1-Deazaadenosine

1-Deazaadenosine: synthesis and activity of base-modified hammerhead ribozymes.[Pubmed:9461461]

Nucleic Acids Res. 1998 Feb 15;26(4):1010-8.

The incorporation of 1-Deazaadenosine (c1A, 1b) into a hammerhead ribozyme and the resulting catalytic activity is described. For this purpose the phosphoramidite 2a and the 3'-phosphonate 2b as well as Fractosil-linked 1-Deazaadenosine (3b) were prepared. The methoxyacetyl group was used for the 6-amino group protection and the triisopropylsilyl residue was introduced as the 2'-OH protecting group. Replacement of residues A14and A15.1 of the hammerhead ribozyme by 1-Deazaadenosine resulted in a significantly reduced catalytic activity. Substitution of the A6, A9 and A13 residues has only a minor influence. The findings observed on ribozymes modified with 1-Deazaadenosine were compared with those containing other adenosine analogues.

N-cycloalkyl derivatives of adenosine and 1-deazaadenosine as agonists and partial agonists of the A(1) adenosine receptor.[Pubmed:10649980]

J Med Chem. 2000 Jan 27;43(2):250-60.

A number of cycloalkyl substituents (from C-3 to C-8) have been introduced on the 6-amino group of adenosine, 1-Deazaadenosine, and 2'-deoxyadenosine, bearing or not a chlorine atom at the 2-position, to evaluate the influence on the A(1) and A(2A) affinity of steric hindrance and lipophilicity. Furthermore, the guanosine 5'-triphosphate (GTP) shift and the maximal induction of guanosine 5'-(gamma-thio)triphosphate ([(35)S]GTPgammaS) binding to G proteins in rat brain membranes were used to determine the intrinsic activity of these nucleosides at the A(1) adenosine receptor. All compounds of the ribose-bearing series proved to be full agonists, the 1-deaza derivatives showing affinities for the A(1) receptor about 10-fold lower than the corresponding adenosines. On the other hand, all the 2'-deoxyribose derivatives bind to the A(1) receptor with affinities in the high nanomolar range, with the 2-chloro substituted compounds showing slightly higher affinities than the 2-unsubstituted counterparts. In terms of the potencies, the most potent compounds proved to be those bearing four- and five-membered rings. Both GTP shifts and [(35)S]-GTPgammaS experiments showed that most of the 2'-deoxyadenosine derivatives are partial agonists. The 2'-deoxyadenosine derivatives which were identified as partial agonists consistently detected fewer A(1) receptors in the high-affinity state than full agonists. However, it is worthwhile noting that there was not a simple linear relationship between receptor occupancy and activation. These results indicate that a critical density of A(1) adenosine receptors in the high-affinity state is required for G protein activation.

2-Nitro analogues of adenosine and 1-deazaadenosine: synthesis and binding studies at the adenosine A1, A2A and A3 receptor subtypes.[Pubmed:10999489]

Bioorg Med Chem Lett. 2000 Sep 18;10(18):2141-4.

The influence of nitro substituents on the properties of adenosine and 1-Deazaadenosine was studied. Combination of a nitro group at the 2-position with several N6 substituents such as cyclopentyl and m-iodobenzyl gave a series of analogues with good adenosine receptor affinity, showing directable selectivity for the A1, A2A and A3 adenosine receptor subtypes.

Binding thermodynamics of the transition state analogue coformycin and of the ground state analogue 1-deazaadenosine to bovine adenosine deaminase.[Pubmed:11697042]

J Enzyme Inhib. 2001;16(3):217-32.

Binding of the transition state analogue coformycin and the ground state analogue 1-deaazadenosine to bovine adenosine deaminase have been thermodynamically characterized. The heat capacity changes for coformycin and 1-Deazaadenosine binding are -4.7 +/- 0.8 kJ/mole-K and -1.2 +/- 0.1 kJ/mole-K, respectively. Since the predominant source of heat capacity change in enzyme interactions are changes in the extent of exposure of nonpolar amino acid side chains to the aqueous environment and the hydrophobic effect is the predominant factor in native structure stabilization, we propose that the binding of either class of ligand is associated with a stabilizing enzyme conformational change with coformycin producing the far greater effect. Analysis of the T dependence of the second order rate constant for formation of the enzyme/coformycin complex further reveals that the conformational change is not rate limiting. We propose that the enzyme may facilitate catalysis via the formation of a stabilizing conformation at the reaction transition state.

Improved synthesis and antitumor activity of 1-deazaadenosine.[Pubmed:3625714]

J Med Chem. 1987 Sep;30(9):1686-8.

A more convenient synthetic route to 1-Deazaadenosine (1) by reduction of the new nucleoside 7-nitro-3-beta-D-ribofuranosyl-3H-imidazo[4,5-b]pyridine (6) is reported. Compound 6 was obtained by reaction of 7-nitroimidazo-[4,5-b]pyridine with 1,2,3,5-tetra-O-acetyl-beta-D-ribofuranose in the presence of stannic chloride followed by treatment with methanolic ammonia. 1-Deazaadenosine (1) showed good activity in vitro as inhibitor of HeLa, KB, P388, and L1210 leukemia cell line growth, with ID50 values ranging from 0.34 microM (KB) to 1.8 microM (P388). The nitro derivative 6 demonstrated moderate activity against the same cell lines.

1-Deazaadenosine is a potent Adenosine deaminase (ADA) inhibitor with a Ki value of 0.66 μM. 1-Deazaadenosine exhibits anti-cancer activities in vitro and has the potential to be a chemotherapy agent for lymphoproliferative disorders.

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