15981-63-2

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When 9-substituted adenines are treated with n-pentyl nitrite in hydrogen atom donating solvents and the resulting reaction mixtures are warmed and photolyzed with visible light, the corresponding 9-substituted purines are isolated.The conversion apparently involves homolysis of the intermediate 6-diazonium salts or azo compounds to produce purinyl radical intermediates.These purinyl radicals can subsequently abstract hydrogen atoms from solvent molecules.We have utilized our deamination procedure for the direct synthesis of the antitumor antibiotic nebularine from adenosine.When the deaminations of 9-substituted adenines are conducted in dry CCl4, CHBr3, or CH2I2, the corresponding 6-chloro-, 6-bromo-, and 6-iodopurines are isolated in good yields.There appears to be no detectable hydrogen abstraction in competition with halogen abstraction in the cases of CHBr3 and CH2I2 solvents.These transformations provide shortened preparative pathways to intermediates useful in the synthesis of other base-modified purines.Under appropriate reaction conditions, conversions to the 6-6' dimers also may be possible.The type of transformation in this report represents one of the first examples of the use of neutral purinyl radicals in nucleic acid chemistry.

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Photolysis of anaerobic solutions of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (2',3',5'-tri-O-acetylnebularine) (1b) in methanol at 2537 Angstroem gave a diastereomeric mixture of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1,6-dihydro-6(R,S)-(hydroxymethyl)purines (2b) plus secondary photoproducts.The presence of oxygen resulted in more rapid formation of the 6-(hydroxymethyl)- (3b), 1,6-dihydro-6,6-bis(hydroxymethyl)- (4b), 6-methyl- (5b), and (R,S)-1,6-dihydro-6-(hydroxymethyl)-6-methyl-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (6b) byproducts.Reevaluation of recently published claims that photoaddition of methanol to nebularine proceeded with high stereoselectivity is presented based on definitive 1H and 13C NMR spectral data and FAB mass spectrometry.

A simple dehydrazination reaction has been achieved in the presence of a catalytic amount of CuSO4 for the first time. With CuSO4 (2 mol%) as a catalyst and water as a solvent, the dehydrazination products were obtained in good yields (66-95%). Moreover, the drugs nebularine and vidarabine were afforded successfully, and vidarabine could be produced on a 0.923 kg scale, which shows good potential for industrial applications.

A mild, chemoselective, and generally high-yielding method for the reductive scission of heterocyclic thioethers is described. Suitable heterocycles have a thioether substituent at the 2-position relative to a ring heteroatom. The convenient and straightforward method is demonstrated with reactants which are not compatible with the standard Raney nickel conditions such as sulfides, sulfones, and thiophenes. In addition, benzyl esters, benzyl amides, and benzyl carbamates are tolerated by the reductive reaction conditions.

A novel approach to the synthesis of purine nucleoside analogues, featuring the reaction of the C6-N1-O- aldonitrone moiety of 9-ribosyl-purine (nebularine) N1-oxide with some representative dipolarophiles, as well as Grignard reagents, is repo

L-Dopa, the standard therapeutic for Parkinson's disease, is inactivated by the enzyme catechol-O-methyltransferase (COMT). COMT catalyzes the transfer of an activated methyl group from S-adenosylmethionine (SAM) to its catechol substrates, such as L-dopa, in the presence of magnesium ions. The molecular recognition properties of the SAM-binding site of COMT have been investigated only sparsely. Here, we explore this site by structural alterations of the adenine moiety of bisubstrate inhibitors. The molecular recognition of adenine is of special interest due to the great abundance and importance of this nucleobase in biological systems. Novel bisubstrate inhibitors with adenine replacements were developed by structure-based design and synthesized using a nucleosidation protocol introduced by Vorbrueggen and co-workers. Key interactions of the adenine moiety with COMT were measured with a radiochemical assay. Several bisubstrate inhibitors, most notably the adenine replacements thiopyridine, purine, N-methyladenine, and 6-methylpurine, displayed nanomolar IC50 values (median inhibitory concentration) for COMT down to 6 nM. A series of six cocrystal structures of the bisubstrate inhibitors in ternary complexes with COMT and Mg2+ confirm our predicted binding mode of the adenine replacements. The cocrystal structure of an inhibitor bearing no nucleobase can be regarded as an intermediate along the reaction coordinate of bisubstrate inhibitor binding to COMT. Our studies show that solvation varies with the type of adenine replacement, whereas among the adenine derivatives, the nitrogen atom at position 1 is essential for high affinity, while the exocyclic amino group is most efficiently substituted by a methyl group. Copyright

During the last decades the nucleoside synthesis has proven to be important. The modified silyl-Hilbert-Johnson nucleoside synthesis modified by Vorbrueggen is one of the most often used methods. We have studied N-glycosilation of modifieded heterocyclic bases by Vorbrueggen method with microwave irradiation and we were able to shorten the reaction time and obtain higher yields. The method was demonstrated by fluoroquinolone and purine. Copyright Taylor & Francis Group, LLC.

