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 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.     

Improved and Reliable Synthesis of 3′‐Azido‐2′,3′‐dideoxyguanosine Derivatives

An improved synthesis of N²‐protected‐3′‐azido‐2′,3′‐dideoxyguanosine 20 and 23 is described. Deoxygenation of 2′‐O‐alkyl (and/or aryl) sulfonyl‐5′‐dimethoxytritylguanosine coupled with [1,2]‐hydride shift rearrangement gave protected 9‐(2‐deoxy‐threo‐pentofuranosyl)guanines ( 10 , 12 and 16 ). This rearrangement was accomplished in high yield with a high degree of stereoselectivity using lithium triisobutylborohydride (l‐Selectride®). Compounds 10 , 12 and 16 were transformed into 3′‐O‐mesylates ( 18 and 21 ), which can be used for 3′‐substitution. The 3′‐azido nucleosides were obtained by treatment of 18 and 21 with lithium azide. This procedure is reproducible with a good overall yield.     

Synthetic Studies on the Isomeric N -Methyl Derivatives of C-Ribavirin

Abstract

The syntheses of all three of the mono-N-methy1 derivatives of C-ribavirin (3-β-D-ribofuranosyl-1, 2, 4-triazole-5-carboxamide, 2) have been accomplished. Reaction of 1-(β-D-ribofuranosyliminomethyl)-2-methyl-hydrazine ( 7 ) with ethyl oxamate (8) in boiling ethanol gave the N′-methyl-C-ribavirin ( 3 ). A similar treatment of β-D-ribofuranosyl-1-carboximidic acid methyl ester ( 6 ) with N′-methyloxamic hydrazide ( 10 ) furnished the N²-methyl-C-ribavirin ( 4 ). Direct methylation of unprotected 2 with methyl iodide in the presence of potassium carbonate in dimethyl sulfoxide gave N ⁴-methyl isomer ( 5 ) as the major product. Structural assignments of 3 , 4 , and 5 were based on the unequivocal synthetic sequences, ¹H and ¹³C NMR data and confirmed by single crystal X-ray diffraction analysis.     

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.     

Synthesis and Antitumour Properties of 2-Thio-5-chloro-nucleosides

Abstract

Four methods are described for the synthesis of 2-thio-5-chlorouracil (1). β- and α-5-Chloro-2-thio-2′-deoxyuridines (12 and 13) were obtained by Lewis acid catalysed condensation of TMS derivative of 1 with 2-deoxy-3,5-di-O-p-toluyl-α-D-ribosyl chloride and deblocking of toluylated derivatives with methanolic ammonia. Selective enzymatic phosphorylation of 12 led to its 5′-monophosphate, the latter being a moderate inhibitor of thymidylate synthase, while 12 showed moderate cytotoxicity in vitro against mouse leukemic cells L15178Y.     

The Discovery of Intramolecular Stereoelectronic Forces That Drive The Sugar Conformation in Nucleosides and Nucleotides

Abstract

This report summarizes our results⁸ on how the determination of the thermodynamics of the two-state North (N, C2′-exo-C3′-endo) ? South (S,C2′-endo-C3′-exo) pseudorotational equilibrium in aqueous solution (pD 0.6 - 12.0) basing on vicinal ³J_HH extracted from ¹H-NMR spectra measured at 500 MHz from 278K to 358K yields an experimental energy inventory of the unique stereoelectronic forces that dictate the conformation of the sugar moiety in β-D-ribonucleosides (rNs), β-D-nucleotides, in the mirror-image β-D- versus β-L-2′-deoxynucleosides (dNs) as well as in α-D- or L- versus β-D- or L-2′-dNs. Our work shows for the first time that the free-energies of the inherent internal flexibilities of β-D- versus β-L-2′-dNs and α-D- versus α-L-2′-dNs are identical, whereas the aglycone promoted tunability of the constituent sugar conformation is grossly affected in the α-nucleosides compared to the β-counterparts.     

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.     

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.     

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.     

Photochemical Synthesis of Phosphonopyrimidine and Phosphonopurine Ribonucleosides

Abstract

Photochemical reaction of 2′,3′-di-O- or 2′,3′, 5′-tri-O-protected 5-bromouridine (1), 8-bromoadenosine (4) and 8-bromoguanosine (10) with triethyl phosphite in a mixture of dimethyl formamide (DMF) and acetonitrile, followed by deprotection, provided the corresponding diethyl phosphonate derivatives (3, 7 and 12).     

Conformation of Diastereomers of Adenosine Cyclic 3′, 5′-Phosphorothioate

Abstract

¹H and ³¹P NMR spectra of cAMP (1) and both diastereomers of cAMPS (2 and 3) were compared with these of structurally related bicyclic phosphate 4 and phosphorothioates 5 and 6. Conformational analysis was also performed by NMR techniques for bicyclic phosphoranilidates 7 and 8 and (Rp)-cdAMP anilidate (9). Chair conformation is predominant for all investigated compounds 1–8, while the phosphoranilidate 9 exists in solution in chair-twist equilibrium. Thus, antagonistic properties of (Rp)-cAMPS with respect to cAMP are inferred by the change in the overall molecular shape caused by the presence of the bulky sulfur atom in the equatorial position of the cAMPS molecule.     

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.     

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.     

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.     

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).     

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.     

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).     

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).     

Synthesis and Biological Evaluation of some Acyclic Nucleoside Cyclic Phosphoramidate Derivatives

Abstract

The acyclic nucleosides 2 were treated with 2-chloro-3-methyl-1-oxa-3-aza-2-phosphacyclopentane (3) in the presence of diisopropylethylamine to give the corresponding phosphoramidite derivatives (4). The phosphoramidite intermediates (4) were oxidized with m-chloroperbenzoic acid to the phosphoramidate derivatives (5). Treatment of 5a,b with ZnBr₂ in CH₃NO₂ gave the corresponding acyclic nucleoside cyclic phosphoramidates (6a,b). Attempts to desilylation of 5c by tetrabutylammonium fluoride (TBAF) resulted in opening of the phosphoramidate ring. The newly synthesized compounds were evaluated for antiviral and antitumor cell activity.