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

• Published in: Molecules (Basel, Switzerland) Vol. 24; no. 8; p. 1453
• Main Authors: Junaid, Ahmad, Lim, Felicia Phei Lin, Zhou, Yvonne Peijun, Chui, Wai Keung, Dolzhenko, Anton V
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 12.04.2019; MDPI
• Subjects: Amines; Aminotriazole; azapurine; Cancer; Chemical compounds; Drug development; Isoguanine; Isothiocyanate; Pharmacology; Phosphorylase; purine isostere; Purines; Triazine; triazole; azapurine; purine isostere; triazine; triazole
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules24081453

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- ][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- ][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.