A series of 46 natural nucleosides and analogues (mainly adenosine-based) were tested as inhibitors of [U-14C]uridine uptake by the concentrative, H+-linked nucleoside transport proteins NupC and NupG from Escherichia coli. The two evolutionarily unrelated transporters showed similar but distinct patterns of inhibition, revealing differing selectivities for the different nucleosides and their analogues. Binding of nucleosides to NupG required the presence of hydroxyl groups at each of the C-3′ and C-5′ positions of ribose, while binding to NupC required only the C-3′ hydroxyl substituent. The greater importance of the ribose moiety for binding to NupG is consistent with the evolutionary relationship between this protein and the oligosaccharide: H+ symporter (OHS) subfamily of the major facilitator superfamily (MFS) of transporters. For both proteins the natural α-configuration at C-3′ and the natural β-configuration at C-1′ was mandatory for ligand binding. N-7 in the imidazole ring of adenosine and the amino group at C-6 were found not to be important for binding and both transporters showed flexibility for substitution at C-6/N6; one or both of N-l and N-3 were important for adenosine analogue binding to NupC but significantly less so for binding to NupG. From the different effects of 8-bromoadenosine on the two transporters it appears that adenosine selectively binds to NupC in an anti- rather than a syn-conformation, whereas NupG is less prescriptive. The pattern of inhibition of NupC by differing nucleoside analogues confirmed the functional relationship of the bacterial transporter to members of the human concentrative nucleoside transporter (CNT) family and reaffirmed the use of the bacterial protein as an experimental model for these physiologically and clinically important mammalian proteins. The specificity data for NupG have been used to develop a homology model of the protein's binding site, based on the X-ray crystallographic structure of the disaccharide transporter LacY from E. coli. We have also developed an efficient general protocol for the synthesis of adenosine and three of its analogues, which is illustrated by the synthesis of [1′-13C]adenosine.

Nonaqueous diazotization-dediazoniation of two types of aminopurine nucleoside derivatives has been investigated. Treatment of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-amino-6-chloropurine (1) with SbCl3/CH2Cl2 was examined with benzyltriethylammonium (BTEA) chloride as a soluble halide source and tert-butyl nitrite (TBN) or sodium nitrite as the diazotization reagent. Optimized yields (>80%) of the 2,6-dichloropurine derivative were obtained with SbCl3. Combinations with SbBr3/CH2Br2 gave the 2-bromo-6-chloropurine product (>60%), and SbI3/CH2I2/THF gave the 2-iodo-6-chloropurine derivative (>45%). Antimony trihalide catalysis was highly beneficial. Mixed combinations (SbX3/CH2X′2; X/X′ = Bt/Cl) gave mixtures of 2-(bromo, chloro, and hydro)-6- chloropurine derivatives that were dependent on reaction conditions. Addition of iodoacetic acid (IAA) resulted in diversion of purine radical species into a 2-iodo-6-chloropurine derivative with commensurate loss of other radical-derived products. This allowed evaluation of the efficiency of SbX3-promoted cation-derived dediazoniations relative to radical-derived reactions. Efficient conversions of adenosine, 2′-deoxyadenosine, and related adenine nucleosides into 6-halopurine derivatives of current interest were developed with analogous combinations.

Surprisingly facile direct substitution reactions with acetyl-protected 6-bromopurine nucleosides are described. Included in the series of bromonucleosides studied is the guanosine derivative N2-2′,3′,5′-tetraacetyl-6-bromopurine ribonucleoside, the synthesis of which is reported here for the first time. Brominated nucleosides had not previously been considered optimal substrates for SNAr reactions given the general reactivity trend for halogenated aromatic systems (i.e. F > Cl > Br > I). However, even weakly nucleophilic aromatic amines give high yields of the substitution products in polar solvents with these 6-bromopurine nucleosides. For primary aromatic amines, secondary aliphatic amines, and imidazole, reaction takes place only at C6, with no effect on the acetyl-protected ribose. In addition, we report the first synthesis of 3′,5′-di-O-acetyl-6-bromopurine-2′-deoxyribonucleoside and its reaction with an arylamine in MeOH in the absence of added metal catalyst. Thus, C6-arylamine derivatives of both adenosine and 2′-deoxyadenosine can be prepared via simple SNAr reactions with the corresponding 6-bromo precursor. We also describe high yielding and C6-selective substitution reactions with 6-bromonucleosides using alcohol and thiol nucleophiles in the presence of added base (DBU). Finally, C6-bromonucleosides are shown to be readily hydrogenated to give purine or 2-aminopurine products in good yield. This work increases the arsenal of reactions and strategies available for the synthesis of nucleoside analogues as potential biochemical tools or new therapeutics.

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A stereoselective photoaddition of methanol to nebularine and 2',3',5'-tri-O-acetylnebularine was investigated.The absolute stereochemistry of the nebularine-methanol photoadduct (2a), a potential transition-state analog of adenosine deaminase, was determined to be 6(S) by X-ray analysis.The addition site of methanol on the purine ring was also chemically demonstrated to be at C(6).Keywords - photoaddition; nebularine; triacetylnebularine; transition-state analog; X-ray analysis; adenosine deaminase; enzyme inhibitor; coformycin; isocoformycin

9-β-D-Ribofuranosylpurine (nebularine) (9) has been synthesized by two methods. (i) 2,6-Dichloro-2',3',5'-tri-O-benzoyl-9-β-D-ribofuranosylpurine (7) on dehalogenation followed by debenzoylation using methanolic ammonia affords nebularine (9). (ii) 6-Chloro-2',3',5'-tri-O-acetyl-9-β-D-ribofuranosylpurine (18) on dehalogenation followed by deacetylation yields 9.Nebularine analogues , 9-β-D-xylofuranosylpurine (12) and 9-α-L-rhamnopyranosylpurine (15) have also been synthesized from 2,6-dichloro-2',3',5'-tri-O-acetyl-9-β-D-xylofuranosylpurine (10) and 2,6-dichloro-2',3',4'-tri-O-benzoyl-9-α-L-rhamnopyranosylpurine (13).Dehalogenation of 10 and 13 followed by deacetylation and debenzoylation with methanolic ammonia affords 12 and 15 respectively.

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