Synthesis and biological activity of some new N6-substituted purine nucleosides

Fleysher, M. H.; Bloch, Alexander; Hakala, Maire; Nichol, Charles A.

doi:10.1021/jm00306a021

Cited by 67 publications

(31 citation statements)

References 1 publication

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“…The N*-4-nitrobenzyl derivative of adenosine was prepared by a modification of the method of Fleysher et al (1969). Adenosine (10.7 g, 40 mmol) was added to 140 ml of dimethylformamide and stirred at 80°C under N 2 until a dear solution resulted.…”

Section: Synthesis Of N*-4-nitrobenzyladenosinementioning

confidence: 99%

[125I]Aminobenzyladenosine, a new radioligand with improved specific binding to adenosine receptors in heart.

Linden¹,

Patel²,

Sadek³

1985

Circulation Research

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The density of adenosine receptors in membranes derived from rat hearts in 25 times lower than the density of receptors in rat brain membranes. Consequently, adenosine radioligands which are useful in brain such as l-[3H]phenylisopropyladenosine, [3H]cyclohexyladenosine, [3H]-2-chloroadenosine and l-[125I]hydroxyphenylisopropyladenosine are of limited usefulness in heart, due to a high ratio of nonspecific to specific binding. We have synthesized a new radioligand, [125I]-N6-4-aminobenzyladenosine, which binds to rat heart membranes with one-sixth the nonspecific binding of the other radioligands. [125I]-N6-4-aminobenzyladenosine bound to rat ventricle membranes with a KD equivalent to that of l-[125I]hydroxyphenylisopropyladenosine and a Bmax of 15.2 fmol/mg protein. [125I]-N6-4-aminobenzyladenosine bound with a higher affinity to brain (KD = 1.93 nM) than to heart membranes (KD = 11.6 nM). At the radioligand KD, 60% of the total [125I]-N6-4-aminobenzyladenosine bound to heart membranes was specifically bound. Iodination of aminobenzyladenosine increased its affinity for the adenosine receptor by 22-fold, possibly due to a steric or hydrophobic effect of iodine. The new ligand was found to be a full adenosine agonist based on its ability to inhibit cyclic adenosinemonophosphate accumulation in isolated embryonic chick heart cells and rat adipocytes. [125I]-N6-4-Aminobenzyladenosine bound to a single affinity site and was displaced from cardiac and brain adenosine receptors by other adenosine analogues with a potency order of l-phenylisopropyladenosine greater than 5'-N-ethylcarboxamide adenosine. These characteristics suggest that the radioligand binds to an Ri adenosine receptor.

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Section: Synthesis Of N*-4-nitrobenzyladenosinementioning

confidence: 99%

[125I]Aminobenzyladenosine, a new radioligand with improved specific binding to adenosine receptors in heart.

Linden¹,

Patel²,

Sadek³

1985

Circulation Research

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“…Several substituted adenosines: 1-N -methyladenosine, N 6 -methyladenosine, N 6 -isopentenyladenosine, and some others have been has been shown that the direct alkylation of adenosine with methyl iodide at room temperature both in N,N -dimethylacetamide and N,Ndimethylformamide (DMF) results in the formation of 1-N -methyladenosine with high yield. [21] 1-N -alkylation of adenosine in DMF at r.t. by other alkyl halides proceeded with much lower yields (25-50%) [24,25] and in some cases elevated temperatures were used to force 1-N -alkylation. [24] The addition of potassium or barium carbonate into the reaction mixture [24,26] was proposed as a possible way to increase the rate of alkylation.…”

Section: Introductionmentioning

confidence: 99%

“…[21] 1-N -alkylation of adenosine in DMF at r.t. by other alkyl halides proceeded with much lower yields (25-50%) [24,25] and in some cases elevated temperatures were used to force 1-N -alkylation. [24] The addition of potassium or barium carbonate into the reaction mixture [24,26] was proposed as a possible way to increase the rate of alkylation. In spite of a number of available approaches for the preparation of alkylated adenosines, there is still a room for the development of simple and reliable methods for the synthesis of this group of natural compounds.…”

