Synthesis of (R - and (S)-1-[[2-Hydroxy-1-(aminomethyl)ethoxy]methyl]-5- benzyluracil,Potent Inhibitors of Uridine Phosphorylase

Abstract

Optically pure (R)- and (S)-1-[[2-hydroxy-1-(aminomethyl) ethoxy]methyl]-5-benzyluracil [(R)-AHPBU and (S)-AHPBU, respectively], two potent uridine phosphorylase inhibitors, have been synthesized via multi-step syntheses starting from independent chiral compounds. The activity of (R)-AHPBU, (S)-AHPBU, and (R,S-AHPBU which have been previously synthesized, on the inhibition of uridine phosphorylase from Sarcoma-180 cells has been studied and compared. The K. values for (R,S)-, (R)- and (S)-AHPBU were determined to be 15·2.3, 17·2.7 and 16·2.0 nM, respectively. This indicates that (R) and (S) optical enantiomers have the same affinity for binding to uridine phosphorylase. These acyclic pyrimidine amino nucleoside analogues represent a new class of potent uridine phosphorylase inhibitors, which has a bulky hydrophobic substituent at the 5-position in the uracil base, yet has remarkably high water solubility.     

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.     

Nucleoside,XLV1) Synthese von 8-β-D-Ribofuranosyl-Leukopterin

Abstract

Model reactions with 2-methylthiopteridin-4,7(3H,8H)-diones (3-5) and 4-benzyloxy-8-methyl-2-thiopteridin-7(8H)-one (11) showed that peracid oxidations lead to the corresponding 2-methylsulfonyl-6-oxo derivatives 8, 9, 10 and 12. The structurally analogous pteridine-N-8-ribosides 19-21 and 26 revealed the same behaviour, which allowed the synthesis of 8-β-D-ribofuranosylleu-copterin (30) from 4-benzyloxy-8-(2,3,5-tri-O-benzoyl-β-D-ribofu-ranosyl)-2-methylthio-pteridi-7(8H)-one (26) via the intermediates 27-29. The newly synthesized compounds have been characterized by elemental analysis and UV spectra.     

The Theory of Set in the Light of Reflex Theory

It is well known to all those acquainted with D. N. Uznadze's theory of set [ustanovka] (1) that this theory was meant to answer the question of "the character and inner structure of human activity" [11; 79]. But, as A. T. Bochorishvili correctly noted, we do not yet have "clarity in basic concepts. … Soviet psychology cannot yet go so far as to speak of the content of the basic concept of the psychology of set, of the content of set itself" [5: 15]. As a panacea for overcoming these differences of opinion, Bochorishvili proposes that we "widely and actively develop investigations of the theoretical bases of the psychology of set as D. N. Uznadze understood if" (ibid.).     

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 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.     

Nucleosides,I Ribosylation of 8-Substituted Theophylline Derivatives

Abstract

The attempted ribosylation reaction of 8-nitro-theophylline (2) with 1-o-acetyl-2, 3, 5-tri-o-benzoyl-D-ribo-furanose (5) failed to give any nucleoside product, whereas the reaction of 8-chlorotheophylline (3) with 5 afforded the 8-chloro-7-(2,3,5-tri-o-benzoyl) β-D-ribofuranosyltheophylline (6) in good yield. The product 6 reacted with benzylamine producing the 8-benzylamino-7-(2, 3, 5-tri-O-benzoyl) β-D-ribo-furanosyltheophylline (10), which could also be synthesised by ribosylation of 8-benzylaminotheophylline (8) with 5. Debenzoylation of 6 and 10 gave the corresponding 7-β-D-ribofuranosyltheophylline nucleosides (7) and (11), respectively. Compound 7 could be converted into 11 by reaction with benzylamine. The newly synthesised compounds have been characterised by elemental analysis, ¹H-NMR and UV spectra.     

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).     

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).     

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.     

Figural After-Effects or the Contrast Illusion

The contrast illusion was studied systematically for a long time by D. N. Uznadze. Experimental findings characteristic of this illusion were published by him first in the Russian (8) and then in the German (18) languages. To produce this illusion, two circles of different size were tachistoscopically presented to the subject 10 or 15 times. After each presentation the subject was required to state which of the circles was the larger: the right or the left. This was the experiment to establish a set [ustanovka] in the course of which the subject developed the readiness, or set, to perceive unequal objects, as is established in critical (control) tests. In the critical test, the subjects, to whom circles of equal size are shown, continue to perceive them as unequal, because they act against a pre-developed set. The effect based on an established set lasts for several displays and, what is of particular interest to us in the given instance, the circle which seems larger is not the one on the side where the larger circle had been presented in the experiments to produce persistent images, but that on the opposite side (where the smaller circle had been seen). This was the manner in which the contrast illusion was discovered, subsequently named the "Uznadze effect" by J. Piaget, who in turn proposed a technique for measuring the strength of this illusion. (17)     

P1-(Thymidine 5′-)P1-amino-triphosphate: Synthesis,Hydrolysis and Reaction with Cytidine in Alkali1

Abstract

The title compound 1 is prepared from thymidine 5′-phos-phorodiamidate (2) and inorganic pyrophosphate (3) in anhydrous DMF, at 30–32°C. The products of alkaline hydrolysis of 1, at room temperature, are: thymidine 5′-phosphoramidate (4), thymidine 3′-phosphoramidate (8) and thymidine (9) as well as 3 and inorganic trimetaphosphate (10). In 1 N NH₄OH, 1 reacts with cytidine (15) to form cytidylyl-/2^T(3′)-5′/-thymidine (16) and a mixture of cytidine 2′,3′-cyclic phosphate (17) and 9.     

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°.     

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.     

Acyclic Nucleosides. Synthesis and Antiherpetic Activity of 9-[[[2-Hydroxy-1-(Hydroxymethyl)Ethyl]Thio]Methyl]Guanine and 1-[[[2-Hydroxy-1-(Hydroxymethyl)Ethyl]Thio]Methyl]Cytosine

Abstract

The synthesis and antiherpetic activity of 9-[[[2-hydroxy-1-(hydroxymethyl)ethyl]thio]methy1]guanine (4) and 1-[[[2-hydroxy-1-(hydroxymethyl)ethyl]thio]methy]cytosine (6), the side-chain thio analogues of ganciclovir (3) and BW A1117U (5), are described. The sidechain synthon 1,3-bis(benzyloxy)-2-[(chloromethyl)thio]propane (11) was prepared in four steps from 1,3-bis(benzyloxy)-2-propanol (7). Alkylation of 2-amino-6-chloro-9H-purine with 11 provided the intermediate 9-substituted-2-amino-6-chloropurine 12, which was conveniently converted to 4 in two steps. Reaction of a fivefold excess of cytosine with 11 provided the desired 1-isomer 14, which was debenzylated to give 6. In contrast with ganciclovir (3) and BW A1117U (5), neither 4 nor 6 had significant in vitro activity against human cytomegalovirus.     

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.     

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.     

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.     

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.     

Metal Carbonate-Mediated Complete Deacylation of Polyacyl Protected Nucleosides

Abstract

Treatment of poly-acetyl or -benzoyl protected ribonucleosides (1a-i) and 2′-deoxyribonucleosides (3a-d) with metal carbonates such as NaHCO₃ or Na₂CO₃ in MeOH gave the corresponding deacylated free ribomucleosides (2a-d and 4a-b) in excellent high yields.