2-dideoxy–β-D-glycero-L-gluco-heptofurano)[2,1-d]imidazolidine-2-thiones (1—3) have been converted into 1-aryl-4-(D-galacto-pentitol-1-yl)-4-imidazo-line-2-thiones (24—26) by acid catalysed isomerization.     

Nucleosides,XLVI1 Syntheses and Reactions of 6- and 7-p-Chlorophenyllumazine Nucleosides

Abstract

The syntheses of 6-(4) and 7-p-chlorphenyl-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-lumazine (6), was well as the debenzoylation to the corresponding free nucleosides 5 and 7, were improved. Thiation of 4 and 6 by P₄S₁₀ led in excellent yields to 4-thiolumazine nucleosides (8, 10) which could be deblocked to 9 and 11 and converted on treatment with ammonia into the isopterin-N-1- ribofuranosides 13 and 14. 2,2′-Anhydro-nucleoside formation worked well with 5 and 7 respectively to give 15 and 16, which formed on acid hydrolysis the 6- and 7-substituted 1-β-D-arabinofuranosyl-lumazines 18 and 19. The new nucleosides have been characterized by UV and ¹H-NMR spectra.     

A New Synthesis of 7-Methyl-8-Oxoguanosine

Abstract

A new, facile synthesis of 7-methyl-8-oxoguanosine is reported. 2-Chloro-7-methylpurine-6, 8-dione (5) was silylated with hexamethyldi-silazane and the silylated intermediate, 6, glycosylated with 1-0-acetyl-2, 3, 5-tri-0-benzoyl-D-ribofuranose to yield 2-chloro-7-methyl-9-(2′, 3′,-5′-tri-0-benzoyl-β-D-ribofuranosyl) purin-6, 8-dione (8). Deprotection of 8 with sodium hydroxide in aqueous methanol gave 2-chloro-7-methyl-9-(β-D-ribofuranosyl) purine-6,8-dione (9), which was aminated with liquid ammonia or methanolic ammonia to yield 7-methyl-8-oxoguanosine (3).     

N4-(3-Methyl-2-Butenyl)-2-(Methylthio)Tubercidin and Its α-Anomer - 7-Deazapurine Nucleosides with Potential Anticytokinin Activity

Abstract

Phase-transfer catalysis of pyrrolo[2,3-d]pyrimidine 4a with the halogenose 5 yields the anomers 6a and 7a. Deprotection with boron trichloride gives the chloro nucleosides 6b and 7b, which are converted into the potential anticytokinin 2 and its α-anomer 3.     

Nucleosides. 131. The Synthesis of 5-(2-Chloro-2-Deoxy-β-D-arabino-Furanosyl)Uracil. Reinterpretation of Reaction of ψ-Uridine With α-Acetoxyisobutyryl Chloride. Studies Directed Toward the Synthesis of 2′-Deoxy-2′-Substituted Arabino-Nucleosides. 2

Abstract

Treatment of ψ-uridine (3) with α-acetoxyisobutyryl chloride in acetonitrile gave, after deprotection, a mixture of four products: 5-(2-chloro-2-deoxy-β-D-arabinofuranosyl)uracil (10a), its 3′-chloro xylo isomer (11a), 2′-chloro-2′-deoxy-ψ-uridine (9a) and 4,2′-anhydro-ψ-uridine (8a). Each component was isolated by column chromatography. Compound 9 was converted to the known 1,3-dimethyl derivative 2 by treatment with DMF-dimethylacetal. Treatment of 10 and 11 with NaOMe/MeOH afforded the same 4,2′-anhydro-C-nucleoside 8. The 1,3-dimethyl analogues of 10 and 11, however, were converted to 2′,3′-anhydro-1,3-dimethyl-ψ-uridine (13) upon base treatment. The epoxide 13 was also prepared in good yield by treatment of 10 and 11 with DMF-dimethylacetal.     

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.