Section: Introductionmentioning

confidence: 99%

Regioselective 1-N-Alkylation and Rearrangement of Adenosine Derivatives

Oslovsky

Drenichev

Mikhailov

2015

Nucleosides, Nucleotides and Nucleic Acids

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Several methods for the preparation of some N(6)-substituted adenosines based on selective 1-N-alkylation with subsequent Dimroth rearrangement were developed. The proposed methods seem to be effective for the preparation of natural N(6)-isopentenyl- and N(6)-benzyladenosines, which are known to possess pronounced biological activities. Direct 1-N-alkylation of 2',3',5'-tri-O-acetyladenosine and 3',5'-di-O-acetyl-2'-deoxyadenosine with alkyl halides in N,N-dimethylformamide (DMF) in the presence of BaCO3 and KI gave 1-N-substituted derivatives with quantitative yields, whereas 1-N-alkylation of adenosine was accompanied by significant O-alkylation. Moreover, the reaction of trimethylsilyl derivatives of N(6)-acetyl-2',3',5'-tri-O-acetyladenosine and N(6)-acetyl-3',5'-di-O-acetyl-2'-deoxyadenosine with alkyl halides leads to the formation of the stable 1-N-substituted adenosines. Dimroth rearrangement of 1-N-substituted adenosines in aqueous ammonia yields pure N(6)-substituted adenosines.

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“…Physical data of the known compounds had been partly reported in the literatures 4,[23][24][25][26] and melting points of 2a and 3a are not identified with the literatures 4,23 although the NMR spectra have proved their structures.…”

Section: Procedures For the Optimization Of Irradiation Time And Powermentioning

confidence: 99%

Microwave assisted synthesis of 6-Substituted aminopurine analogs in water

Qu¹,

Han²,

Zhang³

et al. 2006

J. Braz. Chem. Soc.

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Aminação de derivados de 6-cloropurina em água, assistida por microondas, resultou na preparação de análogos de aminopurina 6-substituídas, em bons rendimentos. Usando um forno de microondas simples, modificado com aparelhagem para refluxo, a aminação do 6-cloro na estrutura da purina ocorreu em condições brandas. Foram preparados 19 análogos conhecidos e 16 desconhecidos de aminopurinas substituídas, através de substituição aromática nucleofílica com filtração simples ou coluna de cromatografia.Microwave assisted amination of 6-chloropurine derivatives with various amines in water resulted in a "green chemistry" protocol for the preparation of 6-substituted aminopurine analogs in very good yields. Using a simply modified microwave oven with the refluxing apparatus, the amination of the 6-chloro in the purine structure occurred smoothly. 19 known and 16 unknown 6-substituted aminopurine analogs were prepared through nucleophilic aromatic substitution with simple filtration or column chromatography.Keywords: amination, 6-substituted aminopurine analogs, nucleophilic substitution, microwave irradiation, amines IntroductionIn modern antiviral and antitumor therapy, an important role is played by modified nucleosides and their analogs, in which modified purine structures are frequently found.1,2 6-Substituted aminopurine analogs, the aminated products of the 6-functional groups in purine structures, continued focusing attention due to their wide range of biological activities (inhibitors of Clostridium feseri growth, 3 cytokinin activity, 4 CIV-CDK (CIV1) and Candida albicans as antifungal medicines, 5 selective kinase, 6 agonists of the A 1 adenosine receptor, 7 the cysteine protease cathepsin K, 8 and platelet aggregation 9 ). Prominent examples of synthetic 6-substituted aminopurine analogs are N-cyclopentyl adenosine (CPA) and N-cyclohexyl adenosine (CHA) (two agonists for the adenosine A 1 receptors). 10The traditional method for the synthesis of 6-substituted aminopurine analogs is the amination of halo, ). However, the complete conversion usually needs 2-24 h and the use of toxic organic solvents or relatively expensive reagents could not be avoided, which dose not conform to the requirement of modern pharmaceutical industry and environmental friendliness.In any case, the development of efficient protocols for the synthesis of aminopurine analogs is still an important goal. Mild reaction conditions, short reaction times and high selectivity and yields are preferable, which makes us pay attention to microwave irradiation. Microwave assisted organic synthesis and functional group conversions have been an increasingly popular field as indicated by numerous publications in the past few years.17 It often leads to rate enhancement, higher yields, easier work-up and better selectivity as well as shortening reaction times compared with the conventional heating methods. In spite of the body of literature about microwave accelerated organic synthesis, the references on the microwave-assisted synthesis of nucleoside com...

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Synthesis and biological activity of some new N6-substituted purine nucleosides

Cited by 67 publications

References 1 publication

[125I]Aminobenzyladenosine, a new radioligand with improved specific binding to adenosine receptors in heart.

[125I]Aminobenzyladenosine, a new radioligand with improved specific binding to adenosine receptors in heart.

Regioselective 1-N-Alkylation and Rearrangement of Adenosine Derivatives

Microwave assisted synthesis of 6-Substituted aminopurine analogs in water

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