Fused Heterocyclic Systems with an s-Triazine Ring. 34. Development of a Practical Approach for the Synthesis of 5-Aza-isoguanines.

Junaid Junaid,Dolzhenko Dolzhenko,Chui Chui,Zhou Zhou,Lim Lim

doi:10.3390/molecules24081453

Abstract

Purine isosteres present excellent opportunities in drug design and development. Using isosteres of natural purines as scaffolds for the construction of new therapeutic agents has been a valid strategy of medicinal chemistry. Inspired by the similarity to isoguanine, we attempted to develop a practical method for the preparation of 5-aza-isoguanines. Several synthetic approaches were explored to establish a robust general protocol for the preparation of these compounds. The significant difference in the reactivity of the C-5 and C-7 electrophilic centers of 1,2,4-triazolo[1,5-a][1,3,5]triazines (5-azapurines) towards nucleophiles was demonstrated. The most practical and general method for the preparation of 5-aza-isoguanines involved a regioselective reaction of ethoxycarbonyl isothiocyanate with a 5-aminotriazole. The intramolecular ring closure of the resulted product followed by the S-methylation afforded 7-methylthio-2-phenyl-1,2,4-triazolo[1,5-a][1,3,5]triazin-5-one, which could be effectively aminated with various amines. The resulted 5-aza-isoguanines resemble a known purine nucleoside phosphorylase inhibitor and could be interesting for further investigations as potential anticancer agents.

Highlights

Purine isosteres attract significant attention from medicinal chemists due to their potential for the development of new therapeutic agents
Earlier we developed convenient syntheses of amino-substituted pyrazolo[1,5-a][1,3,5]triazines and 1,2,4-triazolo[1,5-a][1,3,5]triazines exploiting good reactivity of highly electrophilic 1,3,5-triazine ring substituted with the trichloromethyl group [26,27]
With our interest leaning towards the synthesis of 5-aza-isoguanines, which are 5-oxo-analogues of compounds 3, an initial attempt to prepare 1,2,4-triazolo[1,5-a][1,3,5]triazine 5 bearing reactive trichloromethyl group was based on the previously developed reaction using triazolylurea 4 in place of guanidine 1 (Scheme 2)

Summary

Introduction

Purine isosteres attract significant attention from medicinal chemists due to their potential for the development of new therapeutic agents. These compounds are known to modulate a complex network of processes, which involves regulatory biogenic purines. The purine-like scaffolds incorporating a 1,3,5-triazine ring became privileged in the construction of bioactive molecules [1]. We developed efficient methods for the synthesis of adenine and xanthine analogues built on these scaffolds [5,6,7,8,9,10,11,12,13,14,15]. The synthesis of 5-aza-guanines has been reported [16,17]

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Results

Conclusion