Bioisosterism, enantioselectivity, and molecular modeling of new effective N⁶‐ and/or N(9)‐substituted 2‐phenyl adenines and 8‐aza analogs: Different binding modes to A₁ adenosine receptors

Abstract

Bioisosterism of the adenine and 8-azaadenine nuclei was demonstrated by comparison of A 1 adenosine receptor binding affinity of 2-phenyl N 6 -substituted adenines and the corresponding 8-azaadenines. Some of these new compounds are very potent A 1 adenosine receptor antagonists. This work also describes the synthesis and A 1 adenosine receptor binding of the enantiomers of some 2-phenyladenines substituted with a 1-phenylethyl chiral group in N 6 and N(9) positions. Biological results, showing the same stereoselectivity for all the couples of enantiomers, may supply proof for the hypothesis of a possible double arrangement of 2-phenylsubstituted adenines inside A 1 adenosine receptors. Theoretical studies, based on an improved A 1 adenosine receptor model and consisting of evaluation and comparison of interaction energies in complexes involving some selected chiral ligands, support the above hypothesis. Drug Dev. Res. 54:52-65, 2001.

Synthesis of New 2‐Phenyladenines and 2‐Phenylpteridines and Biological Evaluation as Adenosine Receptor Ligands

“…The chloro-purine 9 was obtained by cyclisation of the diamino derivative 2 with triethylorthoformate and acetic anhydride at reflux temperature as reported in the literature [15]. Displacement of the chlorine atom of 9 with suitable amines in absolute ethanol gave derivatives 10 -12; the same reaction with gaseous ammonia in absolute ethanol gave 2-phenyladenine 13 [28], which was converted in the 2-phenyl-N 6 -(substituted)-phenylcarbamoyladenines 14 and 15 by treatment with the corresponding isocyanates and triethylamine in fresh distilled THF at reflux temperature.…”

“…These compounds were more active than the corresponding 8-azaadenine derivatives synthesized and assayed in the past [15,32] (see compounds III-V in Table 2). Among pteridine derivatives, only compound 4 showed good activity towards A 1 receptors (K i = 66 l 5 nM), compounds 5 -7 showed low activity (in the range of micromolar), and compound 8 was completely inactive for all the receptor subtypes.…”

“…In a recent paper, we demonstrated bioisosterism of the 8-azaadenine (nucleus A, Fig. 1) and adenine nucleus [15]; instead, other modifications (nucleus B, C, D, Fig. 1) caused a decrease of affinity of the compounds with respect to the corresponding adenines.…”

“…phenylpyrimidine 1 [26] by a known synthetic pathway [15]. The diamino derivative 2 was cyclised with glyoxal (40 wt.% solution in water) in ethanol and glacial acetic acid: the compound formed was 2-phenyl-4-hydroxy-pteridine 3 [27] owing to displacement of the chlorine atom by a hydroxyl group.…”

A Novel Practical Synthesis of C‐2‐Arylpurines

“…[1] Purines bearing carbon substituents at the ring carbons have attracted much attention due to their potential biological activities. In particular, C-2-arylpurine derivatives are becoming especially important for drug discovery programs such as those towards anxiolytic agents [2] and interferon inducers, [3] potent/selective c-AMP phosphodiesterase inhibitors, [4] angiotensin II antagonists, [5] , b-AST-IV inhibitors, [6] A 1 adenosine receptor antagonists, [7] or ADA (adenosine deaminase) inhibitors. [8] Despite their importance, synthetic efforts have not been sufficiently directed to the identification of synthetic pathways to provide ready access to these compounds.…”